Buccal tablet

Abstract

The buccal tablet sequentially comprises a first supporting layer, a first functional layer, a hydrophobic film layer, a second functional layer and a second supporting layer, the first functional layer comprises a first functional substance and a first film-forming agent, the second functional layer comprises a second functional substance and a second film-forming agent, and the first supporting layer and the second supporting layer are permeable layers.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of oral products, in particular to an oral tablet. BACKGROUND

[0002] An oral product, such as an oral nicotine product, is a product containing a nicotine active ingredient (nicotine or its derivatives), usually in the form of a powder, tablet, sachet, etc., which is placed in the oral cavity, then dissolves and releases the nicotine active ingredient, and is absorbed through the oral mucosa, thereby relieving nicotine withdrawal symptoms during smoking cessation.

[0003] The oral tablet in the related art is usually made of a soluble material and contains a certain amount of functional substances. When used, the oral tablet is placed in the oral cavity and contacts saliva. The oral tablet can dissolve or swell and release the functional substances.

[0004] However, the current oral tablet has a single function and cannot meet the use requirements of users. SUMMARY

[0005] The present application provides an oral tablet for solving the problem that the current oral tablet has a single function and cannot meet the use requirements of users.

[0006] The present application discloses an oral tablet, which sequentially comprises a first support layer, a first functional layer, a hydrophobic film layer, a second functional layer, and a second support layer. The first functional layer comprises a first functional substance and a first film-forming agent. The second functional layer comprises a second functional substance and a second film-forming agent. The first support layer and the second support layer are both water-permeable layers.

[0007] In an implementation manner of the present application, the swelling speed of the first functional layer in water is higher than the swelling speed of the second functional layer in water.

[0008] In an implementation manner of the present application, the oral tablet further comprises a first flavoring layer, which is located between the first functional layer and the first support layer; and / or the oral tablet further comprises a second flavoring layer, which is located between the second functional layer and the second support layer.

[0009] In an implementation manner of the present application, the second functional layer further comprises a release-controlling agent for controlling the release rate of the second functional substance.

[0010] In an implementation manner of the present application, the first functional layer further comprises at least one of a thickening agent, a plasticizing agent, a sweetening agent, an aromatic agent, a cooling agent, a pH adjusting agent, and an antioxidant agent; and / or the second functional layer further comprises at least one of a thickening agent, a plasticizing agent, a sweetening agent, an aromatic agent, a cooling agent, a pH adjusting agent, and an antioxidant agent.

[0011] In an implementation form of the application, the first functional substance comprises at least one of nicotine and a nicotine derivative; and / or, the second functional substance comprises at least one of nicotine and a nicotine derivative; and / or, the first film-forming agent comprises at least one of hydroxypropyl methyl cellulose, soluble starch, gelatin, gelatin-porous starch composite; and / or, the second film-forming agent comprises at least one of ethyl cellulose, polyoxyethylene, hydroxypropyl methyl cellulose, soluble starch, gelatin; and / or, the sustained-release agent comprises at least one of sodium alginate, carrageenan, mesoporous silica; and / or, the thickening agent comprises at least one of polycarboxyl high-molecular polymer, starch ether derivative, hyaluronic acid sodium-chitosan polyelectrolyte complex; and / or, the plasticizer comprises at least one of glycerol, sorbitol, propylene glycol, polyethylene glycol and xylitol; and / or, the antioxidant comprises at least one of propyl paraben, ascorbic acid, vitamin E, butylated hydroxytoluene and butylated hydroxyanisole.

[0012] In an implementation form of the application, the thickness of the first support layer is 0.1 mm to 0.2 mm; and / or, the thickness of the first functional layer is 0.1 mm to 0.22 mm; and / or, the thickness of the hydrophobic film layer is 0.01 mm to 0.02 mm; and / or, the thickness of the second functional layer is 0.15 mm to 0.25 mm; and / or, the thickness of the second support layer is 0.1 mm to 0.2 mm.

[0013] In an implementation form of the application, the first film-forming agent and the second film-forming agent both comprise hydroxypropyl methyl cellulose, and the ratio of the relative mass fraction of hydroxypropyl methyl cellulose in the first film-forming agent to the relative mass fraction of hydroxypropyl methyl cellulose in the second film-forming agent is 2:1 to 4:1.

[0014] In an implementation form of the application, in the first functional layer, by weight fraction, at least one of the following is included: 10 to 35 parts of the first film-forming agent, 0.5 to 5 parts of the first functional substance, 5 to 10 parts of a thickening agent, 1.5 to 5 parts of a plasticizer, 0.25 to 2 parts of a sweetener, 0.25 to 2 parts of an aroma, 0.25 to 5 parts of a cooling agent, 0.05 to 1 part of a pH regulator, 0.1 to 0.5 part of an antioxidant; and / or, in the second functional layer, by weight fraction, at least one of the following is included: 10 to 40 parts of the second film-forming agent, 0.5 to 5 parts of the second functional substance, 1 to 5 parts of a sustained-release agent, 5 to 15 parts of a thickening agent, 1.5 to 5 parts of a plasticizer, 0.25 to 2 parts of a sweetener, 0.25 to 2 parts of an aroma, 0.25 to 5 parts of a cooling agent, 0.05 to 1 part of a pH regulator, 0.1 to 0.5 part of an antioxidant, wherein the second film-forming agent comprises ethyl cellulose.

[0015] In an implementation form of the application, the first support layer comprises at least one of natural fiber non-woven fabric, synthetic fiber non-woven fabric, PVA non-woven fabric, woven cloth, electrospun nanofiber membrane; and / or, the second support layer comprises at least one of at least one of natural fiber non-woven fabric, synthetic fiber non-woven fabric, PVA non-woven fabric, woven cloth, electrospun nanofiber membrane; and / or, the hydrophobic membrane layer comprises at least one of polyethylene, polypropylene, polytetrafluoroethylene, polyvinylidene fluoride and silicone rubber.

[0016] The application has the following beneficial effects:

[0017] The oral tablet of the application comprises a multi-layer structure, wherein the first support layer and the second support layer located on the outer layer can provide support and protection for the first functional layer and the second functional layer inside; the first functional layer and the second functional layer can provide functional substances for the user to use; the hydrophobic membrane layer can reduce the penetration of moisture, effectively reduce the mutual influence of the first functional layer and the second functional layer, and improve the precise release effect of the oral tablet. In summary, the oral tablet of the application has multiple functions and can better meet the user's use requirements. BRIEF DESCRIPTION OF DRAWINGS

[0018] Figure 1 A structural schematic diagram of an oral tablet related to an embodiment of the application is shown.

[0019] Figure 2 A structural schematic diagram of an oral tablet related to another embodiment of the application is shown.

[0020] Figure 3 A structural schematic diagram of an oral tablet related to another embodiment of the application is shown.

[0021] Figure 4 The nicotine release curve of the oral tablet related to different formulations of the embodiments of the application is shown.

[0022] Figure 5 The residual rate test result graph of the oral tablet related to different formulations of the embodiments of the application is shown.

[0023] Figure 6 The nicotine stability test result graph of the oral tablet related to different formulations of the embodiments of the application is shown. DETAILED DESCRIPTION

[0024] 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 application. However, it will be apparent to one skilled in the art that parts of the 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 application. The features described herein, operations or characteristics described in the specification can be combined in any suitable manner in various embodiments. Also, the various steps or acts in a method can be rearranged or reordered in any suitable manner that is apparent to one skilled in the art. Therefore, the various sequences described in the specification and the accompanying drawings are merely exemplary and are not meant to be restrictive, unless otherwise specified herein.

[0025] In addition, the features, operations or characteristics described in the specification can be combined in any suitable manner in various embodiments. Also, the various steps or acts in a method can be rearranged or reordered in any suitable manner that is apparent to one skilled in the art. Therefore, the various sequences described in the specification and the accompanying drawings are merely exemplary and are not meant to be restrictive, unless otherwise specified herein.

[0026] The serial numbers of components in the text, such as "first", "second", etc., are only used to distinguish the described objects, and do not have any order or technical meaning.

[0027] At present, most of the oral tablet products adopt single-layer structure design, and the functions are relatively single. For example, the single-layer oral dissolving film has a relatively fast release rate, and cannot meet the demand for long-acting release. In view of this, the application creatively provides an oral tablet and a preparation method thereof. The oral tablet of the application has a multi-layer structure.

[0028] In a specific embodiment, the oral tablet of the application can solve at least one of the following problems: the existing oral tablet has a single-layer structure and a single function; the existing oral tablet has a single release rate, and it is difficult to meet the dual demands of immediate release and sustained release; the traditional coating process is difficult to accurately construct a multi-layer functional structure, and the interlayer bonding force is poor; the existing oral tablet is easy to adhere to the oral cavity during use, causing discomfort, or there are residual fragments in the oral cavity after use, which are not easy to take out, reducing the user experience.

[0029] In a specific embodiment, the oral tablet of the application can have at least one of the following effects: having a multi-layer structure and multiple functions; by controlling the specific formula of different functional layers, the functional substances can have multiple release rates, and can provide immediate satisfaction and long-term absorption, better meeting the user's needs; the structure of the oral tablet is stable, and the interlayer bonding is stable; the film of the oral tablet is not easy to adhere to the oral cavity during use, and the residual fragments can be easily taken out after use.

[0030] Figure 1 A structural diagram of a lozenge 100 according to an embodiment of the present application is shown, Figure 2 A structural diagram of a lozenge 100 according to another embodiment of the present application is shown, Figure 3 A structural diagram of a lozenge 100 according to yet another embodiment of the present application is shown. It should be noted that, Figures 1 to 3 For the convenience of showing the structures of different layers, each layer is shown separately. In actual cases, each layer is arranged in contact with each other.

[0031] In an embodiment, the lozenge 100 has a multi-layer structure.

[0032] In an embodiment, the lozenge 100 can include a support layer. The support layer can be water-insoluble. The support layer can have a mesh structure or a porous structure. The support layer can have water permeability. The support layer can have through-holes for saliva to pass through the support layer. It should be noted that the support layer can serve the functions of support and protection, and also allow saliva to pass through and enter other film layers. In addition, after use, by removing the support layer, the undissolved film residues of other film layers can be taken out together, reducing the foreign body sensation caused by residues and improving user experience.

[0033] In an embodiment, the support layer can include at least one of natural fiber non-woven fabric, synthetic fiber non-woven fabric, PVA non-woven fabric, woven fabric, and electrospun nanofiber membrane.

[0034] In an embodiment, the number of support layers can be multiple.

[0035] In an embodiment, at least two support layers can be located on two surfaces of the lozenge 100, respectively.

[0036] In an embodiment, the porosity of the support layer can be 30% to 85%.

[0037] As shown in FIG. 1A, Figure 1 In an embodiment, the support layer can include a first support layer 10 and a second support layer 50.

[0038] In an embodiment, the porosities of the first support layer 10 and the second support layer 50 can be the same. Alternatively, the porosity of the first support layer 10 can be greater than the porosity of the second support layer 50. In this way, water can enter the first functional layer 20 (described later) more quickly.

[0039] In an embodiment, the thickness of the first support layer 10 can be 0.1 mm to 0.2 mm. For example, the thickness of the first support layer 10 can be 0.1 mm, 0.13 mm, 0.15 mm, 0.17 mm, or 0.2 mm.

[0040] In one specific embodiment, the thickness of the second support layer 50 can be 0.1 mm to 0.2 mm. For example, the thickness of the second support layer 50 can be 0.1 mm, 0.13 mm, 0.15 mm, 0.17 mm, or 0.2 mm.

[0041] In one embodiment, the oral tablet 100 may include a functional layer. The functional layer may include functional substances.

[0042] In one specific embodiment, the functional substance may include at least one of nicotine and nicotine derivatives, used to provide a sense of satisfaction.

[0043] In one specific embodiment, nicotine may include natural nicotine and synthetic nicotine. Nicotine derivatives may include one or more of the following: nicotine salts, nicotine in a matrix such as a glycobase or an organometallic complex, nicotine-resin combinations, nicotine inclusion complexes, and non-covalently bound nicotine. Non-covalently bound nicotine includes nicotine lactate, nicotine malate, nicotine salicylate, nicotine cyclodextrin-encapsulated complexes, 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 one or more mixtures of hexamethylnicotine, hexamethylnicotine lactate, hexamethylnicotine malate, hexamethylnicotine salicylate, hexamethylnicotine cyclodextrin encapsulated complex, hexamethylnicotine hydrochloride, hexamethylnicotine dihydrochloride, hexamethylnicotine tartrate, hexamethylnicotine tartrate dihydrate, hexamethylnicotine sulfate, hexamethylnicotine zinc chloride, and hexamethylnicotine benzoate.

[0044] In one specific embodiment, the functional substance may also be selected from other substances with medical or other specific uses, such as vitamins, capsaicin, caffeine, etc., to meet the needs of different users.

[0045] In one specific embodiment, the functional substance may also be selected from other alkaloids or amino acids. For example, alkaloids such as tobacco, coffee, and tea.

[0046] In one embodiment, the functional layer may be located in the inner layer of the oral tablet 100. In another embodiment, the support layer may be located in the outer layer, and the functional layer may be located in the inner layer, thereby protecting the functional layer through the support layer.

[0047] In one specific embodiment, the number of functional layers can be multiple.

[0048] like Figure 1 As shown, in one specific embodiment, the functional layer may include a first functional layer 20 and a second functional layer 40.

[0049] In one embodiment, the oral tablet 100 may include a hydrophobic film layer 30. The hydrophobic film layer 30 is hydrophobic and can block, control, or delay the passage of moisture.

[0050] In one specific embodiment, the hydrophobic membrane layer 30 can be a film of thermoplastic resins such as polyethylene, polypropylene, polyvinyl acetate, and polyester. It should be noted that the hydrophobic membrane layer 30 can block and regulate the path of moisture into the controlled-release layer, delaying the hydration diffusion process, thereby effectively slowing down the release rate of the functional substances in the second functional layer 40. By introducing the hydrophobic membrane layer 30, the controlled-release capability of the multilayer membrane can be significantly improved, making the release of functional substances more stable and controllable.

[0051] In one specific embodiment, the thickness of the hydrophobic film layer 30 can be 0.01 mm to 0.02 mm. For example, the thickness of the hydrophobic film layer 30 can be 0.01 mm, 0.015 mm, or 0.02 mm.

[0052] In one specific embodiment, the first support layer 10, the hydrophobic film layer 30, and the second support layer 50 can be fixedly connected to each other. Therefore, after using the oral tablet 100, the first support layer 10, the hydrophobic film layer 30, and the second support layer 50 can be removed together, reducing the increased difficulty of removal caused by delamination or displacement of the first support layer 10, the hydrophobic film layer 30, and the second support layer 50.

[0053] In one specific embodiment, when the oral tablet 100 is used, the first support layer 10 may be the side closer to the oral mucosa or lips, and the second support layer 50 may be the side closer to the gums or tongue.

[0054] In one specific embodiment, when the oral tablet 100 is used, the second support layer 50 may be the side closer to the oral mucosa or lips, and the first support layer 10 may be the side closer to the gums or tongue.

[0055] like Figure 1 As shown, in one specific embodiment, the oral tablet 100 may sequentially include a first support layer 10, a first functional layer 20, a hydrophobic film layer 30, a second functional layer 40, and a second support layer 50. In this case, the first support layer 10 and the second support layer 50 are located on the outermost layer, providing support and protecting the functional layers, respectively; the first functional layer 20 and the second functional layer 40 contain functional substances; and the hydrophobic film layer 30 is used to reduce the entry of moisture into the second functional layer.

[0056] In one specific embodiment, the first functional layer 20 and the second functional layer 40 contain functional substances. During use, the moisture in saliva causes the first functional layer 20 and the second functional layer 40 to dissolve or swell, releasing the functional substances.

[0057] In an embodiment, the first functional layer 20 includes a first functional substance. The first functional substance can include at least one of nicotine and a nicotine derivative.

[0058] In an embodiment, the second functional layer 40 includes a second functional substance. The second functional substance can include at least one of nicotine and a nicotine derivative.

[0059] In an embodiment, the first functional layer 20 has a higher swelling speed than the second functional layer 40. For example, the first functional layer 20 can have a faster swelling speed by preferentially contacting saliva, a film-forming agent material contained therein, etc., so that the functional substance (i.e., the first functional substance) in the first functional layer 20 is released earlier and / or faster than the functional substance (i.e., the second functional substance) in the second functional layer 40.

[0060] In an embodiment, the first functional layer 20 has a higher release rate of the functional substance (i.e., the first functional substance) than the second functional layer 40 has a release rate of the functional substance (i.e., the second functional substance). Thus, the functional substance of the lozenge 100 can have different release rates, and the functional substance released faster can provide an instant satisfaction, and the functional substance released slower can provide a long-acting satisfaction.

[0061] In an embodiment, the first functional layer 20 can have a thickness of 0.1 mm to 0.22 mm. For example, the first functional layer 20 can have a thickness of 0.1 mm, 0.12 mm, 0.15 mm, 0.2 mm, or 0.22 mm.

[0062] In an embodiment, the second functional layer 40 can have a thickness of 0.15 mm to 0.25 mm. For example, the second functional layer 40 can have a thickness of 0.15 mm, 0.17 mm, 0.2 mm, or 0.25 mm.

[0063] In an embodiment, the first functional layer 20 can include a first film-forming agent and a first functional substance.

[0064] In an embodiment, the first functional layer 20 is quickly water-absorbed and swells upon contact with water, and rapidly releases the first functional substance.

[0065] In an embodiment, the second functional layer 40 can include a second film-forming agent and a second functional substance.

[0066] In an embodiment, the second functional layer 40 is slowly expanded and releases the second functional substance upon being wetted with moisture, and thus realizes a subsequent sustained release.

[0067] In a specific embodiment, the second functional layer 40 can further include a sustained release agent. The sustained release agent is used to further slow down the release of the second functional substance.

[0068] In a specific embodiment, the first functional layer 20 can further include a thickening agent. The thickening agent is used to increase the viscosity, to facilitate the sustained release effect, and to facilitate the interlayer adhesion.

[0069] In a specific embodiment, the second functional layer 40 can further include a thickening agent. The thickening agent is used to increase the viscosity, to facilitate the sustained release effect, and to facilitate the interlayer adhesion.

[0070] In a specific embodiment, the first functional layer 20 can further include at least one of a plasticizer, a sweetener, an aroma, a cooling agent, a pH adjuster, and an antioxidant.

[0071] In a specific embodiment, the second functional layer 40 can further include at least one of a plasticizer, a sweetener, an aroma, a cooling agent, a pH adjuster, and an antioxidant.

[0072] In a specific embodiment, the first film-forming agent can include at least one of hydroxypropyl methylcellulose (HPMC), soluble starch, gelatin, and a gelatin-porous starch composite.

[0073] In a specific embodiment, the hydroxypropyl methylcellulose (HPMC) can be a low viscosity hydroxypropyl methylcellulose (HPMC). For example, it can be at least one of HPMC E3, HPMC E4, and HPMC E5.

[0074] In a specific embodiment, the second film-forming agent can include at least one of ethyl cellulose (EC), polyethylene oxide (PEO), hydroxypropyl methylcellulose, soluble starch, and gelatin.

[0075] In a specific embodiment, the ethyl cellulose (EC) can be a high viscosity ethyl cellulose. For example, it can be at least one of EC N7, EC N8, EC N9, and EC N10.

[0076] In a specific embodiment, the polyethylene oxide (PEO) can be a high viscosity polyethylene oxide. For example, it can be PEO N80.

[0077] In a specific embodiment, the second film-forming agent can include ethyl cellulose and hydroxypropyl methyl cellulose. In this case, the functional substance is uniformly dispersed in the hydrophobic matrix of the ethyl cellulose, forming a micro-“embedded” state, and is slowly diffused through the pores of the matrix or gradually released by erosion of the matrix, so that a long-lasting release matrix can be formed. The ethyl cellulose (EC) can form a dense film when it comes into contact with water, effectively blocking the penetration of water, and has a hydrophobic barrier mechanism. The functional substance needs to be released through the pores of the hydrophobic matrix or after the film is broken, and the release speed is slower. Compared with hydroxypropyl methyl cellulose, ethyl cellulose can achieve a longer and more stable release effect.

[0078] In a specific embodiment, the first film-forming agent and the second film-forming agent both include hydroxypropyl methyl cellulose. In this way, the film-forming can be facilitated.

[0079] In a specific embodiment, the ratio of the relative mass fraction of hydroxypropyl methyl cellulose in the first film-forming agent to the relative mass fraction of hydroxypropyl methyl cellulose in the second film-forming agent is 2:1 to 4:1. For example, the ratio of the relative mass fraction of hydroxypropyl methyl cellulose in the first film-forming agent to the relative mass fraction of hydroxypropyl methyl cellulose in the second film-forming agent can be 2:1, 3:1, or 4:1. That is, a larger proportion of hydroxypropyl methyl cellulose can be included in the first functional layer 20, and a smaller proportion of hydroxypropyl methyl cellulose can be included in the second functional layer 40. In this way, the first functional layer 20 has a faster swelling speed.

[0080] In a specific embodiment, the sustained-release agent can include at least one of sodium alginate, carrageenan (κ type), and mesoporous silica.

[0081] In a specific embodiment, the thickening agent can include at least one of a polycarboxyl high-molecular polymer, a starch ether derivative, and a hyaluronic acid sodium-chitosan polyelectrolyte complex.

[0082] In a specific embodiment, the plasticizer can include at least one of glycerol, sorbitol, propylene glycol, polyethylene glycol, and xylitol. The plasticizer can be used to improve the toughness of the film to avoid the film being too brittle and hard.

[0083] In a specific embodiment, the sweetener can include at least one of xylitol, sorbitol, mannitol, isomalt, lactitol, maltitol, isomaltulose, hydrogenated starch hydrolysate, erythritol, maltotriitol, aspartame, acesulfame potassium, sodium saccharin, sucralose, neotame, cyclamate, thaumatin, rebaudioside, arabitol, and mogroside. It can also be selected from other edible substances, which will not be described here one by one.

[0084] In one specific embodiment, the flavoring agent may include at least one of fragrance, natural essential oil, and natural extract. The fragrance is an edible fragrance, which may include at least one of bergamot fragrance, eucalyptus fragrance, citrus fragrance, lemon fragrance, peppermint fragrance, peppermint fragrance, menthol, licorice fragrance, wintergreen fragrance, tobacco fragrance, coffee fragrance, vanilla fragrance, lime fragrance, apple fragrance, peach fragrance, mango fragrance, cherry fragrance, blueberry fragrance, strawberry fragrance, cola fragrance, cinnamon fragrance, pandan fragrance, and watermelon fragrance. Other types of edible fragrances may also be included, which will not be detailed here.

[0085] In one specific embodiment, the cooling agent may include at least one of menthol, menthol derivatives, WS-3, and WS-23.

[0086] In one specific embodiment, the pH adjuster may include at least one of citric acid, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and magnesium carbonate.

[0087] In one specific embodiment, the antioxidant may include at least one of ethylparaben, ascorbic acid, vitamin E, butylated hydroxytoluene, and butylated hydroxyanisole.

[0088] In one specific embodiment, the first functional layer 20 or the second functional layer 40 may further include a solubilizer, which may include at least one of the following: polyethylene glycol (e.g., PEG-200, PEG-400, PEG-600, etc.), Tween (e.g., Tween-20, Tween-80, etc.), poloxamer, to improve the solubility of the material.

[0089] In one embodiment, the oral tablet 100 may further include a flavoring layer. The flavoring layer includes flavoring agents. Flavoring agents include at least one of sweeteners, flavoring agents, and cooling agents.

[0090] like Figure 2 As shown, in one specific embodiment, the oral tablet 100 may include a first flavoring layer 60.

[0091] In one specific embodiment, the first flavoring layer 60 can be located between the first support layer 10 and the first functional layer 20. Therefore, during use, flavoring agents can be released first from the first flavoring layer 60 to mask the taste of nicotine and improve the palatability. This can increase acceptance for first-time users and others.

[0092] In one specific embodiment, the oral tablet 100 may sequentially include a first support layer 10, a first flavoring layer 60, a first functional layer 20, a hydrophobic film layer 30, a second functional layer 40, and a second support layer 50.

[0093] like Figure 3As shown, in an embodiment, the lozenge 100 can include a first flavoring layer 60 and a second flavoring layer 70. The first flavoring layer 60 is positioned between the first support layer 10 and the first functional layer 20. The second flavoring layer 70 is positioned between the second support layer 50 and the second functional layer 40.

[0094] In an embodiment, the lozenge 100 can include, in order, the first support layer 10, the first flavoring layer 60, the first functional layer 20, the hydrophobic film layer 30, the second functional layer 40, the second flavoring layer 70, and the second support layer 50.

[0095] In an embodiment, the first flavoring layer 60 can include a third film-forming agent and a flavoring agent.

[0096] In an embodiment, the second flavoring layer 70 can include a fourth film-forming agent and a flavoring agent.

[0097] In an embodiment, the third film-forming agent can include at least one of hydroxypropyl methylcellulose, soluble starch, gelatin, and a gelatin-porous starch complex.

[0098] In an embodiment, the fourth film-forming agent can include at least one of hydroxypropyl methylcellulose, soluble starch, gelatin, and a gelatin-porous starch complex.

[0099] In an embodiment, the third film-forming agent or the fourth film-forming agent can be the same as the first film-forming agent.

[0100] In an embodiment, the first functional layer 20 can include, by weight fraction, 10 to 35 parts of the first film-forming agent. For example, the first functional layer 20 can include, by weight fraction, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, or 35 parts of the first film-forming agent.

[0101] In an embodiment, the first functional layer 20 can include, by weight fraction, 7.5 to 20 parts of hydroxypropyl methylcellulose and 5 to 10 parts of soluble starch.

[0102] In an embodiment, the first functional layer 20 can include, by weight fraction, 0.5 to 5 parts of the functional substance. For example, the first functional layer 20 can include, by weight fraction, 0.5 parts, 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 4.5 parts, or 5 parts of the functional substance.

[0103] In an embodiment, the first functional layer 20 can include, by weight fraction, 5 to 10 parts of the thickening agent. For example, the first functional layer 20 can include, by weight fraction, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, or 10 parts of the thickening agent.

[0104] In one embodiment, the first functional layer 20 can include 1.5 to 5 parts by weight of the plasticizer. For example, the first functional layer 20 can include 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts, or 5 parts by weight of the plasticizer.

[0105] In one embodiment, the first functional layer 20 can include 0.25 to 2 parts by weight of the sweetener. For example, the first functional layer 20 can include 0.25 parts, 0.5 parts, 1 part, 1.5 parts, or 2 parts by weight of the sweetener.

[0106] In one embodiment, the first functional layer 20 can include 0.25 to 2 parts by weight of the flavoring agent. For example, the first functional layer 20 can include 0.25 parts, 0.5 parts, 1 part, 1.5 parts, or 2 parts by weight of the flavoring agent.

[0107] In one embodiment, the first functional layer 20 can include 0.25 to 5 parts by weight of the cooling agent. For example, the first functional layer 20 can include 0.25 parts, 0.5 parts, 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts, or 5 parts by weight of the cooling agent.

[0108] In one embodiment, the first functional layer 20 can include 0.05 to 1 parts by weight of the pH adjuster. For example, the first functional layer 20 can include 0.05 parts, 0.1 parts, 0.5 parts, or 1 parts by weight of the pH adjuster.

[0109] In one embodiment, the first functional layer 20 can include 0.1 to 0.5 parts by weight of the antioxidant. For example, the first functional layer 20 can include 0.1 parts, 0.2 parts, 0.3 parts, 0.4 parts, or 0.5 parts by weight of the antioxidant.

[0110] In one embodiment, the second functional layer 40 can include 10 to 40 parts by weight of the second film-forming agent. For example, the second functional layer 40 can include 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, or 40 parts by weight of the second film-forming agent.

[0111] In one embodiment, the second functional layer 40 can include 10 to 20 parts by weight of ethyl cellulose and 2.5 to 7.5 parts by weight of hydroxypropyl methyl cellulose.

[0112] In a specific embodiment, the second functional layer 40 can include 0.5 to 5 parts by weight of the functional substance. For example, the second functional layer 40 can include 0.5 parts, 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 4.5 parts, or 5 parts by weight of the functional substance.

[0113] In a specific embodiment, the second functional layer 40 can include 1 to 5 parts by weight of the sustained-release agent. For example, the second functional layer 40 can include 1 part, 2 parts, 3 parts, 4 parts, or 5 parts by weight of the sustained-release agent.

[0114] In a specific embodiment, the second functional layer 40 can include 5 to 15 parts by weight of the thickening agent. For example, the second functional layer 40 can include 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, or 15 parts by weight of the thickening agent.

[0115] In a specific embodiment, the second functional layer 40 can include 1.5 to 5 parts by weight of the plasticizer. For example, the second functional layer 40 can include 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts, or 5 parts by weight of the plasticizer.

[0116] In a specific embodiment, the second functional layer 40 can include 0.25 to 2 parts by weight of the sweetening agent. For example, the second functional layer 40 can include 0.25 parts, 0.5 parts, 1 part, 1.5 parts, or 2 parts by weight of the sweetening agent.

[0117] In a specific embodiment, the second functional layer 40 can include 0.25 to 2 parts by weight of the flavoring agent. For example, the second functional layer 40 can include 0.25 parts, 0.5 parts, 1 part, 1.5 parts, or 2 parts by weight of the flavoring agent.

[0118] In a specific embodiment, the second functional layer 40 can include 0.25 to 5 parts by weight of the cooling agent. For example, the second functional layer 40 can include 0.25 parts, 0.5 parts, 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts, or 5 parts by weight of the cooling agent.

[0119] In a specific embodiment, the second functional layer 40 can include 0.05 to 1 parts by weight of the pH adjuster. For example, the second functional layer 40 can include 0.05 parts, 0.1 parts, 0.5 parts, or 1 parts by weight of the pH adjuster.

[0120] In a specific embodiment, the second functional layer 40 includes 0.1-0.5 parts by weight of the antioxidant. For example, the second functional layer 40 can include 0.1 parts, 0.2 parts, 0.3 parts, 0.4 parts, or 0.5 parts by weight of the antioxidant.

[0121] The present application provides a preparation method of the buccal tablet 100 (hereinafter sometimes referred to as “preparation method”). It should be noted that the ingredients, amounts, etc. involved in the preparation method can refer to the description of the aforementioned buccal tablet 100 part.

[0122] In a specific embodiment, the preparation method can include the following steps: obtaining the first support layer 10, the hydrophobic film layer 30, and the second support layer 50; obtaining the first film-forming liquid and coating the first film-forming liquid to form the first functional layer 20; obtaining the second film-forming liquid and coating the second film-forming liquid to form the second functional layer 40; stacking the first support layer 10, the first functional layer 20, the hydrophobic film layer 30, the second functional layer 40, and the second support layer 50 in sequence to obtain a composite film, and further obtain the buccal tablet 100.

[0123] In a specific embodiment, the preparation method can include the following steps: coating the first film-forming liquid on the surface of the hydrophobic film layer 30 to obtain the first functional layer 20; coating the second film-forming liquid on the other surface of the hydrophobic film layer to obtain the second functional layer 40; stacking the first support layer 10 and the second support layer 20 on both sides of the hydrophobic film layer, respectively, to obtain a composite film; and treating the composite film by a hot-pressing and cold-rolling alternating process to obtain the buccal tablet 100.

[0124] In a specific embodiment, the hot-pressing and cold-rolling alternating process includes: after the composite film is bonded by a hot-pressing roller (80°C / 0.5MPa), the composite film is shaped by a cold roller (10°C), and the interlayer alignment accuracy is ≤0.1mm. The consistency of the directional release channel is ensured.

[0125] In a specific embodiment, the buccal tablet 100 is prepared by the above preparation method.

[0126] The present application will be further described in detail through specific experimental processes and experimental data embodiments. The following embodiments only further illustrate the present application and should not be understood as limiting the present application. In the present embodiment, 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] (1) Preparation process:

[0128] Process A: raw material preparation. According to the formula, each raw material is weighed and added to the stirred tank in proportion to prepare the first functional film layer and the second functional film layer. The preparation of the first functional film layer includes: adding dry powder such as hydroxypropyl methyl cellulose, gelatin, starch, and essence into a suitable amount of pure water, stirring while adding propylene glycol, and swelling and dissolving hydroxypropyl methyl cellulose to form a uniform viscous film solution; the temperature is controlled within 35℃. The preparation of the second functional film layer includes: dissolving ethyl cellulose in a suitable amount of alcohol solvent (such as ethanol or propylene glycol), then adding gelatin, essence and other water-soluble additives and stirring uniformly, while adding auxiliary materials such as sodium alginate and mixing uniformly. All film solutions are degassed by ultrasonic or vacuum. The hydrophobic film uses a 0.01mm polyethylene film. The support layer uses a cotton fiber non-woven fabric with a porosity of 50%.

[0129] Process B: coating. The hydrophobic film is laid flat on the coating machine, and the first functional film layer is uniformly coated on the surface of the hydrophobic film using a doctor blade or roller, with a film thickness of about 0.2mm. The coating is uniform and no leakage to ensure consistent film thickness. After coating, cover with non-woven fabric. The conveyor belt and roller continue to coat the second functional layer, with a film thickness of about 0.2mm, and then cover the second functional layer with non-woven fabric.

[0130] Process C: drying. The coated film is sent to a tunnel oven and dried with 40-50℃ vacuum nitrogen until the film feels dry and the residual moisture content is less than 5%. Drying time: 30min.

[0131] Process D: compounding. The dried film is subjected to hot pressing-cold roller compounding (after preliminary bonding by hot pressing roller (80℃ / 0.5MPa), cold roller (10℃) rapid shaping, interlayer alignment accuracy ≤0.1mm) to improve the adhesion between the film layers.

[0132] Process E: die cutting and segmentation. The compound film body is cut into independent dosage pieces (30×20mm) according to the specifications.

[0133] Process F: airtight packaging box sealing and storage. Use a vacuum packaging machine and a sealing and hot pressing device to place each piece of oral film in an aluminum foil bag, vacuum or nitrogen sealing and packaging, and put it into a low-humidity sealed bag.

[0134] (2) Formula system

[0135] Four formula systems A, B, C, and D are designed, corresponding to all immediate-release type, fast and slow release type, front slow and rear fast type, and constant speed release type; among them, the all immediate-release type (formula A) does not contain the second functional layer, and the first functional layer is coated on both sides of the hydrophobic film. According to the following four formulas, the above preparation process is used for preparation.

[0136] Formula A:

[0137] Serial number Raw material name Mass fraction (part) 1 Hydroxypropyl methyl cellulose 25.0 2 Gelatin 10.0 3 Soluble starch 10.0 4 Propylene glycol 6.0 5 Nicotine 4.0 6 Peppermint flavor 1.5 7 Steviol glycoside 1.0 8 WS-23 0.5 9 Nipagin ethyl ester 0.3 10 Deionized water 41.7

[0138] Formulation B:

[0139]

[0140] Formulation C:

[0141]

[0142]

[0143] Formulation D:

[0144]

[0145] (3) Nicotine release profile test:

[0146] Nicotine release profile was tested based on Agilent 708-DS dissolution tester, method: USP II paddle method, rotation speed: 75 rpm, temperature: 37℃. Medium: 900 ml PBS (pH 6.8) phosphate buffer (simulated saliva environment). Medium volume 900 ml. Sampling volume: 10 ml, supplemented with an equivalent amount of new medium. HPLC was used for detection. The nicotine release data is as follows:

[0147]

[0148] Figure 4 The nicotine release profile of the different formulations of the oral tablet involved in the embodiments of the present application. From the results, formulation A releases more than 75% in 10 min, nearly 100% in 20 min, and is similar to the traditional oral film. Formulation B releases about 60% in 10 min, and then tends to be stable, formulations C and D release only 20% in the first 10 min due to the addition of more hydrophobic matrix, and then release rapidly. Formulation D is close to a linear release model, which is suitable for long-acting dose control input.

[0149] (4) Residual rate test:

[0150] The nicotine release profile was tested based on Agilent 708-DS dissolution tester, method: USP II paddle method, rotation speed: 75 rpm, temperature: 37℃. Medium: 900 ml PBS (pH 6.8) phosphate buffer (simulated saliva environment). Medium volume 900 ml, sampling and weighing at different time points, and calculating the residual rate. This test explores how long the finished product is completely dissolved, and the insoluble materials such as non-woven fabric and hydrophobic film are 0.05 g, simulating the oral environment and release disintegration rate.

[0151] The residual rate test results are as follows:

[0152]

[0153] Figure 5 Figure is the residual rate test result chart of the different formula of the oral tablet involved in the embodiments of the present application. From the results, the soluble film-forming material in formula A is almost completely dissolved in 20 minutes, and the residual mass is only the insoluble carrier; formula B contains a sustained-release structure, and the film body is released until 30 minutes later before it is significantly reduced; formula C and D release the slowest due to the high EC ratio, and it is close to the residual limit only after 45 minutes.

[0154] (5) Nicotine stability test:

[0155] The oral dissolving film is sealed with an aluminum foil bag for ring testing (temperature / humidity: 40℃±2℃ / 5%RH±5%RH, time: one week), and the nicotine content before and after ring testing is detected. The nicotine content is tested based on HPLC-Aglient GC8890, reagent: isopropyl alcohol (chromatographic grade), ethanol (chromatographic grade) standard: nicotine standard solution in isopropyl alcohol, n-heptadecane (internal standard). The results are as follows:

[0156]

[0157] Figure 6 Figure is the nicotine stability test result chart of the different formula of the oral tablet involved in the embodiments of the present application. From the results before and after ring testing, the environmental factors have little effect on the nicotine content, excluding measurement errors, and there is basically no loss, indicating that the product uses the preparation process (such as sandwich method coating and hot pressing) of the present application, and the nicotine stability is good.

[0158] (6) Water permeability test:

[0159] The water vapor barrier performance of the oral tablet under the condition of 37℃ and high humidity difference is evaluated to provide a basis for the stability and humidity control ability of the oral environment. The MOCON PERMATRAN-W 3 / 34 water vapor transmission rate tester is used, the test temperature is 37℃, the wet side RH is 90%, and the dry side RH is 0%. The test mode is isobaric mode. The oral tablet sample is cut into a sample with a diameter of 80mm, and a microporous clamp is used to fix the sample to ensure good sealing. It is placed in a desiccator for 24h before testing to prevent pre-hydration from affecting the baseline. The results are as follows:

[0160] Sample serial number Formulation WVTR g / m 2 ]] 1 A 124 2 B 122.8 3 C 98.76 4 D 96.34

[0161] From the results, the WVTR (water vapor transmission rate) of formula D is the lowest, and it is similar to formula C, because the hydrophobic structure in the second functional layer is the largest, and it has strong humidity suppression performance.

[0162] (7) Mechanical property test:

[0163] The tensile strength and tear strength of the finished product of different formula structures were tested under standard mechanical conditions, and the film thickness was about 220 μm-280 μm.

[0164] The instrument used was a texture analyzer with a tensile clamp, the speed was 100 mm / min, and the result was compared with the tensile strength (MPa). The tear strength test was carried out at a tensile speed of 50 mm / min. Three parallel samples were measured in each group, and the average value was taken. The results are as follows:

[0165] Sample serial number Formulation Average tensile strength (N) Average tear strength (N) 1 A 18.21 6.89 2 B 20.53 7.35 3 C 23.83 7.67 4 D 25.64 8.92

[0166] Among them, the overall release structure layer with ethyl cellulose as the main substrate rises on the mold, the flexibility decreases but the strength increases significantly. The use of high proportion of hydroxypropyl methyl cellulose has good flexibility, but the mechanical strength is lower.

[0167] 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, some simple deductions or substitutions can be made without departing from the concept of the present application.

Claims

1. A lozenge, characterized in that The first support layer, the first functional layer, the hydrophobic film layer, the second functional layer and the second support layer are sequentially arranged, the first functional layer comprises a first functional substance and a first film forming agent, and the second functional layer comprises a second functional substance and a second film forming agent, wherein the first support layer and the second support layer are both water-permeable layers.

2. The lozenge of claim 1, wherein The swelling speed of the first functional layer in water is higher than the swelling speed of the second functional layer in water.

3. The lozenge of claim 1, wherein The lozenge further comprises a first flavoring layer between the first functional layer and the first support layer. And / or, the lozenge further comprises a second flavoring layer between the second functional layer and the second support layer.

4. The lozenge of claim 1, wherein The second functional layer further comprises a release agent for controlling the release rate of the second functional substance.

5. The lozenge of claim 4, wherein The first functional layer further comprises at least one of a thickening agent, a plasticizing agent, a sweetening agent, an aromatic agent, a cooling agent, a pH adjusting agent and an antioxidant. And / or, the second functional layer further comprises at least one of a thickening agent, a plasticizing agent, a sweetening agent, an aromatic agent, a cooling agent, a pH adjusting agent and an antioxidant.

6. The lozenge of claim 5, wherein The first functional substance comprises at least one of nicotine and a nicotine derivative. And / or, the second functional substance comprises at least one of nicotine and a nicotine derivative. And / or, the first film forming agent comprises at least one of hydroxypropyl methyl cellulose, soluble starch, gelatin and gelatin-porous starch complex. And / or, the second film forming agent comprises at least one of ethyl cellulose, polyoxyethylene, hydroxypropyl methyl cellulose and soluble starch. And / or, the release agent comprises at least one of sodium alginate, carrageenan and mesoporous silica. And / or, the thickening agent comprises at least one of a polycarboxyl high molecular polymer, a starch ether derivative and a sodium hyaluronate-chitosan polyelectrolyte complex. And / or, the plasticizing agent comprises at least one of glycerol, sorbitol, propylene glycol, polyethylene glycol and xylitol. And / or, the antioxidant comprises at least one of nipagin, ascorbic acid, vitamin E, butylated hydroxytoluene and butylated hydroxyanisole.

7. The lozenge of claim 1, wherein The thickness of the first support layer is 0.1mm-0.2mm. And / or, the thickness of the first functional layer is 0.1mm-0.22mm. And / or, the thickness of the hydrophobic film layer is 0.01mm-0.02mm. And / or, the thickness of the second functional layer is 0.15mm-0.25mm. And / or, the thickness of the second support layer is 0.1mm-0.2mm.

8. The lozenge of claim 1, wherein Both the first film forming agent and the second film forming agent comprise hydroxypropyl methyl cellulose, and the ratio of the relative mass fraction of hydroxypropyl methyl cellulose in the first film forming agent to the relative mass fraction of hydroxypropyl methyl cellulose in the second film forming agent is 2:1-4:

1.

9. The lozenge of claim 1, wherein The first functional layer comprises at least one of the following by weight: 10-35 parts of the first film-forming agent, 0.5-5 parts of the first functional substance, 5-10 parts of a thickening agent, 1.5-5 parts of a plasticizer, 0.25-2 parts of a sweetener, 0.25-2 parts of an aromatic agent, 0.25-5 parts of a cooling agent, 0.05-1 parts of a pH regulator, 0.1-0.5 parts of an antioxidant; And / or, the second functional layer comprises at least one of the following by weight: 10-40 parts of the second film-forming agent, 0.5-5 parts of the second functional substance, 1-5 parts of a sustained-release agent, 5-15 parts of a thickening agent, 1.5-5 parts of a plasticizer, 0.25-2 parts of a sweetener, 0.25-2 parts of an aromatic agent, 0.25-5 parts of a cooling agent, 0.05-1 parts of a pH regulator, 0.1-0.5 parts of an antioxidant, wherein the second film-forming agent comprises ethyl cellulose.

10. A lozenge according to any one of claims 1 to 9, wherein The first support layer comprises at least one of natural fiber non-woven fabric, synthetic fiber non-woven fabric, PVA non-woven fabric, woven cloth, electrospun nanofiber membrane; And / or, the second support layer comprises at least one of natural fiber non-woven fabric, synthetic fiber non-woven fabric, PVA non-woven fabric, woven cloth, electrospun nanofiber membrane; And / or, the hydrophobic film layer comprises at least one of polyethylene, polypropylene, polytetrafluoroethylene, polyvinylidene fluoride and silicone rubber.

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