Buccal tablets

Abstract

This application belongs to the field of food or pharmaceutical technology, specifically relating to a lozenge and its preparation method. The lozenge includes: a first sustained-release layer, a barrier layer, and a second sustained-release layer stacked sequentially; wherein, the first sustained-release layer includes active substances and / or flavoring agents; the second sustained-release layer includes active substances and / or flavoring agents; the barrier layer includes a matrix and a thermosensitive phase change layer formed on both sides of the matrix, and when the ambient temperature is ≤40℃, the thermosensitive phase change layer changes from a hydrophobic state to a hydrophilic state. The relatively high temperature during preparation, with the thermosensitive phase change layer in a hydrophobic state, solves the problem of high-moisture-content sustained-release agent slurry penetrating and adhering to equipment during coating and drying. When the lozenge is placed at room temperature, the thermosensitive phase change layer is activated to change from a hydrophobic state to a hydrophilic state, thus ensuring rapid onset and complete release of the lozenge in the oral cavity. Therefore, this solution can simultaneously address the anti-sticking requirements during the production process and the high-efficiency release requirements during use.

Description

Technical Field

[0001] This application belongs to the field of food or pharmaceutical technology, and specifically relates to a lozenge. Background Technology

[0002] In the manufacturing process of multilayer lozenges, a physical barrier layer is typically used to prevent the high-moisture-content slow-release agent slurry from penetrating and sticking to the equipment during coating and drying. However, the physical barrier layer can lead to slow release of the active ingredient, resulting in a poor user experience. Summary of the Invention

[0003] This application aims to provide a lozenge and its preparation method to solve the problem that the physical barrier layer of existing multilayered lozenges causes slow release of active ingredients, resulting in a poor user experience.

[0004] To address the aforementioned technical problems, this application provides a lozenge comprising: a first sustained-release layer, a barrier layer, and a second sustained-release layer sequentially stacked; wherein the first sustained-release layer comprises an active substance and / or a flavoring agent; the second sustained-release layer comprises an active substance and / or a flavoring agent; the barrier layer comprises a matrix and a thermosensitive phase change layer formed on both sides of the matrix, and when the ambient temperature is ≤40℃, the thermosensitive phase change layer changes from a hydrophobic state to a hydrophilic state; the matrix is ​​a liquid-permeable matrix.

[0005] In one embodiment, the thermosensitive phase change layer includes: a phase change host, a phase change modifier, and a film-forming agent.

[0006] In one embodiment, the thermosensitive phase change layer further includes at least one of the following: a first plasticizer and a first anti-adhesion agent.

[0007] In one embodiment, the phase change substrate comprises at least one of the following: polyethylene glycol derivative, poly(N-isopropylacrylamide)-based hydrogel; and / or, the phase change modifier comprises at least one of the following: polyethylene glycol 1500, polyethylene glycol 6000, polyethylene glycol 8000, acrylamide, N-tert-butylacrylamide; and / or, the film-forming agent comprises at least one of the following: hydroxypropyl methylcellulose, polyvinylpyrrolidone; and / or, the first plasticizer comprises at least one of the following: glycerin, propylene glycol, sorbitol; and / or, the first anti-adhesion agent comprises at least one of the following: magnesium stearate, silica, talc; and / or, by weight, the thermosensitive phase change layer comprises: 60-80 parts of phase change substrate, 5-15 parts of phase change modifier, 0.5-2 parts of film-forming agent, 0-5 parts of first plasticizer, and 0-2 parts of first anti-adhesion agent.

[0008] In one embodiment, the thickness of the thermosensitive phase change layer is 10 μm to 30 μm; and / or, the thickness of the first sustained-release layer is 200 mm to 400 mm; and / or, the thickness of the second sustained-release layer is 200 mm to 400 mm; and / or, the thermosensitive phase change layer is a porous structure formed by through-holes, wherein the pores D 50 Its size ranges from 50 nm to 20 μm, and its porosity is 50% to 85%.

[0009] In one embodiment, the lozenge further includes a support layer; the support layer is disposed on the side of the first sustained-release layer and / or the second sustained-release layer opposite to the barrier layer.

[0010] In one embodiment, the support layer includes a first support layer and a second support layer; the first support layer is disposed on the side of the first sustained-release layer opposite to the barrier layer, and the second support layer is disposed on the side of the second sustained-release layer opposite to the barrier layer; wherein, at least one of the first support layer and the second support layer is a liquid-permeable layer.

[0011] In one embodiment, the first sustained-release layer includes a filler, an adhesive, and at least one of a second anti-adhesive, a second plasticizer, a pH adjuster, and a pigment; and / or, the second sustained-release layer includes a filler and an adhesive, and at least one of a second anti-adhesive, a second plasticizer, a pH adjuster, and a pigment.

[0012] In one embodiment, the filler includes: a primary filler and a secondary filler; and / or, the adhesive includes at least one of the following: a gel adhesive and an ionic adhesive.

[0013] In one embodiment, the first sustained-release layer, by weight parts, comprises: 40 to 65 parts of a main filler, 5 to 15 parts of a secondary filler, 5 to 15 parts of a gel binder, 0.5 to 5 parts of an ionic binder, 3 to 12 parts of a second plasticizer, 0.1 to 10 parts of an active ingredient, 0.55 to 16.5 parts of a flavoring agent, 0.1 to 2 parts of a pH adjuster, 0.001 to 0.5 parts of a pigment, and 0.5 to 2 parts of a second anti-adhesive; and / or, the second ... 15 parts of co-filler, 5 to 15 parts of gel binder, 0.5 to 5 parts of ionic binder, 3 to 12 parts of second plasticizer, 0.1 to 10 parts of active substance, 0.55 to 16.5 parts of flavoring agent, 0.1 to 2 parts of pH adjuster, 0.001 to 0.5 parts of pigment, 0.5 to 2 parts of second anti-sticking agent; and / or, the main filler includes at least one of the following: isomaltitol, sorbitol, mannitol, xylitol, erythritol, maltitol, lactose, microcrystalline cellulose, pregelatinized starch, dextrin; and / or, the co-filler... The filler comprises at least one of the following: polydextrose, resistant dextrin, inulin, oat fiber; and / or the gel binder comprises at least one of the following: hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carrageenan, xanthan gum, guar gum, gellan gum, povidone; and / or the ionic binder comprises at least one of the following: sodium alginate, potassium alginate, methoxylated pectin with a degree of esterification less than 50%; and / or the second plasticizer comprises at least one of the following: glycerol, propylene glycol, sorbitol; and / or the active substance comprises at least one of the following: nicotinic acid. The ingredients include nicotine, nicotine salts, plant extracts, vitamins, minerals, and probiotics; and / or, the flavoring agent includes at least one of the following: flavoring, sweetener, cooling agent, acidulant, and saltiness agent; and / or, the pH adjuster includes at least one of the following: citric acid, malic acid, tartaric acid, fumaric acid, phosphoric acid, and sodium bicarbonate; and / or, the pigment includes at least one of the following: titanium dioxide, β-carotene, brilliant blue, allura red, carmine, curcumin, and caramel color; and / or, the second anti-sticking agent includes at least one of the following: magnesium stearate, silicon dioxide, and talc.

[0014] Because the lozenge manufacturing process involves high temperatures, the thermosensitive phase change layer is in a hydrophobic state. This prevents the high-moisture-content slow-release agent slurry from penetrating and sticking to the equipment during coating and drying. Furthermore, after the manufacturing process, the lozenges are placed at room temperature. This cooling process triggers the thermosensitive phase change layer to change from a hydrophobic to a hydrophilic state, ensuring rapid onset and complete release of the lozenge in the mouth. Therefore, this solution addresses both the anti-sticking requirements during lozenge production and the high-efficiency release requirements during use.

[0015] Additional aspects and advantages of this application will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of this application. Attached Figure Description

[0016] The above and / or additional aspects and advantages of this application will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which: Figure 1 These are dissolution curves for the examples and comparative examples. Detailed Implementation

[0017] The embodiments of this application will now be described in detail. Examples of these embodiments are illustrated in the accompanying drawings, wherein the same or similar reference numerals denote the same or similar elements or elements having the same or similar functions throughout. The embodiments described below with reference to the accompanying drawings are exemplary and are only used to explain this application, and should not be construed as limiting this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application without inventive effort are within the scope of protection of this application.

[0018] The terms "first" and "second" in the specification and claims of this application may explicitly or implicitly include one or more of the features. In the description of this application, unless otherwise stated, "multiple" means two or more. Furthermore, "and / or" in the specification and claims indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.

[0019] In the description of this application, it should be understood that the terms "center", "longitudinal", "lateral", "length", "width", "thickness", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", "clockwise", "counterclockwise", "axial", "radial", "circumferential", etc., indicating the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings, are only for the convenience of describing this application and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation, and therefore should not be construed as a limitation of this application.

[0020] In the description of this application, it should be noted that, unless otherwise expressly specified and limited, the terms "installation," "connection," and "joining" should be interpreted broadly. For example, they can refer to a fixed connection, a detachable connection, or an integral connection; they can refer to a direct connection or an indirect connection through an intermediate medium; and they can refer to the internal communication between two components. Those skilled in the art can understand the specific meaning of the above terms in this application based on the specific circumstances.

[0021] This application provides a lozenge comprising: a first sustained-release layer, a barrier layer, and a second sustained-release layer sequentially stacked; wherein the first sustained-release layer comprises an active substance and / or a flavoring agent; the second sustained-release layer comprises an active substance and / or a flavoring agent; the barrier layer comprises a matrix and a thermosensitive phase change layer formed on both sides of the matrix, and the thermosensitive phase change layer changes from a hydrophobic state to a hydrophilic state when the ambient temperature is ≤40℃; the matrix is ​​a liquid-permeable matrix. It should be noted that the liquid-permeable matrix can be a nonwoven fabric permeable to saliva.

[0022] Because the lozenge manufacturing process involves high temperatures, the thermosensitive phase change layer is in a hydrophobic state. This prevents the high-moisture-content slow-release agent slurry from penetrating and sticking to the equipment during coating and drying. Furthermore, after the manufacturing process, the lozenges are placed at room temperature. This cooling process triggers the thermosensitive phase change layer to change from a hydrophobic to a hydrophilic state, ensuring rapid onset and complete release of the lozenge in the mouth. Therefore, this solution addresses both the anti-sticking requirements during lozenge production and the high-efficiency release requirements during use.

[0023] In one embodiment, the lozenge further includes a support layer; the support layer is disposed on the side of the first and / or second sustained-release layers opposite to the barrier layer. The support layer is used to enhance the support strength of the lozenge, thereby providing the user with a different user experience.

[0024] In one embodiment, the support layer includes a first support layer and a second support layer; the first support layer is disposed on the side of the first sustained-release layer opposite to the barrier layer, and the second support layer is disposed on the side of the second sustained-release layer opposite to the barrier layer; wherein, at least one of the first support layer and the second support layer is a liquid-permeable layer. For example, the liquid-permeable layer may be composed of a liquid-permeable nonwoven fabric layer. In some specific embodiments, both the first and second support layers are liquid-permeable layers, and bilateral liquid permeability helps to improve the release rate of active substances and / or flavoring agents; in some specific embodiments, only one of the first and second support layers is a liquid-permeable layer, and the other is a non-liquid-permeable layer. When using the product, the user can adhere the non-liquid-permeable layer tightly to the gums or oral mucosa, thereby helping to protect oral health.

[0025] In one embodiment, the thermosensitive phase change layer includes: a phase change substrate, a phase change modifier, and a film-forming agent. The phase change modifier is used to precisely control the melting point of the phase change substrate to a target range; the film-forming agent is used to ensure the formation of a continuous and uniform functional thin film on the substrate surface.

[0026] Specifically, the phase change host includes at least one of the following: polyethylene glycol derivatives, poly(N-isopropylacrylamide)-based hydrogels.

[0027] The LCST (low critical eutectic temperature) describes the critical temperature point at which a polymer solution undergoes phase separation under temperature changes. Polyethylene glycol (PEG) derivatives and poly(N-isopropylacrylamide) (PNIPAM)-based hydrogels both exhibit temperature-responsive LCST effects, which is the essential reason for achieving thermal shrinkage and expansion, and reversible hydrophobic-hydrophilic transitions.

[0028] The LCST (lowest critical temperature range) of poly(N-isopropylacrylamide) hydrogels is approximately 32°C to 35°C, which is the critical temperature for its molecular chain conformational transformation and closely matches the oral temperature (≤40°C). When the temperature exceeds the LCST (e.g., the production temperature of lozenges is 55°C to 65°C), the hydrophobic effect of the isopropyl hydrophobic groups in the PNIPAM molecular chain becomes dominant, causing conformational contraction of the molecular chain. The originally extended linear segments coil and aggregate, and the hydrophilic groups in the hydrogel network are encapsulated within the hydrophobic core. The network pores collapse due to the chain segment contraction, forming a dense hydrophobic state. At this point, the swelling ratio of the hydrogel is extremely low, and the porosity decreases significantly, preventing adhesive from penetrating into the network and achieving anti-sticking during production.

[0029] When the temperature drops below the LCST (e.g., when lozenges are stored at room temperature after production, or at the oral temperature at the time of administration), the hydrogen bonding between water molecules and the PNIPAM molecular chains strengthens, exceeding the aggregation effect of hydrophobic groups. The molecular chains then unwind from a coiled state to a straightened state. The hydrogel network swells due to the unwinding of the chain segments, forming a porous hydrophilic structure with significantly increased porosity. This allows water and active ingredients to migrate freely in both directions within the network, enabling transdermal drug delivery.

[0030] It should also be noted that the crosslinking density of the poly(N-isopropylacrylamide)-based hydrogel is crucial for achieving intelligent switching between anti-sticking production and drug permeability. Crosslinking density refers to the ratio of poly(N-isopropylacrylamide) to crosslinking agent. In one embodiment, the crosslinking agent accounts for 1 mol% to 4 mol% of the poly(N-isopropylacrylamide) monomer in the poly(N-isopropylacrylamide)-based hydrogel. This ratio represents a medium crosslinking density, which not only avoids gel embrittlement caused by excessive molecular chain aggregation but also ensures the density after network collapse, effectively blocking the penetration of the sustained-release solution. Furthermore, a network with a medium crosslinking density, after swelling at low temperatures, forms pores with smaller diameters (e.g., pore size D). 50 With a diameter of 50nm~20μm and a porosity of 50%~85%, it is more conducive to the free passage of water and active ingredients, while maintaining the mechanical strength of the hydrogel and preventing it from collapsing rapidly in the oral cavity.

[0031] The crosslinking agents typically selected include N,N'-methylenebisacrylamide, divinylbenzene, polyethylene glycol diacrylate, etc.

[0032] Specifically, in the poly(N-isopropylacrylamide)-based hydrogel, the crosslinking agent accounts for 1 mol%, 2 mol%, 3 mol%, 4 mol% of the poly(N-isopropylacrylamide) monomer or any value within the above range.

[0033] In one embodiment, when the phase change host is a poly(N-isopropylacrylamide)-based hydrogel, the phase change modifier is acrylamide (AAm) or N-tert-butylacrylamide.

[0034] In one embodiment, the polyethylene glycol derivative includes at least one of the following: polyethylene glycol-polypropylene glycol-polyethylene glycol triblock copolymer, polyethylene glycol-polylactic acid block copolymer, polyethylene glycol-polylactic acid-glycolic acid copolymer block copolymer, and polyethylene glycol-polycaprolactone block copolymer. In the block copolymer, the ratio of hydrophilic PEG segments to hydrophobic segments determines the phase transition temperature. Therefore, the transition temperature and response rate can be precisely customized by adjusting the PEG chain length and the proportion of hydrophobic segments.

[0035] In one embodiment, when the phase change host is a polyethylene glycol derivative (such as polyethylene glycol 4000, polyethylene glycol 3350, polyethylene glycol 6000), the corresponding phase change modifier includes at least one of the following: polyethylene glycol 1500, polyethylene glycol 6000, and polyethylene glycol 8000.

[0036] Specifically, the film-forming agent includes at least one of the following: hydroxypropyl methylcellulose and polyvinylpyrrolidone.

[0037] In one embodiment, the thermosensitive phase change layer further includes at least one of the following: a first plasticizer and a first anti-adhesion agent.

[0038] The first plasticizer is used to increase the flexibility of the heat-sensitive phase change layer and prevent the crystallized film from becoming too brittle and cracking. It can also be used as a humectant. The first anti-adhesion agent is mainly used in the production of lozenges to prevent the wet or dry film from sticking together when it is being wound and in contact with the equipment, so as to ensure smooth production.

[0039] Specifically, the first plasticizer includes at least one of the following: glycerin, propylene glycol, and sorbitol.

[0040] Specifically, the first anti-adhesion agent includes at least one of the following: magnesium stearate, silica, and talc.

[0041] In one embodiment, the thermosensitive phase change layer comprises, by weight, 60 to 80 parts of phase change substrate, 5 to 15 parts of phase change modifier, 0.5 to 2 parts of film-forming agent, 0 to 5 parts of first plasticizer, and 0 to 2 parts of first anti-adhesion agent. This thermosensitive phase change layer can both form a film smoothly and meet the phase change temperature requirements.

[0042] Specifically, by mass, the thermosensitive phase change layer comprises: 65 to 75 parts of phase change substrate, 8 to 11 parts of phase change modifier, 1 to 1.5 parts of film-forming agent, 1 to 3 parts of first plasticizer, and 0.5 to 1 part of first anti-adhesion agent.

[0043] In one embodiment, the components of the first and second sustained-release layers can be the same or different. For example, the two sustained-release layers can be designed with different flavors, different release rates, and carry different active ingredients (such as a fast-release layer + a slow-release layer) to achieve more complex and superior product functions. To better explain this solution, the following example uses the first and second sustained-release layers having the same components.

[0044] In one embodiment, the first sustained-release layer includes a filler and a binder; it also includes at least one of a second anti-adhesive, a second plasticizer, a pH adjuster, and a pigment. This composition satisfies both the functional requirements of a lozenge and ensures structural stability.

[0045] The fillers include: primary fillers and secondary fillers. Primary fillers are used to ensure the main structure of the lozenge; secondary fillers are used to enhance moisture retention, improve softness, and enhance taste.

[0046] The adhesive includes at least one of the following: gel adhesive and ionic adhesive. Gel adhesives form a viscous gel layer after hydration, which can control the rate of water penetration and diffusion of active substances, and is the key to achieving sustained release; ionic adhesives can undergo ionic cross-linking with cations such as calcium in saliva, enhance gel strength, provide a unique locking sensation and stronger water retention, and thus assist in sustained release.

[0047] The second plasticizer is used to retain the moisture in the slow-release layer, prevent the film from becoming too brittle and cracking, and significantly increase the flexibility, elasticity, and smoothness of the lozenge after curing.

[0048] Flavoring agents include at least one of flavorings, sweeteners, cooling agents, salting agents, and acidifiers. They can mask residual off-flavors, thereby improving the taste.

[0049] pH adjusters are used to regulate the pH value of sustained-release systems to ensure the stability and optimal absorption rate of certain APIs (such as nicotine).

[0050] Pigments are used to give lozenges a more appealing color; synthetic or natural pigments can be selected depending on the product's positioning.

[0051] The second anti-sticking agent is used to reduce material stickiness and improve flowability.

[0052] In one embodiment, the main filler includes at least one of the following: isomaltitol, sorbitol, mannitol, xylitol, erythritol, maltitol, lactose, microcrystalline cellulose, pregelatinized starch, and dextrin.

[0053] In one embodiment, the excipient includes at least one of the following: polydextrose, resistant dextrin, inulin, and oat fiber.

[0054] In one embodiment, the gel adhesive includes at least one of the following: hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carrageenan, xanthan gum, guar gum, gellan gum, and povidone.

[0055] In one embodiment, the ionic binder includes at least one of the following: sodium alginate, potassium alginate, and methoxylated pectin with a degree of esterification of less than 50%.

[0056] Pectin is an acidic polysaccharide naturally found in plant cell walls, with its main chain being polygalacturonic acid. Some of its carboxyl groups are esterified with methanol to form methyl ester groups. The industry classifies pectin according to its degree of methoxylation (DE value, i.e., degree of esterification). High-methoxyl pectin: DE value > 50%, with methylated carboxyl groups accounting for more than half of the molecule; Low-methoxyl pectin: DE value < 50%, with methylated carboxyl groups accounting for less than half.

[0057] In one embodiment, the second plasticizer includes at least one of the following: glycerol, propylene glycol, and sorbitol.

[0058] In one embodiment, the active substance includes at least one of nicotine and nicotine derivatives. For example, nicotine includes natural nicotine and / or synthetic nicotine, and nicotine derivatives include one or more of 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.

[0059] Non-covalently bonded nicotine includes nicotine lactate, nicotine malate, nicotine salicylate, nicotine cyclodextrin encapsulated complex, nicotine hydrochloride, nicotine dihydrochloride, nicotine tartrate, nicotine tartrate dihydrate, nicotine sulfate, nicotine zinc chloride, and nicotine benzoate. Nicotine derivatives also include nicotine with substituents, such as 6-methylnicotine, 6-methylnicotine lactate, 6-methylnicotine malate, 6-methylnicotine salicylate, 6-methylnicotine cyclodextrin encapsulated complex, 6-methylnicotine hydrochloride, 6-methylnicotine dihydrochloride, 6-methylnicotine tartrate, 6-methylnicotine tartrate dihydrate, 6-methylnicotine sulfate, 6-methylnicotine zinc chloride, and one or more mixtures of 6-methylnicotine benzoate.

[0060] Active substances can also be plant extracts (such as curcumin and ginsenosides), vitamins, minerals, probiotics, etc.

[0061] In one embodiment, the flavoring includes at least one of the following: bergamot flavoring, eucalyptus flavoring, citrus flavoring, lemon flavoring, peppermint flavoring, peppermint flavoring, menthol, licorice flavoring, wintergreen flavoring, tobacco flavoring, coffee flavoring, vanilla flavoring, lime flavoring, apple flavoring, peach flavoring, mango flavoring, cherry flavoring, blueberry flavoring, strawberry flavoring, cola flavoring, cinnamon flavoring, pandan flavoring, and watermelon flavoring.

[0062] In one embodiment, the sweetener includes at least one of the following: xylitol, sorbitol, mannitol, iodine, lactitol, maltitol, isomaltitol, hydrogenated starch hydrolysate, erythritol, maltotriol, aspartame, acesulfame potassium, sodium saccharin, sucralose, neotame, cyclamate, alitane, steviol glycosides, arabinitol, and monk fruit sweetener.

[0063] In one embodiment, the cooling agent includes at least one of the following: menthol, menthol derivatives, WS-3, and WS-23.

[0064] In one embodiment, the saltiness agent includes at least one of the following: sodium chloride, monosodium glutamate, and amino acid salt.

[0065] In one embodiment, the acidulant includes at least one of the following: citric acid, malic acid, fumaric acid, and phosphoric acid.

[0066] In one embodiment, the pH adjuster includes at least one of the following: citric acid, malic acid, tartaric acid, fumaric acid, phosphoric acid, and sodium bicarbonate.

[0067] In one embodiment, the pigment includes at least one of the following: titanium dioxide, β-carotene, brilliant blue, allura red, carmine, curcumin, and caramel color.

[0068] In one embodiment, the second anti-sticking agent includes at least one of the following: magnesium stearate, silica, and talc, used to reduce material stickiness and improve flowability.

[0069] In one embodiment, the first sustained-release layer comprises, by weight parts: 40 to 65 parts of a primary filler, 5 to 15 parts of a secondary filler, 5 to 15 parts of a gel binder, 0.5 to 5 parts of an ionic binder, 3 to 12 parts of a second plasticizer, 0.1 to 10 parts of an active substance, 0.55 to 16.5 parts of a flavoring agent, 0.1 to 2 parts of a pH adjuster, 0.001 to 0.5 parts of a pigment, and 0.5 to 2 parts of a second anti-adhesive agent. This formulation satisfies both the sustained-release performance of the active substance and ensures structural stability.

[0070] Specifically, by weight, the first sustained-release layer comprises: 50 to 60 parts of primary filler, 8 to 11 parts of secondary filler, 7 to 12 parts of gel binder, 2 to 4 parts of ionic binder, 6 to 9 parts of secondary plasticizer, 5 to 7 parts of active substance, 5 to 10 parts of flavoring agent, 1 to 1.2 parts of pH adjuster, 0.2 to 0.3 parts of pigment, and 1 to 1.6 parts of secondary anti-sticking agent.

[0071] In one embodiment, the second sustained-release layer comprises, by weight parts: 40 to 65 parts of a primary filler, 5 to 15 parts of a secondary filler, 5 to 15 parts of a gel binder, 0.5 to 5 parts of an ionic binder, 3 to 12 parts of a second plasticizer, 0.1 to 10 parts of an active substance, 0.55 to 16.5 parts of a flavoring agent, 0.1 to 2 parts of a pH adjuster, 0.001 to 0.5 parts of a pigment, and 0.5 to 2 parts of a second anti-sticking agent.

[0072] Specifically, by weight, the second sustained-release layer comprises: 50 to 60 parts of primary filler, 8 to 11 parts of secondary filler, 7 to 12 parts of gel binder, 2 to 4 parts of ionic binder, 6 to 9 parts of secondary plasticizer, 5 to 7 parts of active substance, 5 to 10 parts of flavoring agent, 1 to 1.2 parts of pH adjuster, 0.2 to 0.3 parts of pigment, and 1 to 1.6 parts of secondary anti-sticking agent.

[0073] In one embodiment, the thickness of the thermosensitive phase change layer is 10μm to 30μm, which ensures that the thermosensitive phase change layer forms a continuous and dense barrier state at the production temperature.

[0074] Specifically, the thickness of the thermosensitive phase change layer is 10 μm, 20 μm, 30 μm or any value within the above range.

[0075] In one embodiment, the thickness of the first sustained-release layer is 200mm to 400mm. This thickness avoids the burst release of active substances caused by excessive thinness, resulting in a short duration of action, while also preventing excessive thickness from causing slow release and insufficient effectiveness. This achieves uniform, long-lasting, and controllable release of active substances.

[0076] Specifically, the thickness of the first sustained-release layer is 200 mm, 300 mm, 400 mm, or any value within the above range.

[0077] In one embodiment, the thickness of the second sustained-release layer is 200mm to 400mm. This thickness avoids the burst release of active substances caused by excessive thinness, resulting in a short action time, while also preventing the release from being too slow and the effect from being insufficient due to excessive thickness. This achieves uniform, long-lasting, and controllable release of active substances.

[0078] Specifically, the thickness of the second sustained-release layer is 200 mm, 300 mm, 400 mm, or any value within the above range.

[0079] This application also provides a method for preparing a lozenge, the method comprising: 1. Preparation of thermosensitive phase change slurry and slow-release slurry.

[0080] 1.1 Dissolve the components of the thermosensitive phase change layer in water and mix to obtain the thermosensitive phase change slurry.

[0081] The thermosensitive phase change layer comprises, by mass parts: 60 to 80 parts of phase change host, 5 to 15 parts of phase change modifier, 0.5 to 2 parts of film-forming agent, 0 to 5 parts of first plasticizer, and 0 to 2 parts of first anti-adhesion agent.

[0082] 1.2 Dissolve the components of the slow-release layer in water and mix to obtain a thermosensitive phase change slurry.

[0083] The sustained-release layer, by weight, comprises: 40 to 65 parts of primary filler, 5 to 15 parts of secondary filler, 5 to 15 parts of gel binder, 0.5 to 5 parts of ionic binder, 3 to 12 parts of secondary plasticizer, 0.1 to 10 parts of active substance, 0.55 to 16.5 parts of flavoring agent, 0.1 to 2 parts of pH adjuster, 0.001 to 0.5 parts of pigment, and 0.5 to 2 parts of secondary anti-sticking agent.

[0084] 2. Thermosensitive phase change slurry and slow-release slurry are sequentially coated on the surface of the substrate, and the oral tablets are obtained after curing and cooling.

[0085] 2.1 A thermosensitive phase change slurry is coated on one side of a nonwoven fabric, and a first thermosensitive phase change layer is formed by a first drying process, wherein the nonwoven fabric is the substrate.

[0086] The coating amount of the thermosensitive phase change slurry is 15g / m² to 25g / m².

[0087] Specifically, the coating amount of the thermosensitive phase change slurry is 15 g / m², 20 g / m², 25 g / m², or any value within the above range.

[0088] The parameters for the first drying process include: temperature of 40℃~50℃ and time of 1min~5min.

[0089] Specifically, the temperature for the first drying is 40°C, 45°C, 50°C or any value within the above range, and the time is 1 min, 3 min, 5 min or any value within the above range.

[0090] 2.2. A slow-release slurry is coated on the first thermosensitive phase change layer, and the first slow-release layer is formed by a second drying process.

[0091] The coating thickness of the slow-release slurry is 200mm~400mm.

[0092] Specifically, the coating thickness of the slow-release slurry is 200mm, 300mm, 400mm or any value within the above range.

[0093] The parameters for the second drying process include: a temperature of 70℃~85℃ and a time of 2min~8min.

[0094] Specifically, the temperature for the second drying is 70°C, 75°C, 80°C, 85°C or any value within the above range; the time is 2 min, 4 min, 6 min, 8 min or any value within the above range.

[0095] 2.3 Cover the first support layer on the first sustained-release layer, and obtain the initial lozenge after the first pressing and the first curing. Finally, place the initial lozenge at room temperature to obtain the lozenge.

[0096] The pressure of the first pressing is 0.2MPa~0.3MPa.

[0097] Specifically, the pressure of the first pressing is 0.2MPa, 0.25MPa, 0.3MPa or any value within the above range.

[0098] The parameters for the first curing process include: temperature of 85℃~100℃ and time of 2min~8min.

[0099] Specifically, the first curing temperature is 85℃, 95℃, 100℃ or any value within the above range; the time is 2min, 4min, 6min, 8min or any value within the above range.

[0100] When the initial lozenge is placed at room temperature, the thermosensitive phase change layer is activated, causing it to change from a dense state during production to a porous state, providing migration channels for the active components.

[0101] In one embodiment, the lozenge has a five-layer structure, therefore, after obtaining the initial lozenge, it further includes: 2.4. A thermosensitive phase change slurry is coated on the other side of the nonwoven fabric, and a second thermosensitive phase change layer is formed by a third drying process.

[0102] The coating amount of the thermosensitive phase change slurry is 15g / m² to 25g / m².

[0103] Specifically, the coating amount of the thermosensitive phase change slurry is 15 g / m², 20 g / m², 25 g / m², or any value within the above range.

[0104] The parameters for the third drying process include: temperature of 40℃~50℃ and time of 1min~5min.

[0105] Specifically, the temperature for the third drying is 40°C, 45°C, 50°C or any value within the above range, and the time is 1 min, 3 min, 5 min or any value within the above range.

[0106] 2.5. Apply a slow-release slurry onto the second thermosensitive phase change layer, and form the second slow-release layer through a fourth drying process.

[0107] The coating thickness of the slow-release slurry is 200mm~400mm.

[0108] Specifically, the coating thickness of the slow-release slurry is 200mm, 300mm, 400mm or any value within the above range.

[0109] The parameters for the fourth drying process include: temperature of 70℃~85℃ and time of 2min~8min.

[0110] Specifically, the fourth drying temperature is 70℃, 75℃, 80℃, 85℃ or any value within the above range; the time is 2min, 4min, 6min, 8min or any value within the above range.

[0111] 2.3 Cover the second support layer on the second sustained-release layer, and obtain the initial lozenge after the second pressing and second curing. Finally, cool the initial lozenge to obtain the lozenge.

[0112] The pressure of the second pressing is 0.2MPa~0.3MPa.

[0113] Specifically, the pressure for the second pressing is 0.2 MPa, 0.25 MPa, 0.3 MPa, or any value within the above range.

[0114] The parameters for the second curing process include: temperature of 85℃~100℃ and time of 2min~8min.

[0115] Specifically, the second curing temperature is 85℃, 95℃, 100℃ or any value within the above range; the time is 2min, 4min, 6min, 8min or any value within the above range.

[0116] Cooling can be done in a cooling device or by placing the tablet directly at room temperature, as long as the temperature of the lozenge is ≤40℃.

[0117] To better understand this solution, examples and comparative models are also provided below.

[0118] Example 1 Methods for preparing lozenges include: 1. Dissolve the components of the thermosensitive phase change layer in water and mix to obtain the thermosensitive phase change slurry.

[0119] The thermosensitive phase change slurry includes: 75 parts of the phase change host polyethylene glycol 4000, 5 parts of the phase change modifier polyethylene glycol 8000, 0.5 parts of the film-forming agent hydroxypropyl methylcellulose, and 19.5 parts of water.

[0120] 2. Dissolve the components of the slow-release layer in water and mix to obtain a thermosensitive phase change slurry.

[0121] The thermosensitive phase change slurry includes: 40 parts of isomaltitol as the main filler, 10 parts of polydextrose as the auxiliary filler, 12 parts of hydroxypropyl methylcellulose as the gel binder, 2 parts of sodium alginate as the ionic binder, 8 parts of glycerin as the second plasticizer, 1.44 parts of nicotine as the active substance, 6.7 parts of flavoring agent (6 parts of peppermint flavoring + 0.30 parts of WS-23 + 0.40 parts of sucralose), 0.6 parts of citric acid as the pH adjuster, and 19.26 parts of water.

[0122] 3. A thermosensitive phase change slurry is coated on one side of the nonwoven fabric, and a first thermosensitive phase change layer is formed through a first drying process.

[0123] The coating amount of the thermosensitive phase change slurry is 20 g / m².

[0124] The parameters for the first drying process include: a temperature of 50°C and a time of 5 minutes.

[0125] 4. A slow-release slurry is coated on the first thermosensitive phase change layer, and the first slow-release layer is formed by a second drying process.

[0126] The coating thickness of the slow-release slurry is 200mm.

[0127] The parameters for the second drying process include: a temperature of 70°C and a time of 8 minutes.

[0128] 5. Cover the first support layer on the first sustained-release layer, and obtain the initial lozenge after the first pressing and the first curing. Finally, place the initial lozenge at room temperature to obtain the lozenge.

[0129] The pressure for the first pressing is 0.3 MPa.

[0130] The parameters for the first curing step include: temperature of 100℃ and time of 2 minutes.

[0131] 6. A thermosensitive phase change slurry is coated on the other side of the nonwoven fabric, and a second thermosensitive phase change layer is formed by a third drying process.

[0132] The coating amount of the thermosensitive phase change slurry is 20 g / m².

[0133] The parameters for the third drying process include: a temperature of 50°C and a time of 5 minutes.

[0134] 7. Apply a slow-release slurry onto the second thermosensitive phase change layer, and form the second slow-release layer through a fourth drying process.

[0135] The coating thickness of the slow-release slurry is 200mm.

[0136] The parameters for the fourth drying step include: a temperature of 70°C and a time of 8 minutes.

[0137] 8. Cover the second support layer on the second sustained-release layer, and obtain the initial lozenge through the second pressing and the second curing. Finally, place the initial lozenge at room temperature to obtain the lozenge.

[0138] The pressure for the second pressing is 0.3 MPa.

[0139] The parameters for the second curing process include: a temperature of 100°C and a time of 2 minutes.

[0140] 9. Placing the initial lozenge at room temperature will activate the thermosensitive phase change layer, transforming it from a dense state during production to a porous state, providing migration channels for the active ingredients.

[0141] Comparative Example 1 The difference from Example 1 is that there is no thermosensitive phase change layer.

[0142] The following in vitro dissolution experiments were conducted on the lozenges of Example 1 and Comparative Example 1. Specifically, the experiments were conducted in a simulated oral environment at 37 degrees Celsius. Five parallel tests (n=5) were performed on each type of lozenge sample. Samples were taken at eight key time points: 1, 3, 5, 10, 20, 30, 45, and 60 minutes. The dissolution ratio (dissolution ratio = nicotine content at each time point / total nicotine content) was calculated, and the cumulative release concentration of nicotine was determined by high performance liquid chromatography (HPLC). The data are shown in Table 1.

[0143] Table 1. Data for Examples and Comparative Cases

[0144] As can be seen from the data in Table 1, the lozenge of Example 1 has intelligent triggering, rapid onset of action, and sustained release performance, which comprehensively surpasses traditional processes. Specifically: Improved onset speed: Within 1 minute, Example 1 released 2.5 mg / g of nicotine, while the conventional method released only 0.2 mg / g. The effective concentration of Example 1 is 12.5 times that of the control group. This indicates that the intelligent phase change membrane of Example 1 can respond to saliva and open a highly efficient release channel the moment it enters the mouth, achieving an instant gratification within 1 minute, perfectly solving the problem of delayed onset of action caused by physical barriers in traditional hydrophobic fabric solutions.

[0145] Improved Total Release and Bioavailability: During the entire 60-minute release cycle, Example 1 achieved a total release of 11.3 mg / g, approaching the theoretical total (12 mg / g), demonstrating extremely high bioavailability. In contrast, the comparative example, due to the adsorption and retention effect of the hydrophobic cloth, ultimately released only 10.52 mg / g, resulting in a significant waste of active material. This means that, with the same feed amount, Example 1 can provide a more efficient product.

[0146] Enhanced ability to continuously release: such as Figure 1 As shown, the release curve of Example 1 exhibits an ideal rapid rise-plateau maintenance characteristic. After 30 minutes, the release concentration stabilizes at a high plateau of 9.2 mg / g to 10.7 mg / g, providing a solid pharmacological basis for a sustained 40-minute experience. In contrast, the release curve of the comparative example remains consistently low and slow, failing to reach the high concentration plateau of this invention throughout the process, resulting in a weak and short-lived user experience.

[0147] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "illustrative embodiment," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of this application. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0148] Although embodiments of this application have been shown and described, those skilled in the art will understand that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of this application, the scope of which is defined by the claims and their equivalents.

Claims

1. A lozenge, characterized in that, The lozenge comprises: a first sustained-release layer, a barrier layer, and a second sustained-release layer, which are stacked in sequence; Wherein, the first sustained-release layer includes active substances and / or flavoring agents; the second sustained-release layer includes active substances and / or flavoring agents; the barrier layer includes a matrix and a thermosensitive phase change layer formed on both sides of the matrix, and when the ambient temperature is ≤40℃, the thermosensitive phase change layer changes from a hydrophobic state to a hydrophilic state; the matrix is ​​a liquid-permeable matrix.

2. The lozenge according to claim 1, characterized in that, The thermosensitive phase change layer includes: a phase change host, a phase change modifier, and a film-forming agent.

3. The lozenge according to claim 2, characterized in that, The thermosensitive phase change layer further includes at least one of the following: a first plasticizer and a first anti-adhesion agent.

4. The lozenge according to claim 3, characterized in that, The phase change host includes at least one of the following: polyethylene glycol derivative, poly(N-isopropylacrylamide)-based hydrogel; And / or, the phase change modifier includes at least one of the following: polyethylene glycol 1500, polyethylene glycol 6000, polyethylene glycol 8000, acrylamide, N-tert-butylacrylamide; And / or, the film-forming agent includes at least one of the following: hydroxypropyl methylcellulose, polyvinylpyrrolidone; And / or, the first plasticizer comprises at least one of the following: glycerol, propylene glycol, sorbitol; And / or, the first anti-adhesive agent comprises at least one of the following: magnesium stearate, silica, talc; And / or, by mass parts, the thermosensitive phase change layer comprises: 60 to 80 parts of phase change host, 5 to 15 parts of phase change modifier, 0.5 to 2 parts of film-forming agent, 0 to 5 parts of first plasticizer, and 0 to 2 parts of first anti-adhesion agent.

5. The lozenge according to claim 1, characterized in that, The thickness of the thermosensitive phase change layer is 10μm~30μm; And / or, the thickness of the first sustained-release layer is 200mm~400mm; And / or, the thickness of the second sustained-release layer is 200mm~400mm; And / or, the thermosensitive phase change layer is a porous structure formed by through-holes, wherein the pores D 50 Its size ranges from 50 nm to 20 μm, and its porosity is 50% to 85%.

6. The lozenge according to claim 1, characterized in that, The lozenge further includes a support layer; the support layer is disposed on the side of the first sustained-release layer and / or the second sustained-release layer away from the barrier layer.

7. The lozenge according to claim 6, characterized in that, The support layer includes a first support layer and a second support layer; the first support layer is disposed on the side of the first sustained-release layer opposite to the barrier layer, and the second support layer is disposed on the side of the second sustained-release layer opposite to the barrier layer. Wherein, at least one of the first support layer and the second support layer is a liquid-permeable layer.

8. The lozenge according to any one of claims 1 to 7, characterized in that, The first sustained-release layer includes a filler, an adhesive, and at least one of a second anti-adhesive, a second plasticizer, a pH adjuster, and a pigment; And / or, the second sustained-release layer includes a filler and an adhesive, and further includes at least one of a second anti-adhesive, a second plasticizer, a pH adjuster, and a pigment.

9. The lozenge according to claim 8, characterized in that, The filler includes: a primary filler and a secondary filler; And / or, the adhesive includes at least one of the following: gel adhesive, ionic adhesive.

10. The lozenge according to claim 9, characterized in that, By weight, the first sustained-release layer comprises: 40 to 65 parts of main filler, 5 to 15 parts of auxiliary filler, 5 to 15 parts of gel binder, 0.5 to 5 parts of ionic binder, 3 to 12 parts of second plasticizer, 0.1 to 10 parts of active substance, 0.55 to 16.5 parts of flavoring agent, 0.1 to 2 parts of pH adjuster, 0.001 to 0.5 parts of pigment, and 0.5 to 2 parts of second anti-sticking agent; And / or, by weight, the second sustained-release layer comprises: 40 to 65 parts of primary filler, 5 to 15 parts of secondary filler, 5 to 15 parts of gel binder, 0.5 to 5 parts of ionic binder, 3 to 12 parts of second plasticizer, 0.1 to 10 parts of active substance, 0.55 to 16.5 parts of flavoring agent, 0.1 to 2 parts of pH adjuster, 0.001 to 0.5 parts of pigment, and 0.5 to 2 parts of second anti-sticking agent; And / or, the main filler includes at least one of the following: isomaltitol, sorbitol, mannitol, xylitol, erythritol, maltitol, lactose, microcrystalline cellulose, pregelatinized starch, dextrin; And / or, the excipients include at least one of the following: polydextrose, resistant dextrin, inulin, oat fiber; And / or, the gel adhesive comprises at least one of the following: hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carrageenan, xanthan gum, guar gum, gellan gum, or povidone; And / or, the ionic binder comprises at least one of the following: sodium alginate, potassium alginate, or methoxylated pectin with a degree of esterification of less than 50%. And / or, the second plasticizer comprises at least one of the following: glycerol, propylene glycol, sorbitol; And / or, the active substance includes at least one of the following: nicotine, nicotine salts, plant extracts, vitamins, minerals, and probiotics; And / or, the flavoring agent includes at least one of the following: flavoring, sweetener, cooling agent, acidulant, and salting agent; And / or, the pH adjuster includes at least one of the following: citric acid, malic acid, tartaric acid, fumaric acid, phosphoric acid, sodium bicarbonate; And / or, the pigment includes at least one of the following: titanium dioxide, β-carotene, brilliant blue, allura red, carmine, curcumin, caramel color; And / or, the second anti-adhesive includes at least one of the following: magnesium stearate, silica, talc.

Images