Dissolving oral adhesion tablets

Abstract

Disclosed is a dissolvable oral adhesion tablet for sustained release, wherein the tablet contains an active ingredient, and the tablet is a multilayer tablet comprising a first layer and a second layer, the first layer being a mucosal adhesion layer comprising a natural gum mucosal adhesion agent, and the second layer comprising at least one sugar alcohol.

Description

Technical Field

[0001] The]]The present invention relates to an eluting buccal tablet for sustained release as described in the claims.]]

Background Art

[0002] Some tablets are known to provide sustained release of some active ingredients. However, such tablets can be inconvenient for users due to the slow dissolution of the tablets. Furthermore, slow dissolution can lead to unintentional swallowing of the active ingredient, which can further result in an unpleasant experience for the user. In addition to being an unpleasant experience, unintentional swallowing hinders the buccal absorption of the active ingredient, and thus a decrease in efficacy and undesirable side effects such as bad taste, throat irritation and / or coughing can be expected.]]

[0003] At the same time, due to the slow dissolution, it is desirable to provide a tablet with a good mouthfeel; otherwise, the user may stop using it or may expel the tablet prematurely due to discomfort.]]

[0004] The object of the present invention is to overcome the drawbacks of the prior art.]]

Summary of the Invention

[0005] The present invention relates to an eluting buccal tablet for sustained release,]] wherein the tablet contains an active ingredient,]] the tablet is a multilayer tablet comprising a first layer and a second layer,]] the first layer is a mucoadhesive layer containing a natural gum mucoadhesive, and the second layer contains at least one sugar alcohol.]]

[0006] The advantage of the present invention is that a desirable sustained delivery of the active ingredient can be obtained.]]

[0007] Specifically, by selectively including a natural gum mucosal adhesive in the first layer, the tablet can adhere to the mucosal surface of the gums or the lip after being inserted between the gums and the lip, thereby immobilizing the tablet. This immobilization facilitates sustained release, as the tablet is inserted into a low-exposure area of ​​the oral cavity with low salivary flow and minimal interaction with the tongue. This significantly extends the disintegration time of the tablet. On the other hand, adhesion to either the gums or the lip promotes a significant improvement in oral comfort for the user, because simultaneous adhesion to both the gums and lip is perceived as unpleasant, for example, because it prevents the gums and lip from moving freely relative to each other. Based on this insight, the tablet comprises both a first layer, which is a mucosal adhesive layer, and a second layer containing a sugar alcohol.

[0008] Furthermore, by using natural gum mucosal adhesives, the release profile of the active ingredient can be modified as desired.

[0009] A further advantage of the present invention may be the desirable mouthfeel and release, which are facilitated by the use of natural gum mucosal adhesives.

[0010] A further advantage of the present invention is that the natural gum mucosal adhesive during swallowing may provide health benefits in the intestinal system, for example, due to its prebiotic properties.

[0011] It should be noted that the intended use of the tablet is to insert it between the gums and lips, preferably with the first layer facing the gums or lips, thereby allowing the first layer to adhere to the gums or lips and facilitate the fixation of the tablet. Therefore, the layered structure of the tablet having a mucosal adhesive layer on one side facilitates this advantageous use.

[0012] In this context, the term "gum" refers to the gingiva, that is, the mucous membrane tissue that covers the teeth. It should be noted that the term "gum" should not be confused with the term "natural gum mucosal adhesive."

[0013] According to an advantageous embodiment of the present invention, the tablet adheres to the gums.

[0014] In a preferred embodiment of the present invention, the tablet adheres to the gums. In this embodiment, the first layer adheres to the gums.

[0015] In this context, the term "dissolving oral adhesion tablet" refers to an orally administered tablet that can adhere to the mucosal surface of the oral cavity, particularly the gums or lips, preferably the gums, by a mucosal adhesion layer. The tablet is generally dissolvable in saliva or water, in the sense that its main component is water-soluble. To avoid any ambiguity, it should be noted that the tablets according to the present invention are non-chewing gum tablets, meaning they do not contain a gum base and are not chewing gum.

[0016] As used herein, the term “elute” refers to the process by which a solid substance enters a solvent (oral saliva) and produces a solution. Unless otherwise stated, elution means the complete dissolution of the compound in question.

[0017] In this context, it should be noted that the term “sustained release” refers to the release of an active ingredient over a prolonged period, particularly over a period of at least 30 minutes, e.g., at least 45 minutes, e.g., at least 1 hour. It should be noted that sustained release may also be called controlled release or extended release. According to embodiments of the present invention, tablets are adapted for the release of an active ingredient over prolonged periods, such as 1 to 10 hours, 2 to 8 hours, or 3 to 6 hours. Sustained release, i.e., sustained release of the active ingredient, may be achieved by the tablet being an oral adhesion tablet, i.e., by a tablet that adheres to the mucosal surface of the oral cavity, particularly the gums or lips, preferably the gums, making it suitable for providing sustained release of the active ingredient over a prolonged period. In embodiments of the present invention, sustained release should not be understood as limiting, and in such embodiments, the present invention relates to an eluting oral adhesion tablet containing an active ingredient, wherein the tablet is a multilayer tablet comprising a first layer and a second layer, the first layer being a mucosal adhesion layer comprising a natural gum mucosal adhesion agent, and the second layer comprising at least one sugar alcohol.

[0018] In this context, the term “mucosal adhesive layer” refers to a first layer containing a natural gum mucosal adhesive, thereby allowing the first layer to adhere to the mucosal surface of the oral cavity, particularly the gums or lips, preferably the gums. It should be noted that, due to the tablet being inserted between the gums and lips, the mucosal adhesive effect should facilitate adhesion despite any ongoing squeezing or constricting effects from the gums and lips, so that the tablet remains substantially fixed during the user’s normal activities, including eating and drinking. Therefore, the terms “mucosal adhesive layer” and “first layer” may be used interchangeably. It should be further noted that the first layer is at least partially exposed so as to be in contact with the oral mucosal surface, such as the gums or lips, to facilitate adhesion thereto.

[0019] In this context, it should be noted that the term "second layer" refers to a layer that does not provide the adhesive effect of the first layer. Therefore, the second layer may act as a non-adhesive layer to allow the tablet to adhere specifically to only one side, thereby allowing the gums and lips to move freely relative to each other.

[0020] As used herein, the term “natural gum mucosal adhesive” refers to a biocompatible polysaccharide polymer obtained from non-marine plant resources (i.e., non-marine plants), seaweed, or by bacterial fermentation, which exhibits adhesion upon contact with mucosal surfaces. Therefore, natural gum mucosal adhesives can facilitate the delivery and sustained release of active ingredients. Consequently, synthetic polymers such as polyvinylpyrrolidone are not included.

[0021] While not bound by theory, it is intended that natural gums, due to their ability to form ions, may facilitate the release of active ingredients, particularly nonionic active ingredients. Note that the terms "natural gum mucosal adhesive" and "natural gum" may be used interchangeably.

[0022] As used herein, the term "active ingredient" refers to a compound having a physiological effect, including but not limited to nootropic agents, sleep aids, bactericides, dietary supplements, nutraceuticals, active pharmaceutical ingredients, etc. On the other hand, active ingredients are not considered to cover, for example, sweeteners and flavoring agents. Similarly, simple organic and inorganic acids, bases, and buffers included as pH regulators are not considered active ingredients within the scope of the present invention.

[0023] According to an advantageous embodiment of the present invention, the tablet is a compressed tablet.

[0024] In this context, the term "compressed" refers to being formed by compression from a plurality of particles and / or granules using a tablet forming machine such as a rotary press. The tablet of the above embodiment is a compressed tablet formed by compressing at least a first powdery composition and a second powdery composition to obtain first and second layers respectively. Typically, the tablet can be produced in a multi-step process by first compressing the first or second layer and then sequentially compressing the other layer to obtain a multi-layer tablet. When the tablet is a two-layer tablet, it can be produced in a two-step process by compressing the first or second layer and then compressing the other layer to obtain a two-layer tablet.

[0025] In an embodiment of the present invention, the first layer is compressed.

[0026] In an embodiment of the present invention, the second layer is compressed.

[0027] According to an advantageous embodiment of the present invention, the tablet is composed of a plurality of compressed particles.

[0028] In an embodiment of the present invention, the first layer is composed of a plurality of compressed particles.

[0029] In an embodiment of the present invention, the second layer is composed of a plurality of compressed particles.

[0030] According to an advantageous embodiment of the present invention, the first layer and the second layer are fused by compression.

[0031] In embodiments of the present invention, the active ingredient comprises one or more active ingredients selected from the group consisting of aspirin, caffeine, cannabinoids, cetirizine, chlorpheniramine maleate, dextromethorphan, dimenhydrinate, diphenhydramine, doxylamine succinate, famotidine, fexofenadine, levocetirizine, loratadine, meclizine, melatonin, omeprazole, phenylephrine, pseudoephedrine, theanine, and any combination thereof.

[0032] In embodiments of the present invention, the active ingredient comprises one or more active ingredients selected from the group consisting of aspirin, caffeine, cannabinoids, cetirizine, chlorpheniramine maleate, dextromethorphan, dimenhydrinate, diphenhydramine, doxylamine succinate, famotidine, fexofenadine, levocetirizine, loratadine, meclizine, melatonin, omeprazole, phenylephrine, pseudoephedrine, theanine, paraxanthine, probiotics, and any combination thereof.

[0033] In embodiments of the present invention, the active ingredient is selected from the group consisting of aspirin, caffeine, cannabinoids, cetirizine, chlorpheniramine maleate, dextromethorphan, dimenhydrinate, diphenhydramine, doxylamine succinate, famotidine, fexofenadine, levocetirizine, loratadine, meclizine, melatonin, omeprazole, phenylephrine, pseudoephedrine, theanine, and any combination thereof.

[0034] In embodiments of the present invention, the active ingredient is selected from the group consisting of aspirin, caffeine, cannabinoids, cetirizine, chlorpheniramine maleate, dextromethorphan, dimenhydrinate, diphenhydramine, doxylamine succinate, famotidine, fexofenadine, levocetirizine, loratadine, meclizine, melatonin, omeprazole, phenylephrine, pseudoephedrine, theanine, paraxanthine, probiotics, and any combination thereof.

[0035] In embodiments of the present invention, the active ingredient comprises one or more active pharmaceutical ingredients selected from the group consisting of diphenhydramine, cetirizine, loratadine, chlorpheniramine maleate, levocetirizine, meclizine, dextromethorphan, phenylephrine, famotidine, omeprazole, doxylamine succinate, melatonin, and any combinations and mixtures thereof.

[0036] In some embodiments of the present invention, the active ingredient comprises diphenhydramine. In some embodiments of the present invention, the active ingredient comprises cetirizine. In some embodiments of the present invention, the active ingredient comprises loratadine. In some embodiments of the present invention, the active ingredient comprises chlorpheniramine maleate. In some embodiments of the present invention, the active ingredient comprises chlorpheniramine levocetirizine. In some embodiments of the present invention, the active ingredient comprises meclizine. In some embodiments of the present invention, the active ingredient comprises dextromethorphan. In some embodiments of the present invention, the active ingredient comprises phenylephrine. In some embodiments of the present invention, the active ingredient comprises famotidine. In some embodiments of the present invention, the active ingredient comprises omeprazole. In some embodiments of the present invention, the active ingredient comprises doxylamine succinate. In some embodiments of the present invention, the active ingredient comprises melatonin. In some embodiments of the present invention, the active ingredient comprises paraxanthine. In some embodiments of the present invention, the active ingredient comprises one or more probiotics.

[0037] In some embodiments of the present invention, the active ingredient comprises one or more antihistamine components selected from the group consisting of diphenhydramine, cetirizine, loratadine, chlorpheniramine maleate, levocetirizine, and any combinations and mixtures thereof.

[0038] In some embodiments of the present invention, the active ingredient comprises one or more antitussive components, including dextromethorphan.

[0039] In some embodiments of the present invention, the active ingredient comprises one or more motion sickness medication components, including meclizine.

[0040] In some embodiments of the present invention, the active ingredient comprises one or more decongestant components, including phenylephrine.

[0041] In embodiments of the present invention, the active ingredient comprises one or more antiheartburn agents, such as one or more antiheartburn agents selected from the group consisting of famotidine, omeprazole, and any combination thereof.

[0042] In some embodiments of the present invention, the active ingredient comprises one or more antisomnia agents, such as one or more antisomnia agents selected from the group consisting of doxylamine succinate, melatonin, and any combination and mixture thereof. Antisomnia agents may also be called sleep aids.

[0043] In embodiments of the present invention, the active ingredient comprises one or more selected from the group consisting of diphenhydramine, fexofenadine, dimenhydrinate, pseudoephedrine, aspirin, theanine, and any combination thereof.

[0044] In embodiments of the present invention, the active ingredient includes an antihistamine selected from the group consisting of diphenhydramine, cetirizine, fexofenadine, loratadine, chlorpheniramine maleate, levocetirizine, and any combination thereof.

[0045] In embodiments of the present invention, the active ingredient includes motion sickness medications selected from the group consisting of dimenhydrinate, meclizine, and any combination thereof.

[0046] In embodiments of the present invention, the active ingredient includes an antitussive agent such as dextromethorphan.

[0047] In embodiments of the present invention, the active ingredient includes a decongestant such as pseudoephedrine.

[0048] In embodiments of the present invention, the active ingredient includes an analgesic such as aspirin.

[0049] In embodiments of the present invention, the active ingredient includes a stimulant such as a stimulant selected from the group consisting of caffeine, theanine, and any combination thereof. The terms theanine and L-theanine may be used interchangeably.

[0050] In embodiments of the present invention, the active ingredient includes a stimulant selected from the group consisting of caffeine, theanine, paraxanthine, and any combination thereof. The terms theanine and L-theanine may be used interchangeably.

[0051] In embodiments of the present invention, the active ingredient includes nootropic agents selected from the group consisting of caffeine, theanine, creatine, bacopa, ginseng (panax ginseng), ginkgo biloba, and any combination thereof.

[0052] In embodiments of the present invention, the active ingredient includes nootropic agents such as caffeine, theanine, creatine, bacopa, ginseng, ginkgo biloba, paraxanthine, and any combination thereof.

[0053] In embodiments of the present invention, the active ingredient includes health supplements and / or nutritional supplements.

[0054] According to an advantageous embodiment of the present invention, the active ingredient comprises an orally absorbable active ingredient.

[0055] According to an advantageous embodiment of the present invention, the active ingredient includes an active pharmaceutical ingredient.

[0056] In some embodiments of the present invention, the active ingredient comprises one or more active ingredients present in an amount of 2 to 30 mg in the oral tablet. In some embodiments of the present invention, the active ingredient comprises one or more active ingredients present in an amount of 2 to 20 mg in the oral tablet. In some embodiments of the present invention, the active ingredient comprises one or more active ingredients present in an amount of 2 to 10 mg in the oral tablet.

[0057] According to an advantageous embodiment of the present invention, the active ingredient is selected from the group consisting of caffeine, melatonin, nicotine, and a combination of nicotine and caffeine.

[0058] According to embodiments of the present invention, the active ingredient is selected from the group consisting of caffeine, melatonin, nicotine, paraxanthine, and a combination of nicotine and caffeine.

[0059] According to an advantageous embodiment of the present invention, the active ingredient is selected from the group consisting of caffeine, nicotine, and any combination thereof.

[0060] According to embodiments of the present invention, the active ingredient is selected from the group consisting of caffeine, nicotine, paraxanthine, and any combination thereof.

[0061] According to an advantageous embodiment of the present invention, the active ingredient comprises melatonin.

[0062] In embodiments of the present invention, the active ingredient is melatonin.

[0063] According to an advantageous embodiment of the present invention, the active ingredient includes caffeine.

[0064] When the active ingredient contains caffeine, especially when caffeine is present in the second layer, it may be advantageous to include the binder in the same layer as the caffeine.

[0065] In embodiments of the present invention, the active ingredient is caffeine.

[0066] According to an advantageous embodiment of the present invention, the active ingredient comprises nicotine.

[0067] In embodiments of the present invention, the active ingredient is nicotine.

[0068] In embodiments of the present invention, the active ingredients include nicotine and caffeine.

[0069] In embodiments of the present invention, the active ingredient includes a nicotine salt.

[0070] In embodiments of the present invention, the active ingredient comprises nicotine bicarbonate tartrate.

[0071] In embodiments of the present invention, the active ingredient includes nicotine bound to an ion exchange resin.

[0072] In embodiments of the present invention, the active ingredient is nicotine bound to an ion exchange resin.

[0073] In embodiments of the present invention, the active ingredient comprises nicotine bound to a polarilex resin. As used herein, the term "NPR" refers to nicotine bound to a polarilex resin.

[0074] According to an advantageous embodiment of the present invention, the active ingredient comprises paraxanthine.

[0075] In embodiments of the present invention, the active ingredient is paraxanthine.

[0076] According to an advantageous embodiment of the present invention, the tablet contains paraxane in an amount of at least 10 mg, for example, at least 20 mg.

[0077] In embodiments of the present invention, the tablets contain paraxane in an amount of 10 to 200 mg, for example, 20 to 100 mg.

[0078] According to an advantageous embodiment of the present invention, the active ingredient comprises one or more probiotics.

[0079] According to an advantageous embodiment of the present invention, the tablet contains one or more probiotics in an amount of at least 2 mg, for example, at least 5 mg.

[0080] In embodiments of the present invention, the tablet contains one or more probiotics in an amount of 2 to 100 mg, for example, 5 to 50 mg.

[0081] According to an advantageous embodiment of the present invention, the tablet contains caffeine in an amount of at least 10 mg, for example, at least 20 mg.

[0082] In embodiments of the present invention, the tablets contain caffeine in an amount of 10 to 200 mg, for example, 20 to 100 mg.

[0083] In embodiments of the present invention, the tablet contains the active ingredient in an amount of at least 10 mg, for example, at least 20 mg.

[0084] In embodiments of the present invention, the tablets contain the active ingredient in an amount of 10 to 200 mg, for example, 20 to 100 mg.

[0085] According to an advantageous embodiment of the present invention, the tablet contains melatonin in an amount of at least 0.5 mg, for example, at least 1 mg.

[0086] In embodiments of the present invention, the tablets contain melatonin in an amount of 0.5 to 20 mg, for example, 0.5 to 15 mg, for example, 1 to 10 mg.

[0087] According to an advantageous embodiment of the present invention, the tablet contains the active ingredient in an amount of at least 0.5 mg, for example, at least 1 mg.

[0088] In embodiments of the present invention, the tablets contain the active ingredient in an amount of 0.5 to 20 mg, for example, 0.5 to 15 mg, for example, 1 to 10 mg.

[0089] According to an advantageous embodiment of the present invention, the tablet contains nicotine in an amount of at least 0.5 mg, for example, at least 1 mg.

[0090] In embodiments of the present invention, the tablet contains nicotine in an amount of 0.5 to 10 mg, for example, 1 to 4 mg.

[0091] In embodiments of the present invention, the tablets contain the active ingredient in an amount of 0.5 to 10 mg, for example, 1 to 4 mg.

[0092] According to an advantageous embodiment of the present invention, the tablet has a weight ratio of the content of the active ingredient to the content of the sugar alcohol, where the weight ratio is at least 1:600, for example at least 1:400, for example at least 1:200, for example at least 1:100.

[0093] In embodiments of the present invention, the active ingredient is a cannabinoid, such as cannabichromene (CBC), cannabichromenic acid (CBCV), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerol propyl variant (CBGV), cannabicyclol (CBL), cannabinol (CBN), cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinol (THC), or tetrahydrocannabinolic acid. The product contains one or more cannabinoids selected from the group consisting of CBD (THCA), tetrahydrocannabivarin (THCV), tetrahydrocannabivarinic acid (THCV A), and any combination thereof. More preferably, one or more cannabinoids are CBD or THC, or contain both.

[0094] In embodiments of the present invention, the tablet contains cannabidiol (CBD). In embodiments of the present invention, the tablet contains tetrahydrocannabinol (THC).

[0095] In embodiments of the present invention, the tablet contains one or more cannabinoids in an amount of at least 5 mg, for example, at least 10 mg, for example, at least 20 mg.

[0096] In embodiments of the present invention, the tablet contains one or more cannabinoids in an amount of 5 to 200 mg, for example, 10 to 150 mg, for example, 10 to 100 mg, for example, 20 to 75 mg, for example, 20 to 50 mg.

[0097] According to an advantageous embodiment of the present invention, the active ingredient is contained in the first layer.

[0098] An advantage of the above embodiment may be that it can minimize or avoid the undesirable roughness of the second layer, which can otherwise be avoided. This may be particularly advantageous when the second layer contains an active ingredient, especially when the active ingredient in the second layer has relatively low solubility in water, such as caffeine.

[0099] According to an advantageous embodiment of the present invention, the active ingredient is contained in the second layer.

[0100] An advantage of the above embodiment may be that local irritation can be avoided or minimized by avoiding direct and fixed contact between the active ingredient layer and the oral mucosa. When the active ingredient comes into contact with the oral mucosa, local irritation can occur, especially if the contact is prolonged, as is the case when the active ingredient is contained in a mucosal adhesive layer that adheres to the oral mucosa. Nevertheless, while minimizing such local irritation, the tablets of the above embodiment can significantly benefit from being fixed between the gums and lips, as the dissolution of the tablet remains in a relatively isolated environment between the gums and lips, in contrast to being placed on the tongue, for example.

[0101] In embodiments of the present invention, the first layer contains at least a portion of the active ingredient.

[0102] In embodiments of the present invention, the second layer contains at least a portion of the active ingredient.

[0103] In embodiments of the present invention, the first layer contains a portion of the active ingredient, and the second layer contains a portion of the active ingredient.

[0104] In embodiments of the present invention, the active ingredient comprises a first portion and a second portion, the first layer comprising the first portion and the second layer comprising the second portion.

[0105] According to an advantageous embodiment of the present invention, the tablet comprises one or more further active ingredients.

[0106] According to an advantageous embodiment of the present invention, the tablet has a dissolution time of at least 1 hour.

[0107] According to embodiments of the present invention, the tablets have a dissolution time of at least 30 minutes, for example, at least 45 minutes.

[0108] According to an advantageous embodiment of the present invention, the tablet has a dissolution time of 10 hours or less, for example, 8 hours or less, for example, 6 hours or less.

[0109] In embodiments of the present invention, the tablets have a dissolution time of 1 to 10 hours, for example, 2 to 8 hours, or for example, 3 to 6 hours.

[0110] In embodiments of the present invention, the tablets have a dissolution time of 30 minutes to 10 hours, for example 45 minutes to 8 hours, for example 1 to 6 hours.

[0111] In embodiments of the present invention, the first layer has an elution time of at least 30 minutes, for example, at least 45 minutes, for example, at least 1 hour.

[0112] In embodiments of the present invention, the first layer has an elution time of 10 hours or less.

[0113] In embodiments of the present invention, the first layer has an elution time of 30 minutes to 10 hours, for example 45 minutes to 10 hours, for example 1 to 10 hours, for example 2 to 8 hours.

[0114] In embodiments of the present invention, the second layer has an elution time of at least 30 minutes, for example, at least 45 minutes, for example, at least 1 hour.

[0115] In embodiments of the present invention, the second layer has an elution time of 10 hours or less.

[0116] In embodiments of the present invention, the second layer has an elution time of 30 minutes to 10 hours, for example 45 minutes to 10 hours, for example 1 to 10 hours, for example 2 to 8 hours.

[0117] In the embodiments of the present invention, the elution time in the above embodiment is the in vitro elution time.

[0118] In vitro dissolution time is measured according to European Pharmacopeia 9.0, section 2.9.1, Disintegration of tablets and capsules.

[0119] In the embodiments of the present invention, the elution time in the above embodiment is the in vivo elution time.

[0120] According to embodiments of the present invention, the in vivo dissolution time was measured by at least six trained evaluators, who refrained from eating or drinking for at least 30 minutes before the start of any test, weighed the tablets, and placed the first tablet in the mouth between the upper lip and gums so that it was facing the gums, and the in vivo dissolution time was recorded as the point at which the dissolution of the tablet was substantially complete.

[0121] According to embodiments of the present invention, the in vivo elution time was measured according to Example 4.

[0122] According to an advantageous embodiment of the present invention, the tablet contains a pH adjusting agent, such as an alkaline pH adjusting agent, such as an alkaline buffering agent.

[0123] The use of pH adjusters, particularly alkaline pH adjusters, can be especially advantageous when the active ingredient contains nicotine.

[0124] In embodiments of the present invention, the first layer does not contain a pH adjusting agent.

[0125] In embodiments of the present invention, the pH adjusting agent in the first layer is an alkaline pH adjusting agent, such as an alkaline buffering agent.

[0126] In embodiments of the present invention, the second layer does not contain a pH adjusting agent.

[0127] In embodiments of the present invention, the pH adjusting agent in the second layer is an alkaline pH adjusting agent, such as an alkaline buffering agent.

[0128] In embodiments of the present invention, the pH adjusting agent is a buffering agent, such as an alkaline buffering agent.

[0129] In embodiments of the present invention, the tablet contains a pH adjusting agent in an amount of at least 0.2% by weight of the tablet, for example, at least 0.5% by weight of the tablet, for example, at least 1% by weight of the tablet, for example, at least 2% by weight of the tablet.

[0130] In embodiments of the present invention, the tablet contains a pH adjusting agent in an amount of at least 0.2 to 10% by weight of the tablet, for example, at least 0.5 to 8% by weight of the tablet, for example, at least 1 to 6% by weight of the tablet, for example, at least 2 to 4% by weight of the tablet.

[0131] In embodiments of the present invention, the pH adjusting agent is included in the first layer.

[0132] In embodiments of the present invention, the pH adjusting agent is included in the second layer.

[0133] In embodiments of the present invention, the pH adjusting agent includes a pH adjusting agent selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, trometamol, amino acids, dialkali hydrogen phosphate, trialkali phosphate, or any combination thereof.

[0134] In embodiments of the present invention, the pH adjusting agent is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, trometamol, amino acids, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, or any combination thereof.

[0135] In embodiments of the present invention, the pH adjusting agent is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, or any combination thereof.

[0136] In embodiments of the present invention, the pH adjusting agent contains or is sodium carbonate.

[0137] In embodiments of the present invention, the pH adjusting agent includes trometamol.

[0138] In the context of this invention, the term trometamol refers to (tris(hydroxymethyl)aminomethane), and is sometimes also called Tris buffer.

[0139] In embodiments of the present invention, the pH adjusting agent includes an amino acid.

[0140] According to an advantageous embodiment of the present invention, the natural gum mucosal adhesive includes a natural gum mucosal adhesive selected from the group consisting of xanthan gum, konjac gum, tara gum, gellan gum, locust bean gum, gum arabic, alginate, pullulan, tragacanth gum, karaya gum, fenugreek gum, cassia gum, carrageenan, agar, alginic acid and its salts, and any combination thereof.

[0141] According to embodiments of the present invention, the natural gum mucosal adhesive is selected from the group consisting of xanthan gum, konjac gum, tara gum, gellan gum, locust bean gum, gum arabic, alginate, pullulan, tragacanth gum, karaya gum, fenugreek gum, cassia gum, carrageenan, agar, alginic acid and its salts, and any combination thereof.

[0142] According to embodiments of the present invention, the natural gum mucosal adhesive includes a natural gum mucosal adhesive selected from the group consisting of chitosan, pectin, guar gum, xanthan gum, konjac gum, tara gum, gellan gum, locust bean gum, gum arabic, alginate, pullulan, tragacanth gum, karaya gum, fenugreek gum, cassia gum, carrageenan, agar, alginic acid and its salts, and any combination thereof.

[0143] According to embodiments of the present invention, the natural gum mucosal adhesive is selected from the group consisting of chitosan, pectin, guar gum, xanthan gum, konjac gum, tara gum, gellan gum, locust bean gum, gum arabic, alginate, pullulan, tragacanth gum, karaya gum, fenugreek gum, cassia gum, carrageenan, agar, alginic acid and its salts, and any combination thereof.

[0144] According to embodiments of the present invention, the natural gum mucosal adhesive includes a natural gum mucosal adhesive selected from the group consisting of chitosan, pectin, xanthan gum, konjac gum, tara gum, locust bean gum, gum arabic, pullulan, fenugreek gum, cassia gum, carrageenan, alginic acid and its salts, and any combination thereof.

[0145] According to embodiments of the present invention, the natural gum mucosal adhesive is selected from the group consisting of chitosan, pectin, xanthan gum, konjac gum, tara gum, locust bean gum, gum arabic, pullulan, fenugreek gum, cassia gum, carrageenan, alginic acid and its salts, and any combination thereof.

[0146] According to embodiments of the present invention, the natural gum mucosal adhesive includes a natural gum mucosal adhesive selected from the group consisting of chitosan, pectin, locust bean gum, guar gum, karaya gum, tragacanth, gum arabic, and any combination thereof.

[0147] According to embodiments of the present invention, the natural gum mucosal adhesive is selected from the group consisting of chitosan, pectin, locust bean gum, guar gum, karaya gum, tragacanth, gum arabic, and any combination thereof.

[0148] In embodiments of the present invention, the natural gum mucosal adhesive includes a natural gum mucosal adhesive selected from the group consisting of xanthan gum, konjac gum, tara gum, gellan gum, locust bean gum, gum arabic, pullulan, tragacanth gum, karaya gum, fenugreek gum, cassia gum, and any combination thereof.

[0149] In embodiments of the present invention, the natural gum mucosal adhesive is selected from the group consisting of xanthan gum, konjac gum, tara gum, gellan gum, locust bean gum, gum arabic, pullulan, tragacanth gum, karaya gum, fenugreek gum, cassia gum, and any combination thereof.

[0150] In embodiments of the present invention, the natural gum includes at least one natural gum selected from the group consisting of gum arabic, guar gum, locust bean gum, gellan gum, xanthan gum, and any combination thereof.

[0151] In embodiments of the present invention, the natural gum is selected from the group consisting of gum arabic, guar gum, locust bean gum, gellan gum, xanthan gum, and any combination thereof.

[0152] According to an advantageous embodiment of the present invention, the natural gum comprises xanthan gum and / or gum arabic.

[0153] In embodiments of the present invention, the natural gum consists of xanthan gum and / or gum arabic.

[0154] According to an advantageous embodiment of the present invention, the natural gum mucosal adhesive comprises gum arabic.

[0155] In embodiments of the present invention, the natural gum mucosal adhesive consists of gum arabic.

[0156] According to an advantageous embodiment of the present invention, the natural gum mucosal adhesive comprises xanthan gum.

[0157] In embodiments of the present invention, the natural gum mucosal adhesive is made of xanthan gum.

[0158] According to an advantageous embodiment of the present invention, the first layer comprises a natural gum mucosal adhesive in an amount of at least 40% by weight of the tablet, for example, at least 50% by weight of the first layer, for example, at least 55% by weight of the first layer, for example, at least 60% by weight of the first layer.

[0159] According to an advantageous embodiment of the present invention, the first layer comprises a natural gum mucosal adhesive in an amount of at least 35% by weight of the first layer, for example, at least 40% by weight of the first layer, for example, at least 50% by weight of the first layer, for example, at least 55% by weight of the first layer, for example, at least 60% by weight of the first layer.

[0160] An advantage of the above embodiment may be that the tablet adheres efficiently to the gums.

[0161] According to an advantageous embodiment of the present invention, the first layer contains a natural gum mucosal adhesive in an amount of 90% by weight or less of the first layer, for example, 85% by weight or less of the first layer, for example, 80% by weight or less of the first layer.

[0162] An advantage of the above embodiment may be that it facilitates the final dissolution of the first layer. While a sufficiently high content of natural gum mucosal adhesive may be desirable to ensure the tablet adheres to the gums, if the content of natural gum mucosal adhesive is too high, the first layer may have an undesirably long dissolution time that far exceeds the usage time desired by the user. Also, if the content of natural gum mucosal adhesive is too high, in some embodiments, the tablet may perform poorly in terms of the delivery of the active ingredient.

[0163] In embodiments of the present invention, the first layer contains a natural gum mucosal adhesive in an amount of 40-90% by weight of the tablet, for example, 50-90% by weight of the first layer, for example, 55-85% by weight of the first layer, for example, 60-80% by weight of the first layer.

[0164] In embodiments of the present invention, the first layer contains a natural gum mucosal adhesive in an amount of 35-90% by weight of the first layer, for example, 40-90% by weight of the first layer, for example, 50-90% by weight of the first layer, for example, 55-85% by weight of the first layer, for example, 60-80% by weight of the first layer.

[0165] According to an advantageous embodiment of the present invention, the first layer comprises gum arabic in an amount of at least 35% by weight of the first layer, for example, at least 40% by weight of the first layer, for example, at least 50% by weight of the first layer, for example, at least 55% by weight of the first layer, for example, at least 60% by weight of the first layer.

[0166] In embodiments of the present invention, the first layer contains gum arabic in an amount of 35-90% by weight of the first layer, for example, 40-90% by weight of the first layer, for example, 50-90% by weight of the first layer, for example, 55-85% by weight of the first layer, for example, 60-80% by weight of the first layer.

[0167] According to an advantageous embodiment of the present invention, the second layer comprises less than 20% by weight of a mucosal adhesive, for example less than 10% by weight of a mucosal adhesive, for example less than 5% by weight of a mucosal adhesive, for example less than 1% by weight of a mucosal adhesive, for example less than 0.2% by weight of a mucosal adhesive, and substantially no mucosal adhesive, for example.

[0168] According to embodiments of the present invention, the second layer contains 0% to less than 20% by weight of a mucosal adhesive, for example, 0.01% to less than 10% by weight of a mucosal adhesive, for example, 0.02% to less than 5% by weight of a mucosal adhesive, for example, 0.05% to less than 1% by weight of a mucosal adhesive, for example, 0.1% to less than 0.2% by weight of a mucosal adhesive, and substantially contains no mucosal adhesive, for example.

[0169] In embodiments of the present invention, the second layer comprises a mucosal adhesive selected from xanthan gum, alginates, and combinations thereof.

[0170] It should be noted that if the second layer contains a relatively small amount of a specific mucosal adhesive such as xanthan gum and / or alginate, as in the above embodiment, the mucosal adhesive can also be considered an elution modifier that slows down the elution of the second layer and / or the release of the active ingredient from the second layer.

[0171] According to an advantageous embodiment of the present invention, the second layer does not contain a mucosal adhesive.

[0172] In embodiments of the present invention, the second layer is provided as a non-adhesive layer due to its low content or absence of a mucosal adhesive.

[0173] In embodiments of the present invention, the second layer contains less than 20% by weight of a natural gum mucosal adhesive, for example less than 10% by weight of a natural gum mucosal adhesive, for example less than 5% by weight of a natural gum mucosal adhesive, for example less than 1% by weight of a natural gum mucosal adhesive, for example less than 0.2% by weight of a natural gum mucosal adhesive, and substantially does not contain a natural gum mucosal adhesive.

[0174] In embodiments of the present invention, the second layer contains 0% to less than 20% by weight of a natural gum mucosal adhesive, for example 0.01% to less than 10% by weight of a natural gum mucosal adhesive, for example 0.02% to less than 5% by weight of a natural gum mucosal adhesive, for example 0.05% to less than 1% by weight of a natural gum mucosal adhesive, for example 0.1% to less than 0.2% by weight of a natural gum mucosal adhesive, and substantially contains no natural gum mucosal adhesive, for example.

[0175] In embodiments of the present invention, the second layer does not contain a natural gum mucosal adhesive.

[0176] In embodiments of the present invention, the first layer contains a substance selected from the group consisting of gelatin, chitosan, carboxymethylcellulose and its sodium salt, hydroxypropylmethylcellulose, polyvinyl alcohol, gellan gum, agar, agarose, and combinations thereof, in an amount of less than 20% by weight of the first layer, for example, less than 10% by weight of the first layer, for example, less than 5% by weight of the first layer, for example, less than 2% by weight of the first layer, for example, less than 1% by weight of the first layer, for example, 0% by weight of the first layer.

[0177] In embodiments of the present invention, the first layer does not contain any substance selected from the group consisting of gelatin, chitosan, carboxymethylcellulose and its sodium salt, hydroxypropylmethylcellulose, polyvinyl alcohol, gellan gum, agar, agarose, and combinations thereof.

[0178] In embodiments of the present invention, the first layer contains in less than 20% by weight of the first layer, for example, less than 10% by weight of the first layer, for example, less than 5% by weight of the first layer, for example, less than 2% by weight of the first layer, for example, less than 1% by weight of the first layer, for example, 0% by weight of the first layer, a substance selected from the group consisting of gelatin, pectin, starch, cellulose derivatives, agarose, chitosan and chitosan derivatives, hyaluronic acid, polyvinylpyrrolidone (PVP), polyacrylate, polyhydroxyethyl methacrylate (PHEMA), polyvinyl alcohol (PVA), lectin, thiolated polymer, polyethylene glycol (PEG), sodium alginate, guar gum, kariya gum, gellan gum, agar, letene, tragacanth, and combinations thereof.

[0179] In embodiments of the present invention, the first layer does not contain any substance selected from the group consisting of gelatin, pectin, starch, cellulose derivatives, agarose, chitosan and chitosan derivatives, hyaluronic acid, polyvinylpyrrolidone (PVP), polyacrylate, polyhydroxymethacrylate (PHEMA), polyvinyl alcohol (PVA), lectin, thiolated polymer, polyethylene glycol (PEG), sodium alginate, guar gum, kariya gum, gellan gum, agar, letene, tragacanth, and combinations thereof.

[0180] In embodiments of the present invention, the first layer does not contain hydroxypropyl methylcellulose.

[0181] In embodiments of the present invention, the first layer does not contain carboxymethylcellulose.

[0182] In embodiments of the present invention, the first layer does not contain a cellulose derivative.

[0183] In embodiments of the present invention, the tablets do not contain polyvinylpyrrolidone.

[0184] According to an advantageous embodiment of the present invention, the first layer contains a sugar alcohol in an amount of at least 5% by weight of the first layer, for example, at least 8% by weight of the first layer, for example, at least 10% by weight of the first layer, for example, at least 15% by weight of the first layer.

[0185] In embodiments of the present invention, at least one sugar alcohol of the first layer comprises the sugar alcohol in an amount of 5 to 50% by weight of the first layer, for example, 8 to 40% by weight of the first layer, for example, 10 to 30% by weight of the first layer, for example, at least 15 to 30% by weight of the first layer.

[0186] According to an advantageous embodiment of the present invention, the first layer contains a sugar alcohol in an amount of 50% by weight or less of the first layer, for example, 40% by weight or less of the first layer, for example, 30% by weight or less of the first layer.

[0187] According to an advantageous embodiment of the present invention, the second layer contains a sugar alcohol in an amount of at least 10% by weight of the second layer, for example, at least 20% by weight of the second layer, for example, at least 30% by weight of the second layer, for example, at least 40% by weight of the second layer.

[0188] In embodiments of the present invention, the second layer contains a sugar alcohol in an amount of 10 to 90% by weight of the second layer, for example, 20 to 80% by weight of the second layer, for example, 30 to 70% by weight of the second layer, for example, 40 to 60% by weight of the second layer.

[0189] According to an advantageous embodiment of the present invention, at least one sugar alcohol in the first layer comprises a sugar alcohol selected from the group consisting of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol, and any combination thereof.

[0190] In embodiments of the present invention, at least one sugar alcohol in the first layer is selected from the group consisting of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol, and any combination thereof.

[0191] According to an advantageous embodiment of the present invention, at least one sugar alcohol in the first layer comprises a sugar alcohol selected from the group consisting of xylitol, maltitol, erythritol, isomalt, sorbitol, lactitol, and any combination thereof.

[0192] In embodiments of the present invention, at least one sugar alcohol in the first layer is selected from the group consisting of xylitol, maltitol, erythritol, isomalt, sorbitol, lactitol, and any combination thereof.

[0193] In embodiments of the present invention, at least one sugar alcohol in the first layer comprises sorbitol and / or xylitol, for example, sorbitol and / or xylitol.

[0194] In embodiments of the present invention, at least one sugar alcohol in the first layer comprises sorbitol, for example, sorbitol.

[0195] In embodiments of the present invention, at least one sugar alcohol in the first layer comprises xylitol, and is, for example, xylitol.

[0196] According to an advantageous embodiment of the present invention, at least one sugar alcohol in the second layer comprises a sugar alcohol selected from the group consisting of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol, and any combination thereof.

[0197] In embodiments of the present invention, at least one sugar alcohol in the second layer is selected from the group consisting of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol, and any combination thereof.

[0198] According to an advantageous embodiment of the present invention, at least one sugar alcohol in the second layer comprises a sugar alcohol selected from the group consisting of xylitol, maltitol, erythritol, isomalt, sorbitol, lactitol, and any combination thereof.

[0199] In embodiments of the present invention, at least one sugar alcohol of the second layer is selected from the group consisting of xylitol, maltitol, erythritol, isomalt, sorbitol, lactitol, and any combination thereof.

[0200] In embodiments of the present invention, at least one sugar alcohol in the second layer comprises sorbitol and / or xylitol, for example, sorbitol and / or xylitol.

[0201] In embodiments of the present invention, at least one sugar alcohol in the second layer comprises sorbitol, for example, sorbitol.

[0202] In embodiments of the present invention, at least one sugar alcohol in the second layer comprises xylitol, and is, for example, xylitol.

[0203] According to an advantageous embodiment of the present invention, the first layer contains a water-insoluble component in an amount of 30% by weight or less of the first layer, for example, 20% by weight or less of the first layer, for example, 10% by weight or less of the first layer.

[0204] According to embodiments of the present invention, the first layer contains a water-insoluble component in an amount of 0 to 30% by weight of the first layer, for example, 0.1 to 20% by weight of the first layer, or for example, 1 to 10% by weight of the first layer.

[0205] As used herein, the term "water solubility" refers to relatively high water solubility, for example, water solubility of more than 5 grams of a water-soluble composition or substance per 100 mL of water, measured at 25 degrees Celsius, atmospheric pressure, and pH 7.0. Here, atmospheric pressure refers to approximately 1 atmosphere, i.e., a pressure of 101,325 Pascals (Pa), or a pressure in the range of 90,000 to 110,000 Pascals (Pa).

[0206] When referring to a composition or substance that is "soluble," it means water-soluble unless otherwise specified.

[0207] Similarly, the term "water-insoluble" refers to relatively low water solubility, for example, less than 5 grams of a water-soluble composition or substance per 100 mL of water, measured at 25 degrees Celsius, atmospheric pressure, and pH 7.0. Here, atmospheric pressure refers to approximately 1 atmosphere, i.e., a pressure of 101,325 Pascals (Pa), or a pressure in the range of 90,000 to 110,000 Pascals (Pa).

[0208] When referring to a composition or substance that is "insoluble," it means insoluble in water unless otherwise specified.

[0209] According to an advantageous embodiment of the present invention, the first layer comprises one or more binders.

[0210] An advantage of the above embodiment may be that the elution rate of the first layer can be changed, that is, the binder can be used as an elution modifier. Thus, the elution rate of the first layer can be adjusted with respect to the elution rate of the second layer, preferably by bringing the elution rates of the first and second layers closer together. Therefore, in an advantageous embodiment of the present invention, the elution time of the first layer is between half the elution time of the second layer and twice the elution time of the second layer.

[0211] The binder may, advantageously, be included in the first layer, thereby achieving the desired tackiness during tablet formation.

[0212] As used herein, the term “binder” refers to a component that promotes tackiness to a powder composition during tablet manufacturing, thereby facilitating the formation of layers and thus facilitating the production of tablets having the desired mechanical strength. In the context of the present invention, natural gum mucoadhesives are not considered binders. In embodiments of the present invention, the binder may be selected from cellulose and cellulose derivatives.

[0213] According to an advantageous embodiment of the present invention, the first layer contains a binder in an amount of at least 1% by weight of the first layer, for example, at least 2% by weight of the first layer, for example, at least 4% by weight of the first layer.

[0214] According to embodiments of the present invention, the first layer contains a binder in an amount of 1 to 20% by weight of the first layer, for example, 2 to 15% by weight of the first layer, for example, 4 to 10% by weight of the first layer.

[0215] According to embodiments of the present invention, the binder for the first layer comprises at least one binder selected from the group consisting of cellulose, carboxymethylcellulose and its salts, ethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, and any combination thereof.

[0216] According to an advantageous embodiment of the present invention, the binder for the first layer comprises at least one binder selected from the group consisting of cellulose, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, and any combination thereof.

[0217] According to an advantageous embodiment of the present invention, the binder for the first layer comprises at least one binder selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, carboxymethylcellulose, and any combination thereof.

[0218] According to an advantageous embodiment of the present invention, the second layer comprises a binder.

[0219] An advantage of the above embodiment may be that the elution rate of the second layer can be changed, that is, the binder can be used as an elution modifier. Thus, the elution rate of the second layer can be adjusted with respect to the elution rate of the first layer, preferably by bringing the elution rates of the first and second layers closer together. Therefore, in an advantageous embodiment of the present invention, the elution time of the first layer is between half the elution time of the second layer and twice the elution time of the second layer.

[0220] Another advantage of the above embodiment is that the dissolution rates of the first and second layers can be synchronized, or at least substantially synchronized. In particular, if the second layer contains an active ingredient, synchronized or substantially synchronized dissolution can provide improved mouthfeel and taste masking.

[0221] The binder may, advantageously, be included in the second layer, thereby achieving the desired tackiness during tablet formation.

[0222] Another advantage of the above embodiment is that, particularly when the second layer contains an active ingredient with relatively low solubility in water, such as caffeine, a smoother, less rough surface of the second layer can be obtained during use of the tablet.

[0223] According to an advantageous embodiment of the present invention, the second layer contains a binder in an amount of at least 1% by weight of the second layer, for example, at least 2% by weight of the second layer, for example, at least 4% by weight of the second layer.

[0224] According to embodiments of the present invention, the second layer contains a binder in an amount of 1 to 20% by weight of the second layer, for example, 2 to 15% by weight of the first layer, for example, 4 to 10% by weight of the second layer.

[0225] According to embodiments of the present invention, the binder for the second layer comprises at least one binder selected from the group consisting of cellulose, carboxymethylcellulose and its salts, ethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, and any combination thereof.

[0226] According to an advantageous embodiment of the present invention, the binder for the second layer comprises at least one binder selected from the group consisting of cellulose, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, and any combination thereof.

[0227] According to an advantageous embodiment of the present invention, the binder for the second layer comprises at least one binder selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, carboxymethylcellulose, and any combination thereof.

[0228] According to an advantageous embodiment of the present invention, the first layer constitutes at least 10% by weight of the tablet, for example, at least 20% by weight of the tablet, for example, at least 30% by weight of the tablet.

[0229] In embodiments of the present invention, the first layer constitutes 10 to 60% by weight of the tablet, for example, at least 10 to 50% by weight of the tablet, for example, 20 to 30% by weight of the tablet.

[0230] According to an advantageous embodiment of the present invention, the second layer constitutes at least 40% by weight of the tablet, for example, at least 50% by weight of the tablet, for example, at least 60% by weight of the tablet.

[0231] In embodiments of the present invention, the second layer constitutes 40-90% by weight of the tablet, for example, at least 50-90% by weight of the tablet, for example, 70-80% by weight of the tablet.

[0232] According to an advantageous embodiment of the present invention, the first layer has a weight of at least 20 mg, for example, at least 40 mg, for example, at least 60 mg.

[0233] In embodiments of the present invention, the first layer has a weight of 20 to 200 mg, for example, 40 mg to 150 mg, for example, at least 60 to 100 mg.

[0234] According to an advantageous embodiment of the present invention, the second layer has a weight of at least 50 mg, for example, at least 75 mg, for example, at least 100 mg.

[0235] In embodiments of the present invention, the second layer has a weight of 50 to 400 mg, for example, 75 to 300 mg, for example, 100 to 200 mg.

[0236] According to an advantageous embodiment of the present invention, the tablet is a two-layer tablet.

[0237] In embodiments of the present invention, the tablet further comprises a third layer.

[0238] According to an advantageous embodiment of the present invention, the tablet is a three-layer tablet.

[0239] In embodiments of the present invention, the tablet includes a third layer which is a mucosal adhesive layer containing a mucosal adhesive.

[0240] In embodiments of the present invention, the tablet includes a third layer which is a mucosal adhesive layer containing a natural gum mucosal adhesive.

[0241] In embodiments of the present invention, the tablet includes a third layer which is an orally disintegrating tablet layer.

[0242] Therefore, in the above embodiment, the tablet includes a third layer which is an orally disintegrating tablet layer, also known as an ODT layer (ODT is an abbreviation for orally disintegrating tablet).

[0243] Please note that the orally disintegrating tablet layer is sometimes called the fast-disintegrating tablet layer or FDT layer.

[0244] In embodiments of the present invention, the disintegrant comprises or consists of a disintegrant selected from superdisintegrants such as crosslinked polymers, including crospovidone, croscarmellose, sodium starch glycolate, and any combination thereof.

[0245] In embodiments of the present invention, the tablet comprises a third layer, the third layer containing a disintegrant in an amount of 0.5 to 15% by weight of the third layer, for example, 1 to 10% by weight of the third layer.

[0246] In embodiments of the present invention, the tablet includes a plurality of layers, such as a third layer.

[0247] According to an advantageous embodiment of the present invention, the tablet has a weight of at least 100 mg, for example, at least 150 mg, for example, at least 200 mg.

[0248] According to an advantageous embodiment of the present invention, the tablet has a weight of 600 mg or less, for example, 500 mg or less, for example, 400 mg or less.

[0249] In embodiments of the present invention, the tablets have a weight of 100 to 600 mg, for example 150 to 500 mg, for example 200 to 400 mg, for example about 300 mg.

[0250] According to an advantageous embodiment of the present invention, the first layer has a surface that is at least partially substantially flat or concave.

[0251] In embodiments of the present invention, the first layer has a flat surface.

[0252] In embodiments of the present invention, the first layer has a concave surface.

[0253] According to an advantageous embodiment of the present invention, the first layer has a surface having at least one dimple.

[0254] In embodiments of the present invention, the first layer has a flat surface containing one or more dimples.

[0255] In embodiments of the present invention, the second layer has a convex surface.

[0256] According to an advantageous embodiment of the present invention, the tablet contains a flavoring agent.

[0257] Flavorings may be used to their advantage as a way to mask the taste of the active ingredients.

[0258] In embodiments of the present invention, the tablets contain a flavoring agent in an amount of at least 0.1% by weight of the tablet, for example, at least 0.2% by weight of the tablet.

[0259] In embodiments of the present invention, the tablets contain a flavoring agent in an amount of 0.1 to 15.0% by weight of the tablet, for example, 0.1 to 10.0% by weight of the tablet, for example, 0.1 to 5.0% by weight of the tablet, for example, 0.2 to 3.0% by weight of the tablet.

[0260] In embodiments of the present invention, the flavoring is contained in the first and second layers, that is, both layers contain the flavoring.

[0261] In embodiments of the present invention, the first layer contains a flavoring.

[0262] In an advantageous embodiment of the present invention, the flavoring is contained in the first layer.

[0263] According to an advantageous embodiment of the present invention, the first layer does not contain flavorings.

[0264] In embodiments of the present invention, the second layer contains a flavoring.

[0265] In an advantageous embodiment of the present invention, the flavoring is contained in the second layer.

[0266] In the embodiment of the future, the tablet has a first ratio of the weight percentage content of flavoring in the first layer to the weight percentage content of the active ingredient in the first layer, and a second ratio of the weight percentage content of flavoring in the second layer to the weight percentage content of the active ingredient in the second layer, wherein the first ratio is smaller than the second ratio.

[0267] In the embodiment of the Future, the tablet has a first ratio of the weight percentage content of the active ingredient in the first layer to the weight percentage content of the flavoring in the first layer, and a second ratio of the weight percentage content of the active ingredient in the second layer to the weight percentage content of the flavoring in the second layer, wherein the first ratio is greater than the second ratio.

[0268] In embodiments of the present invention, the tablets contain a high-intensity sweetener.

[0269] In embodiments of the present invention, the high-intensity sweetener is selected from sucralose, aspartam, acesulfame salts such as acesulfame potassium, alitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcone, thaumatin, monellin, stevioside, and any combination thereof.

[0270] In embodiments of the present invention, the first layer contains a high-intensity sweetener.

[0271] In embodiments of the present invention, the second layer contains a high-intensity sweetener.

[0272] According to an advantageous embodiment of the present invention, the second layer does not contain a foaming agent.

[0273] In embodiments of the present invention, the tablets do not contain an effervescent agent.

[0274] According to an advantageous embodiment of the present invention, the tablet has a maximum dimension of at least 5 mm.

[0275] According to an advantageous embodiment of the present invention, the first layer has an exposed surface area of ​​at least 0.2 cm².

[0276] According to an advantageous embodiment of the present invention, the second layer is not in contact with the oral mucosa surface that is in contact with the first layer during use.

[0277] For example, if the first layer is positioned to adhere to the gums (gingival mucosa), the second layer will not come into contact with the gums.

[0278] In embodiments of the present invention, the first layer and the second layer have the same width.

[0279] In embodiments of the present invention, the first layer has a first width, the second layer has a second width, and the first width is offset from the second width by 5% or less, for example, 2% or less.

[0280] In this embodiment of the present invention, the first width is the same as the second width.

[0281] In embodiments of the present invention, the first layer and the second layer have the same width.

[0282] According to an advantageous embodiment of the present invention, the tablet has a hardness of at least 20N, for example, at least 30N.

[0283] According to embodiments of the present invention, the tablets have a hardness of 20 to 200 N, for example, 30 to 150 N.

[0284] According to an advantageous embodiment of the present invention, the tablet has a water content of less than 2% by weight of the tablet, for example, less than 1% by weight of the tablet.

[0285] In embodiments of the present invention, the tablet has a water content of 0 to 2% by weight of the tablet, for example, 0.01 to 1% by weight of the tablet.

[0286] It should be noted that within the scope of the present invention, it is understood that neither the first layer nor the second layer contains any coating.

[0287] According to embodiments of the present invention, the coating can be added to the claimed tablet.

[0288] According to embodiments of the present invention, the tablets are free of coatings.

[0289] The present invention further relates to an oral adhesion tablet for sustained release, comprising at least a first layer which is a mucosal adhesion layer containing an active ingredient and a natural gum mucosal adhesion agent.

[0290] According to an advantageous embodiment of the present invention, the tablet is provided as a single-layer tablet.

[0291] In embodiments of the present invention, a tablet according to any one of claims 68 to 70 includes any of the features disclosed in any embodiment of this specification. [Modes for carrying out the invention]

[0292] As used herein, the term "nicotine" refers to free base nicotine; nicotine salts; nicotine bound to a carrier, such as nicotine bound to an ion exchange resin, nicotine bound to zeolite; nicotine bound to a fiber or a fine particle, nicotine bound to CaCO3, nicotine bound to a sugar alcohol; and any form of nicotine including mixtures thereof. As used herein, binding is to be understood as the ionic bonding, adsorption or absorption of nicotine onto the carrier depending on the type of the carrier.

[0293] When referring to the amount of nicotine in milligrams, this amount should be understood as the nicotine dosage, i.e., this amount refers to the amount of pure nicotine.

[0294] When referring to the amount of nicotine in weight percent, this amount should be understood as the actual amount of the nicotine source related to the designated term such as the first layer or a tablet. That is, a 75 mg first layer containing nicotine hydrogen tartrate in an amount of 4% by weight refers to a first layer containing 3 mg of nicotine hydrogen tartrate (i.e., 1 mg of pure nicotine).

[0295] Nicotine also includes nicotine not obtained from tobacco, often referred to as synthetic nicotine. Nicotine can be included in the first layer. In an embodiment, nicotine is included in the first layer but not in the second layer.

[0296] As used herein, the term "free base nicotine" refers to the non-protonated form of nicotine. Free base nicotine can be provided as a liquid or mixed with an amount of an ion exchange resin; a water-soluble composition such as a sugar alcohol or a water-soluble fiber; or a water-insoluble fiber; or modified calcium carbonate. Free base nicotine includes both free base nicotine extracted from tobacco and synthetically produced free base nicotine, but free base nicotine is not provided in the form of tobacco or powdered tobacco.

[0297] As used herein, the term "nicotine salt" refers to the ionized form of nicotine bound to a counterion.

[0298] As used herein, the term "NBT" refers to nicotine hydrogen tartrate and its hydrates.

[0299] As used herein, the terms "%" and "percent" refer to weight percent, unless otherwise specified.

[0300] As used herein, the term "release of the active ingredient" refers to the active ingredient becoming bioavailable, i.e., available for absorption through the mucosa in the oral cavity. Some forms of the active ingredient require dissolution to become bioavailable, while other forms may be readily absorbed into the body without dissolution. For example, for the active ingredient to be bioavailable, the matrix of the tablet should disintegrate. Some forms of the active ingredient require further release of the active ingredient, e.g., from a carrier, such as nicotine being released from a nicotine ion exchange resin such as nicotine polacrillex. Other forms of the active ingredient, such as active ingredient salts, may readily dissolve upon disintegration of the tablet matrix. Furthermore, some forms of the active ingredient may not require dissolution. This applies, for example, to nicotine free base, which is released upon disintegration of the solid dosage form matrix.

[0301] As used herein, the term "pH regulator" refers to a drug that actively adjusts and regulates the pH value of a solution to which the drug is added or will be added. In the context of the present invention, the pH regulator does not contain the active ingredient.

[0302] When referring to the amount of a component by terms such as "less than" or "below", this generally means that the specific component is either absent or present in amounts ranging from trace amounts to the specified maximum amount.

[0303] <统一格式错误,已修正为 As used herein, the term “flavoring” is understood to have the ordinary meaning of the term in the art. Flavorings include liquid and powder flavorings. Therefore, flavorings do not include sweeteners (such as sugars, sugar alcohols, and high-intensity sweeteners), nor acids that provide pure acidity / sourness, nor compounds that provide pure saltiness (e.g., NaCl) or pure bitterness. Flavorings may be natural or synthetic flavorings.

[0304] Typically, tablets may contain ingredients selected from the group consisting of fillers, flavorings, binders, disintegrants (hereinafter referred to as super-disintegrants), emulsifiers, antioxidants, pH adjusters (hereinafter referred to as alkaline and acidic pH adjusters), high-intensity sweeteners, colorants, lubricants, lubricants, or any combination thereof.

[0305] In embodiments of the present invention, the disintegrant comprises or consists of a disintegrant selected from the group consisting of crospovidone, croscarmellose, sodium starch glycolate, and any combination thereof.

[0306] In an advantageous embodiment of the present invention, the tablets contain a bulk sweetener as a filler component.

[0307] In an advantageous embodiment of the present invention, the first layer contains a bulk sweetener as a filler component.

[0308] In an advantageous embodiment of the present invention, the second layer contains a bulk sweetener as a filler component.

[0309] In an advantageous embodiment of the present invention, the first and second layers contain a bulk sweetener as a filler component.

[0310] The tablets may contain different bulk sweeteners in addition to at least one sugar alcohol. The bulk sweeteners include sugar sweeteners and / or non-sugar sweeteners.

[0311] Examples of sugar sweeteners include, but are not limited to, sugar-containing components such as sucrose, dextrose, maltose, saccharose, lactose, sorbose, dextrin, trehalose, D-tagatose, dried invert sugar, fructose, levulose, and galactose, either alone or in combination.

[0312] Examples of non-carbohydrate sweeteners generally include, but are not limited to, sugar alcohols (sometimes called polyols) such as xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol, and combinations thereof.

[0313] A combination of sugars and / or non-sugar sweeteners may be used in the tablets.

[0314] Bulk sweeteners may often support the flavor profile of the tablet.

[0315] In embodiments of the present invention, the bulk sweetener may be supplemented with other usable fillers, including, for example, magnesium carbonate and calcium carbonate, sodium sulfate, crushed limestone, silicate compounds such as magnesium silicate and aluminum silicate, kaolin and clay, aluminum oxide, silicon oxide, talc, titanium dioxide, monocalcium phosphate, dicalcium phosphate and tricalcium phosphate, fiber, plant fibers such as wheat fiber, oat fiber, and pea fiber, and combinations thereof.

[0316] In embodiments of the present invention, the filler includes an inorganic filler.

[0317] In embodiments of the present invention, the first layer includes an inorganic filler.

[0318] In embodiments of the present invention, the inorganic filler is selected from the group consisting of magnesium carbonate, calcium carbonate, magnesium hydroxide, and any combination thereof.

[0319] In an embodiment of the present invention, the inorganic filler contains calcium carbonate.

[0320] In an embodiment of the present invention, the inorganic filler is calcium carbonate.

[0321] In an embodiment of the present invention, the inorganic filler contains magnesium carbonate.

[0322] In an embodiment of the present invention, the inorganic filler is magnesium carbonate.

[0323] In an embodiment of the present invention, the inorganic filler contains magnesium hydroxide.

[0324] In an embodiment of the present invention, the inorganic filler is magnesium hydroxide.

[0325] In an embodiment of the present invention, the first layer contains the inorganic filler in an amount of at least 2% by weight, for example at least 4% by weight, of the first layer.

[0326] In an embodiment of the present invention, the first layer contains the inorganic filler in an amount of 2 to 20% by weight, for example 4 to 10% by weight, of the first layer.

[0327] In an embodiment of the present invention, the first layer contains a natural gum mucoadhesive and an inorganic filler in a weight ratio of the content of the natural gum mucoadhesive to the inorganic filler of 7:4 to 45, for example 9:5 to 35:2.

[0328] High-intensity artificial sweeteners can also be used in combination with the above-mentioned bulk sweeteners. For example, high-intensity sweeteners include, but are not limited to, sucralose, aspartame, salts of acesulfame, alitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcone, thaumatin, monellin, stevioside (a natural-strength sweetener), etc., either alone or in combination.

[0329] The level of artificial sweetener use varies considerably and depends on factors such as the potency and release rate of the sweetener, the desired sweetness of the product, the level and type of flavoring used, and cost considerations. Therefore, the effective concentration of artificial sweetener may vary from about 0.001% to about 8% by weight (e.g., about 0.02% to about 8% by weight).

[0330] In embodiments in which the tablets contain flavorings, different flavorings may be used.

[0331] Available flavors include, for example, almond, almond amaretto, apple, bavarian cream, black cherry, black sesame, blueberry, brown sugar, bubble gum, butterscotch, cappuccino, caramel, caramel cappuccino, cheesecake (graham crust), cinnamon red hot, cotton candy, circus cotton candy, clove, coconut, coffee, clear coffee, double chocolate, energy cow, graham cracker, grape juice, green apple, Hawaiian punch, honey, Jamaican rum, Kentucky bourbon, kiwi, koolada, lemon, lemon lime, tobacco, maple syrup, maraschino cherry, marshmallow, menthol, milk chocolate, mocha, Mountain Dew, peanut butter, pecan, peppermint, raspberry, banana, ripe banana, root beer, and RY. 4. Spearmint, Strawberry, Sweet Cream, Sweet Tart, Sweetener, Toasted Almond, Tobacco, Tobacco Blend, Vanilla Bean Ice Cream, Vanilla Cupcake, Vanilla Swirl, Vanillin, Waffle, Belgian Waffle, Watermelon, Whipped Cream, White Chocolate, Wintergreen, Amaretto, Banana Cream, Black Walnut, Blackberry, Butter, Butter Rum, Cherry, Chocolate Hazelnut, Cinnamon Roll, Cola, Crème de Menthol, Eggnog, English Toffee, Guava, Lemonade, Licorice, Maple, Mint Chocolate Chip, Orange Cream, Peach, Piña Colada, Pineapple, Plum, Pomegranate, Pralines and Cream, Red Licorice Flavors include licorice, saltwater toffee, strawberry banana, strawberry, kiwi, tropical punch, tutti frutti, vanilla, or any combination thereof.

[0332] According to embodiments of the present invention, the flavoring agent may be used to mask the taste of nicotine and / or the taste of an alkaline pH adjuster.

[0333] In embodiments of the present invention, the tablet contains a lubricant. Silicon dioxide may be used as the lubricant. Other lubricants suitable for use in tablets may also be used within the scope of the present invention.

[0334] In embodiments of the present invention, the tablets contain a lubricant. Magnesium stearate and / or sodium stearyl fumarate may be used as the lubricant. Other lubricants suitable for use in tablets may also be used within the scope of the present invention. [Examples]

[0335] Example 1: Preparation of tablets containing first and second layers. The composition of the second layer, i.e., the layer containing at least one sugar alcohol, is prepared by pouring about half of the sugar alcohol into a mixing bowl, followed by the other ingredients except the lubricant, and finally the remaining sugar alcohol. The ingredients are turned / mixed using a mixer (Turbula or Duma) at 49 rpm for 4 to 10 minutes.

[0336] Add the lubricant and mix the ingredients further at 49 rpm for 1-2 minutes.

[0337] The composition of the first layer, i.e., the mucosal adhesion layer, is prepared by pouring all components except the lubricant into a mixing bowl. The components are turned / mixed using a mixer (Turbula or Duma) at 49 rpm for 4 to 10 minutes.

[0338] Add the lubricant and mix the ingredients further at 49 rpm for 1-2 minutes.

[0339] The smoothed powder blend is sequentially transferred to the hopper of the tablet forming machine.

[0340] Next, the second layer is compressed with a compressive force of approximately 3-8 kN, and then the first layer is fused with the second layer by compressing it with a compressive force of approximately 20-30 kN. Unless otherwise specified, the punch used was a 12.00 mm, circular, shallow concave, B-tool.

[0341] The tablets are manufactured using laboratory-scale machinery, such as a RIVA Piccola tablet press. The tablet forming machine is operated by adjusting the filling depth and compression force so that the tablet weight and hardness meet acceptable standards. Pre-pressure may be included to avoid capping.

[0342] Example 1A: Preparation of tablets containing a single layer. The composition of the mucosal-adhering tablets is prepared by pouring about half of the sugar alcohol into a mixing bowl, then pouring the other ingredients, excluding the lubricant, into the mixing bowl, and finally pouring in the remaining sugar alcohol. The ingredients are turned / mixed using a mixer (Turbula or Duma) at 49 rpm for 4 to 10 minutes.

[0343] Add the lubricant and mix the ingredients further at 49 rpm for 1-2 minutes.

[0344] The smoothed powder blend is sequentially transferred to the hopper of the tablet forming machine.

[0345] Next, the tablets were compressed with a compressive force of approximately 20-30 kN. Unless otherwise specified, the punch used was a 12.00 mm, circular, shallow concave, B-tool.

[0346] The tablets are manufactured using laboratory-scale machinery, such as a RIVA Piccola tablet press. The tablet forming machine is operated by adjusting the filling depth and compression force so that the tablet weight and hardness meet acceptable standards. Pre-pressure may be included to avoid capping.

[0347] Example 1B: Preparation of a three-layer tablet, i.e., a tablet comprising a first, second, and third layer. The composition of the third layer is prepared by pouring all ingredients except the lubricant into a mixing bowl. The ingredients are turned / mixed using a mixer (Turbula or Duma) at 49 rpm for 4 to 10 minutes.

[0348] Add the lubricant and mix the ingredients further at 49 rpm for 1-2 minutes.

[0349] The composition of the second layer, i.e., the layer containing at least one sugar alcohol, is prepared by pouring about half of the sugar alcohol into a mixing bowl, followed by the other ingredients except the lubricant, and finally the remaining sugar alcohol. The ingredients are turned / mixed using a mixer (Turbula or Duma) at 49 rpm for 4 to 10 minutes.

[0350] Add the lubricant and mix the ingredients further at 49 rpm for 1-2 minutes.

[0351] The composition of the first layer, i.e., the mucosal adhesion layer, is prepared by pouring all components except the lubricant into a mixing bowl. The components are turned / mixed using a mixer (Turbula or Duma) at 49 rpm for 4 to 10 minutes.

[0352] Add the lubricant and mix the ingredients further at 49 rpm for 1-2 minutes.

[0353] The smoothed powder blend is sequentially transferred to the hopper of the tablet forming machine.

[0354] Next, the first layer is compressed with a compressive force of approximately 1-6 kN, and then the second layer is fused with the first layer by compressing it with a compressive force of approximately 2-8 kN. Finally, the third layer is fused with the second layer by compressing it with a compressive force of approximately 20-40 kN. Unless otherwise specified, the punch used was a 12.00 mm, circular, shallow concave, B-tool.

[0355] The tablets are manufactured using the PZ-TRE rotary tablet press available from B&D Italia, but other standard equipment for manufacturing three-layer tablets, such as the PTK PR3500 or Hata three-layer tablet press, can also be used. The tablet forming machine is operated by adjusting the filling depth and compression force so that the tablet weight and hardness meet acceptable standards. Pre-pressure may be included to avoid capping.

[0356] Example 2: Tablet composition Example 2A: Caffeine tablets 400 mg tablets were prepared, each having a second layer of 300 mg and a first layer of 100 mg. The tablets were prepared according to Example 1.

[0357] C1 is prepared as a 400 mg single-layer tablet, with the active ingredient provided as the first layer.

[0358] The punch used was a 12.00mm, circular, shallow concave punch, B-tool.

[0359] Next, the second layer is compressed with a compressive force of approximately 3-8 kN, and then the first layer is fused with the second layer by compressing it with a compressive force of approximately 20-30 kN.

[0360] [Table 1]

[0361] Preferred high-intensity sweeteners (HIS) may include, for example, sucralose, acesulfame potassium, and mixtures thereof. Other high-intensity sweeteners, such as aspartame, acesulfame salts including acesulfame potassium, alitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcone, thaumatin, monellin, and stevioside, may also be used individually or in combination within the scope of the present invention.

[0362] Fruit flavorings and mixtures thereof, menthol, peppermint and mixtures thereof may be used as flavorings in the above formulation. Other flavorings may also be used within the scope of the present invention.

[0363] In the above, MgSt (magnesium stearate) is used as a lubricant. Other lubricants, such as sodium stearyl fumarate, may also be used within the scope of the present invention.

[0364] Example 2B: Melatonin tablets and nicotine tablets 400 mg tablets were prepared, each having a second layer of 300 mg and a first layer of 100 mg. The tablets were prepared according to Example 1.

[0365] The punch used was a 12.00mm, circular, shallow concave punch, B-tool.

[0366] Next, the second layer is compressed with a compressive force of approximately 3-8 kN, and then the first layer is fused with the second layer by compressing it with a compressive force of approximately 20-30 kN.

[0367] [Table 2]

[0368] Sodium carbonate is used as an alkaline pH adjuster. Further usable alkaline pH adjusters include sodium bicarbonate, potassium carbonate, potassium bicarbonate, trometamol, amino acids, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, or any combination thereof.

[0369] The alternative components listed in relation to AT1 to AT6 in Table 1 may similarly be applied to AT11 to AT17.

[0370] Example 2C 300 mg tablets were prepared, each having a second layer of 200 mg and a first layer of 100 mg. The tablets were prepared according to Example 1.

[0371] The punch used was a 12.00mm, circular, shallow concave punch, B-tool.

[0372] Next, the second layer is compressed with a compressive force of approximately 3-8 kN, and then the first layer is fused with the second layer by compressing it with a compressive force of approximately 20-30 kN.

[0373] [Table 3]

[0374] The alternative components described in relation to AT1 to AT6 may similarly be applied to AT21 to AT26.

[0375] Example 2D 450 mg tablets were prepared, each having a second layer of 350 mg and a first layer of 100 mg. The tablets were prepared according to Example 1.

[0376] The punch used was a 12.00mm, circular, shallow concave punch, B-tool.

[0377] Next, the second layer is compressed with a compressive force of approximately 3-8 kN, and then the first layer is fused with the second layer by compressing it with a compressive force of approximately 20-30 kN.

[0378] [Table 4]

[0379] The alternative components described in relation to AT1 to AT6 may similarly be applied to AT31 to AT38.

[0380] Example 2E: 400 mg tablets were prepared, each having a second layer of 300 mg and a first layer of 100 mg. The tablets were prepared according to Example 1.

[0381] The punch used was a 12.00mm, circular, shallow concave punch, B-tool.

[0382] Next, the second layer is compressed with a compressive force of approximately 3-8 kN, and then the first layer is fused with the second layer by compressing it with a compressive force of approximately 20-30 kN.

[0383] [Table 5]

[0384] The alternative components described in relation to AT1 to AT6 may similarly be applied to AT41 to AT46.

[0385] Example 2F: 400 mg tablets were prepared, each having a second layer of 300 mg and a first layer of 100 mg. The tablets were prepared according to Example 1.

[0386] The punch used was a 12.00mm, circular, shallow concave punch, B-tool.

[0387] Next, the second layer is compressed with a compressive force of approximately 3-8 kN, and then the first layer is fused with the second layer by compressing it with a compressive force of approximately 20-30 kN.

[0388] [Table 6]

[0389] The alternative components described in relation to AT1 to AT6 may similarly be applied to AT51 to AT53.

[0390] Example 2G: 400 mg tablets were prepared, each having a second layer of 300 mg and a first layer of 100 mg. The tablets were prepared according to Example 1.

[0391] The punch used was a 12.00mm, circular, shallow concave punch, B-tool.

[0392] Next, the second layer is compressed with a compressive force of approximately 3-8 kN, and then the first layer is fused with the second layer by compressing it with a compressive force of approximately 20-30 kN.

[0393] [Table 7]

[0394] The alternative components described in relation to AT1 to AT6 may similarly be applied to AT61 to AT66.

[0395] Example 2H: 400 mg tablets were prepared, each having a second layer of 300 mg and a first layer of 100 mg. The tablets were prepared according to Example 1.

[0396] The punch used was a 12.00mm, circular, shallow concave punch, B-tool.

[0397] Next, the second layer is compressed with a compressive force of approximately 3-8 kN, and then the first layer is fused with the second layer by compressing it with a compressive force of approximately 20-30 kN.

[0398] [Table 8]

[0399] In Table 7A, sucralose was used as a high-intensity sweetener. The flavoring could also be, for example, a combination of peppermint and menthol.

[0400] The alternative components described in relation to AT1 to AT6 may similarly be applied to AT71 to AT76.

[0401] Example 2I: A 300 mg single-layer tablet. The tablet was prepared according to Example 1A.

[0402] The punch used was a 12.00mm, circular, shallow concave punch, B-tool.

[0403] The tablets are compressed with a compressive force of approximately 20-40 kN.

[0404] [Table 9]

[0405] Table 7B shows that sucralose was used as a high-intensity sweetener. The flavoring could also be, for example, a combination of peppermint and menthol.

[0406] The alternative components described in relation to AT1 to AT6 may similarly be applied to AT81 to AT83.

[0407] Example 2J: A 270 mg tablet was prepared, each having a first layer of 70 mg and a second layer of 200 mg. The tablet was prepared according to Example 1.

[0408] The punch used was 8.00mm, circular, with a convex dimple, and was a D-tool.

[0409] Next, the second layer is compressed with a compressive force of approximately 3-8 kN, and then the first layer is fused with the second layer by compressing it with a compressive force of approximately 20-30 kN.

[0410] [Table 10]

[0411] In Table 7C, sucralose was used as a high-intensity sweetener. The flavoring could also be, for example, a combination of peppermint and menthol.

[0412] The alternative components described in relation to AT1 to AT6 may similarly be applied to AT91 to AT93.

[0413] Example 2K: Tablets of various sizes were prepared according to Example 1B.

[0414] The punch used for samples AT101-AT106 was 12.00 mm, circular, with a shallow concave surface, and was a B-tool.

[0415] The punch used for sample AT107 was 10.00 mm in diameter, circular, and had a convex dimple.

[0416] Next, the first layer is compressed with a compressive force of approximately 1 to 6 kN, and then the second layer is fused with the first layer by compressing it with a compressive force of approximately 2 to 8 kN. Finally, the third layer is fused with the second layer by compressing it with a compressive force of approximately 20 to 40 kN.

[0417] [Table 11]

[0418] In Table 7D, sucralose was used as a high-intensity sweetener. The flavoring could also be, for example, a combination of peppermint and menthol.

[0419] Please note that Pearlitol Flash is a commercially available, ready-to-use product containing mannitol and starch in a mannitol-to-starch weight ratio of approximately 4:1.

[0420] The alternative components described in relation to AT1 to AT6 may similarly be applied to AT101 to AT107.

[0421] Example 2L: A 500 mg tablet was prepared, each having a first layer of 100 mg, a second layer of 300 mg, and a third layer of 100 mg. The tablet was prepared according to Example 1B.

[0422] The punch used was a 12.00mm, circular, shallow concave punch, B-tool.

[0423] Next, the first layer is compressed with a compressive force of approximately 1 to 6 kN, and then the second layer is fused with the first layer by compressing it with a compressive force of approximately 2 to 8 kN. Finally, the third layer is fused with the second layer by compressing it with a compressive force of approximately 20 to 40 kN.

[0424] [Table 12]

[0425] In Table 7E, sucralose was used as a high-intensity sweetener. The flavoring could also be, for example, a combination of peppermint and menthol.

[0426] You may use other organic acids, such as malic acid, instead of citric acid.

[0427] Streptococcus salivarius K12 can be obtained, for example, as the commercially available BLIS K12 (trademark).

[0428] The alternative components described in relation to AT1 to AT6 may similarly be applied to AT111 to AT116.

[0429] Example 2M: A 500 mg tablet was prepared, each having a first layer of 100 mg, a second layer of 300 mg, and a third layer of 100 mg. The tablet was prepared according to Example 1B.

[0430] The punch used was a 12.00mm, circular, shallow concave punch, B-tool.

[0431] Next, the first layer is compressed with a compressive force of approximately 1 to 6 kN, and then the second layer is fused with the first layer by compressing it with a compressive force of approximately 2 to 8 kN. Then, the third layer is fused with the second layer by compressing it with a compressive force of approximately 20 to 40 kN.

[0432] [Table 13]

[0433] In Table 7F, sucralose was used as a high-intensity sweetener. The flavoring could also be, for example, a combination of peppermint and menthol.

[0434] The alternative components described in relation to AT1 to AT6 may similarly be applied to AT121 to AT126.

[0435] Example 2N: A 270 mg tablet was prepared, each having a first layer of 70 mg and a second layer of 200 mg. The tablet was prepared according to Example 1.

[0436] The punch used was a 12.00mm, circular, shallow concave punch, B-tool.

[0437] Next, the second layer is compressed with a compressive force of approximately 3-8 kN, and then the first layer is fused with the second layer by compressing it with a compressive force of approximately 20-30 kN.

[0438] [Table 14]

[0439] In Table 7G, sucralose was used as a high-intensity sweetener. The flavoring could also be, for example, a combination of peppermint and menthol.

[0440] You may use other organic acids, such as malic acid, instead of citric acid.

[0441] Streptococcus salivarius K12 can be obtained, for example, as the commercially available BLIS K12 (trademark).

[0442] The alternative components described in relation to AT1 to AT6 may similarly be applied to AT131 to AT133.

[0443] Example 20: A 300 mg single-layer tablet. The tablet was prepared according to Example 1A.

[0444] The punch used was a 12.00mm, circular, shallow concave punch, B-tool.

[0445] The tablets are compressed with a compressive force of approximately 20-40 kN.

[0446] [Table 15]

[0447] In Table 7H, sucralose was used as a high-intensity sweetener. A flavoring agent such as peppermint may also be used.

[0448] The alternative components described in relation to AT1 to AT6 may similarly be applied to AT141 to AT142.

[0449] Example 2P: 400 mg tablets were prepared, each having a second layer of 300 mg and a first layer of 100 mg. The tablets were prepared according to Example 1.

[0450] The punch used was a 12.00mm, circular, shallow concave punch, B-tool.

[0451] Next, the second layer is compressed with a compressive force of approximately 3-8 kN, and then the first layer is fused with the second layer by compressing it with a compressive force of approximately 20-30 kN.

[0452] [Table 16]

[0453] Table 7I shows that sucralose was used as a high-intensity sweetener. A flavoring such as peppermint may also be used.

[0454] The alternative components described in relation to AT1 to AT6 may similarly be applied to AT151 to AT154.

[0455] Example 2Q: Nicotine 150 mg tablets were prepared, each having a first layer of 35 mg and a second layer of 115 mg. The tablets were prepared according to Example 1.

[0456] The punch used was 8.00mm, circular, with a convex dimple, and was a D-tool.

[0457] Next, the second layer is compressed with a compressive force of approximately 1 to 5 kN, and then the first layer is fused with the second layer by compressing it with a compressive force of approximately 8 to 15 kN.

[0458] [Table 17]

[0459] In Table 7J, sucralose was used as a high-intensity sweetener. The flavoring could also be, for example, peppermint.

[0460] The alternative components described in relation to AT1 to AT6 may similarly be applied to AT161.

[0461] Example 3: Evaluation of Tablets AT2 (containing 30 mg of caffeine), AT12 (containing 20 mg of melatonin), and AT17 (containing approximately 9 mg of NBT corresponding to 3 mg of nicotine) were evaluated by a panel of six trained evaluators.

[0462] Trained evaluators refrained from eating or drinking for at least 30 minutes before the start of the test. Each trained evaluator was an objectively designated healthy individual according to specified requirements.

[0463] For the test, tablets were weighed and placed between the upper lip and gums in the mouth, with the first layer, i.e., the mucosal adhesive layer, facing the gums. At specific time points, e.g., 15, 30, and 60 minutes, the content of the active ingredient was measured in any remaining tablet residue. After the desired test time was reached, the tablets were removed and weighed directly into measuring glasses for use in the analysis of the active ingredient content. The active ingredient content was extracted into the appropriate buffer and then analyzed by standard HPLC techniques.

[0464] Participants were free to evaluate the tablets during the test in terms of mouthfeel, taste, and other sensory parameters.

[0465] If the dissolution of the tablet was substantially completed before reaching a specific point in time, the dissolution time was recorded as the in vivo dissolution time of the tablet.

[0466] The tablets were repeatedly measured for each of the six subjects, resulting in a total of 12 measurements for each sample. The average of the 12 measurements was calculated, and the weight % release was determined based on the original content of the active ingredient in the sample.

[0467] The evaluated tablets were found to be a highly suitable delivery vehicle for active ingredients such as caffeine, melatonin, and nicotine, providing a desirable mouthfeel and taste profile while delivering a remarkable release of the active ingredients.

[0468] Example 4: In vivo elution time The in vivo dissolution times of the selected tablets (determined according to Example 3) were tested and are shown in Table 8 below.

[0469] [Table 18]

[0470] As can be seen from Table 8, the dissolution time of the tablets can vary considerably, and the presence of binders in AT61-AT65 and AT3 resulted in a longer dissolution time than that of tablet AT66, which does not contain a binder.

[0471] Example 5: Sensory Evaluation Caffeine-containing tablets AT53 to AT55 (40 mg caffeine) were evaluated for bitterness and taste intensity according to the in vivo evaluation method outlined in Example 3.

[0472] Bitterness and taste intensity were each rated on a scale of 0 to 4, with 4 representing the strongest bitterness or taste intensity, and 0 indicating no bitterness or taste was detected.

[0473] [Table 19]

[0474] Therefore, it was found that tablets without flavorings in the first layer have high flavor intensity and no bitterness, and this is not affected by changing the amount of binder in the first layer.

[0475] Example 6. In vivo elution time The in vivo dissolution times of the selected tablets (determined according to Example 3) were tested and are shown in Table 10 below.

[0476] [Table 20]

[0477] As can be seen from Table 10, the dissolution time of the tablets could be gradually changed by adjusting the amount of binder, for example, 0-10% for AT71-AT73 and 5-10% for AT82-AT83.

[0478] Example 7. Release of the active ingredient The release of caffeine as an active ingredient was tested in vivo.

[0479] The evaluators were selected and prepared according to Example 3, and the tablets were used according to Example 3.

[0480] At specific time points after the start of the test (30 and 60 minutes), the remaining portion of the tablet was removed, and the residual caffeine content was determined using standard HPLC techniques. Caffeine release was then determined as the difference between the initial caffeine content and the residual caffeine content. The results are shown in Table 11 below.

[0481] [Table 21]

[0482] As can be seen from Table 11, caffeine is released gradually over time (sustained release). Comparing the release times of AT153 and AT154, it is noteworthy that the release can be slowed down by increasing the amount of binder applied (in this case, HPC).

[0483] Example 8. Adhesion of tablets Tablet AT64 and comparative tablet C2 were evaluated for their adhesive properties.

[0484] The evaluators selected according to Example 3 were instructed to insert the tablet between the gums and lips, with the adhesive first layer facing the gums.

[0485] The adhesion of the tablets was evaluated again 1 minute and 5 minutes after insertion. Each evaluator provided the same response, as shown in Table 12 below.

[0486] [Table 22]

[0487] As can be seen from Table 12, comparative table C2 is evaluated as not adhesive because the content of the mucosal adhesive in the first layer is very low (only 10%). Tablet AT64 of the present invention, which has a sufficient content of natural gum mucosal adhesive in the first layer, is adhesive both 1 minute and 5 minutes after insertion onto the gums.

[0488] Example 9. Consumer Evaluation AT161 tablets were evaluated in an In-Home User Test with a consumer panel of healthy test users, including both men and women. The consumer panel consisted of 74 test users. All test users were regular smokers who reported smoking more than four cigarettes per day for at least the last six months prior to the evaluation period.

[0489] Each user was supplied with the nicotine tablet type AT161 of the present invention and instructed that they were free to use or not use them for 14 days at home, at work, and anywhere else. At the same time, users were free to use other nicotine-containing products, including tobacco.

[0490] Each user rated their likelihood of using the product (i.e., the likelihood of using the nicotine tablets of the present invention outside of the test) on a scale of 1 to 5 (5 being the most likely to use the tablets).

[0491] 74% of the test users rated the tablets at least 3, and 30% of the test users rated the tablets 5 out of 5.

[0492] For comparison, benchmark levels were established based on similar tests of 40 different nicotine-containing oral care products (i.e., non-tobacco). The benchmark level was scored at 57% compared to 74% for the tablets of the present invention.

[0493] Furthermore, it should be noted that approximately 73% of users reported a reduction in tobacco use during the trial.

[0494] Furthermore, test users reported that, on average, 82% of their nicotine product consumption was due to tobacco use before the trial, but this number decreased to approximately 47% during the trial period. Therefore, a significant reduction in tobacco use was reported, which may be attributable to the use of the nicotine tablets of the present invention.

[0495] Test users also reported a desire to smoke before and after using the AT161 tablets of the present invention during the test period. The desire to smoke reported immediately before using the AT161 tablets of the present invention is shown in Table 13 below.

[0496] [Table 23]

[0497] Table 14 below shows the craving for smoking reported immediately after the use of the tablet AT161 of the present invention.

[0498] [Table 24]

[0499] As can be seen from Tables 13-14, the AT161 tablet of the present invention was generally effective in providing relief from nicotine craving, that is, in substantially reducing the desire to smoke.

[0500] In fact, it has been generally observed that the urge to smoke gradually decreases before the use of the AT161 tablet of the present invention.

[0501] This demonstrates the general effectiveness of the nicotine tablets of the present invention in helping smokers reduce their tobacco use.

[0502] Example 10. Evaluation Tablets AT91 and AT93 were evaluated in terms of dissolution time and mouthfeel.

[0503] The in vivo dissolution times of tablets AT91 and AT93 (determined according to Example 3) were tested and are shown in Table 15 below.

[0504] [Table 25]

[0505] It is noteworthy that AT93, which contains a binder, xanthan gum, and alginate, dissolves more slowly than AT91, which does not contain these components.

[0506] Regarding mouthfeel, AT93 was rated as having an improved mouthfeel compared to AT91 in terms of smoothness throughout the entire dissolution time.

[0507] Example 11. Evaluation Tablets AT101 to AT106 were evaluated in terms of dissolution time and mouthfeel.

[0508] The in vivo dissolution times (determined according to Example 3) for tablets AT101-AT106, all having a binder in an adhesive first layer and a non-adhesive second layer of the same composition, were determined to be in the range of 140-160 minutes for all samples.

[0509] However, despite significant differences in the elution of the rapidly soluble third layer containing Pearlitol Flash, nearly identical overall in vivo elution times were observed. In vivo elution of the third layer ranged from 5 to 8 minutes for samples AT101, AT103, and AT106, which had the highest Pearlitol Flash content, while samples AT102, AT104, and AT105, which contained a blend of Pearlitol Flash and xylitol, showed in vivo elution times of 10 to 15 minutes.

[0510] Each tablet was evaluated as having a desirable mouthfeel, and AT105 and AT106 were found to provide excellent smoothness while maintaining a firm texture.

[0511] Example 12. Evaluation Tablet AT107 was evaluated in terms of dissolution time and mouthfeel.

[0512] The in vivo dissolution time of tablet AT107 (determined according to Example 3) was tested and is shown in Table 17 below.

[0513] [Table 26]

[0514] The AT107 tablets were rated as having a desirable mouthfeel, for example, in terms of smoothness. The tablet size was also rated as very comfortable.

[0515] Example 13. Adhesion evaluation Tablets AT74 to AT76 were evaluated by a panel of evaluators according to Example 3, based on perceived adhesion on a scale of 0 to 12. The results are shown in Table 18 below.

[0516] [Table 27]

[0517] As shown in Table 18, adhesion is gradually improved by increasing the amount of natural gum mucosal adhesive in the first layer.

Claims

1. A dissolvable oral-adhering tablet for sustained release, The aforementioned tablet contains an active ingredient, The tablet is a multilayer tablet comprising a first layer and a second layer, A dissolvable oral adhesive tablet wherein the first layer is a mucosal adhesive layer containing a natural gum mucosal adhesive, and the second layer contains at least one sugar alcohol.

2. The tablet according to claim 1, wherein the tablet adheres to the gums.

3. The tablet according to claim 1 or 2, wherein the tablet is a compressed tablet.

4. The tablet according to any one of claims 1 to 3, wherein the tablet is composed of a plurality of compressed particles.

5. The tablet according to any one of claims 1 to 4, wherein the first layer and the second layer are fused by compression.

6. The tablet according to any one of claims 1 to 5, wherein the active ingredient is an orally absorbable active ingredient.

7. The tablet according to any one of claims 1 to 6, wherein the active ingredient comprises an active pharmaceutical ingredient.

8. The tablet according to any one of claims 1 to 7, wherein the active ingredient is selected from the group consisting of caffeine, melatonin, nicotine, and a combination of nicotine and caffeine.

9. The tablet according to any one of claims 1 to 8, wherein the active ingredient is selected from the group consisting of caffeine, nicotine, and any combination thereof.

10. A tablet according to any one of claims 1 to 9, wherein the active ingredient comprises melatonin.

11. A tablet according to any one of claims 1 to 10, wherein the active ingredient comprises caffeine.

12. The tablet according to any one of claims 1 to 11, wherein the active ingredient comprises nicotine.

13. The tablet according to any one of claims 1 to 12, wherein the active ingredient comprises paraxanthine.

14. The tablet according to any one of claims 1 to 13, wherein the tablet contains paraxanthine in an amount of at least 10 mg, for example, at least 20 mg.

15. The tablet according to any one of claims 1 to 14, wherein the active ingredient comprises one or more probiotics.

16. The tablet according to any one of claims 1 to 15, wherein the tablet contains one or more probiotics in an amount of at least 2 mg, for example, at least 5 mg.

17. The tablet according to any one of claims 1 to 16, wherein the tablet contains caffeine in an amount of at least 10 mg, for example, at least 20 mg.

18. The tablet according to any one of claims 1 to 17, wherein the tablet contains melatonin in an amount of at least 0.5 mg, for example, at least 1 mg.

19. The tablet according to any one of claims 1 to 18, wherein the tablet contains nicotine in an amount of at least 0.5 mg, for example, at least 1 mg.

20. The tablet according to any one of claims 1 to 19, wherein the tablet has a weight ratio of the content of the active ingredient to the content of the sugar alcohol, and the weight ratio is at least 1:600, for example at least 1:400, for example at least 1:200, for example at least 1:

100.

21. The tablet according to any one of claims 1 to 20, wherein the active ingredient is contained in the first layer.

22. The tablet according to any one of claims 1 to 21, wherein the active ingredient is contained in the second layer.

23. The tablet according to any one of claims 1 to 22, wherein the tablet comprises one or more further active ingredients.

24. The tablet according to any one of claims 1 to 23, wherein the tablet has a dissolution time of at least one hour.

25. The tablet according to any one of claims 1 to 24, wherein the tablet has a dissolution time of 10 hours or less, for example, 8 hours or less, for example, 6 hours or less.

26. The tablet according to any one of claims 1 to 25, wherein the tablet comprises a pH adjusting agent, for example, an alkaline pH adjusting agent, for example, an alkaline buffering agent.

27. The tablet according to any one of claims 1 to 26, wherein the natural gum mucosal adhesive comprises a natural gum mucosal adhesive selected from the group consisting of xanthan gum, konjac gum, tara gum, gellan gum, locust bean gum, gum arabic, alginate, pullulan, tragacanth gum, karaya gum, fenugreek gum, cassia gum, carrageenan, agar, alginic acid and its salts, and any combination thereof.

28. The tablet according to any one of claims 1 to 27, wherein the natural gum mucosal adhesive comprises gum arabic.

29. The tablet according to any one of claims 1 to 28, wherein the natural gum mucosal adhesive comprises xanthan gum.

30. The tablet according to any one of claims 1 to 29, wherein the first layer contains the natural gum mucosal adhesive in an amount of at least 35% by weight of the first layer, for example, at least 40% by weight of the first layer, for example, at least 50% by weight of the first layer, for example, at least 55% by weight of the first layer, for example, at least 60% by weight of the first layer.

31. The tablet according to any one of claims 1 to 30, wherein the first layer contains the natural gum mucosal adhesive in an amount of 90% by weight or less of the first layer, for example, 85% by weight or less of the first layer, for example, 80% by weight or less of the first layer.

32. The tablet according to any one of claims 1 to 31, wherein the second layer comprises less than 20% by weight of a mucosal adhesive, for example less than 10% by weight of a mucosal adhesive, for example less than 5% by weight of a mucosal adhesive, for example less than 1% by weight of a mucosal adhesive, for example less than 0.2% by weight of a mucosal adhesive, and substantially contains, for example, no mucosal adhesive.

33. The tablet according to any one of claims 1 to 32, wherein the second layer does not contain a mucosal adhesive.

34. The tablet according to any one of claims 1 to 33, wherein the first layer contains a sugar alcohol in an amount of at least 5% by weight of the first layer, for example, at least 8% by weight of the first layer, for example, at least 10% by weight of the first layer, for example, at least 15% by weight of the first layer.

35. The tablet according to any one of claims 1 to 34, wherein the first layer contains a sugar alcohol in an amount of 50% by weight or less of the first layer, for example, 40% by weight or less of the first layer, for example, 30% by weight or less of the first layer.

36. The tablet according to any one of claims 1 to 35, wherein the second layer contains a sugar alcohol in an amount of at least 10% by weight of the second layer, for example, at least 20% by weight of the second layer, for example, at least 30% by weight of the second layer, for example, at least 40% by weight of the second layer.

37. The tablet according to any one of claims 1 to 36, wherein at least one sugar alcohol in the first layer comprises a sugar alcohol selected from the group consisting of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol, and any combination thereof.

38. The tablet according to any one of claims 1 to 37, wherein the at least one sugar alcohol in the first layer comprises a sugar alcohol selected from the group consisting of xylitol, maltitol, erythritol, isomalt, sorbitol, lactitol, and any combination thereof.

39. The tablet according to any one of claims 1 to 38, wherein the at least one sugar alcohol in the second layer comprises a sugar alcohol selected from the group consisting of xylitol, maltitol, mannitol, erythritol, isomalt, sorbitol, lactitol, and any combination thereof.

40. The tablet according to any one of claims 1 to 39, wherein the at least one sugar alcohol in the second layer comprises a sugar alcohol selected from the group consisting of xylitol, maltitol, erythritol, isomalt, sorbitol, lactitol, and any combination thereof.

41. The tablet according to any one of claims 1 to 40, wherein the first layer contains a water-insoluble component in an amount of 30% by weight or less of the first layer, for example, 20% by weight or less of the first layer, for example, 10% by weight or less of the first layer.

42. The tablet according to any one of claims 1 to 41, wherein the first layer comprises one or more binders.

43. The tablet according to any one of claims 1 to 42, wherein the first layer contains a binder in an amount of at least 1% by weight of the first layer, for example, at least 2% by weight of the first layer, for example, at least 4% by weight of the first layer.

44. The tablet according to any one of claims 1 to 43, wherein the binder of the first layer comprises at least one binder selected from the group consisting of cellulose, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, and any combination thereof.

45. The tablet according to any one of claims 1 to 44, wherein the binder of the first layer comprises at least one binder selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, carboxymethylcellulose, and any combination thereof.

46. The tablet according to any one of claims 1 to 45, wherein the second layer comprises a binder.

47. The tablet according to any one of claims 1 to 46, wherein the second layer contains a binder in an amount of at least 1% by weight of the second layer, for example, at least 2% by weight of the second layer, for example, at least 4% by weight of the second layer.

48. The tablet according to any one of claims 1 to 47, wherein the binder of the second layer comprises at least one binder selected from the group consisting of cellulose, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, and any combination thereof.

49. The tablet according to any one of claims 1 to 48, wherein the binder of the second layer comprises at least one binder selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, carboxymethylcellulose, and any combination thereof.

50. The tablet according to any one of claims 1 to 49, wherein the first layer constitutes at least 10% by weight of the tablet, for example, at least 20% by weight of the tablet, for example, at least 30% by weight of the tablet.

51. The tablet according to any one of claims 1 to 50, wherein the second layer constitutes at least 40% by weight of the tablet, for example, at least 50% by weight of the tablet, for example, at least 60% by weight of the tablet.

52. The tablet according to any one of claims 1 to 51, wherein the first layer has a weight of at least 20 mg, for example, at least 40 mg, for example, at least 60 mg.

53. The tablet according to any one of claims 1 to 52, wherein the second layer has a weight of at least 50 mg, for example, at least 75 mg, for example, at least 100 mg.

54. The tablet according to any one of claims 1 to 53, wherein the tablet is a two-layer tablet.

55. The tablet according to any one of claims 1 to 54, wherein the tablet is a three-layer tablet.

56. The tablet according to any one of claims 1 to 55, wherein the tablet has a weight of at least 100 mg, for example, at least 150 mg, for example, at least 200 mg.

57. The tablet according to any one of claims 1 to 56, wherein the tablet has a weight of 600 mg or less, for example, 500 mg or less, for example, 400 mg or less.

58. The tablet according to any one of claims 1 to 57, wherein the first layer has a surface that is at least partially substantially flat or concave.

59. The tablet according to any one of claims 1 to 58, wherein the first layer has a surface comprising at least one dimple.

60. The tablet according to any one of claims 1 to 59, wherein the tablet contains a flavoring agent.

61. The tablet according to any one of claims 1 to 62, wherein the first layer does not contain a flavoring agent.

62. The tablet according to any one of claims 1 to 61, wherein the second layer does not contain a foaming agent.

63. The tablet according to any one of claims 1 to 62, wherein the tablet has a maximum dimension of at least 5 mm.

64. The tablet according to any one of claims 1 to 63, wherein the first layer has an exposed surface area of ​​at least 0.2 cm².

65. The tablet according to any one of claims 1 to 64, wherein the second layer is not in contact with the oral mucosal surface that is in contact with the first layer during use.

66. The tablet according to any one of claims 1 to 65, wherein the tablet has a hardness of at least 20 N, for example, at least 30 N.

67. The tablet according to any one of claims 1 to 66, wherein the tablet has a water content of less than 2% by weight of the tablet, for example, less than 1% by weight of the tablet.

68. A dissolvable oral adhesion tablet for sustained release, wherein the tablet contains an active ingredient, and the tablet comprises at least a first layer which is a mucosal adhesion layer containing a natural gum mucosal adhesion agent.

69. The tablet according to claim 68, wherein the tablet is provided as a single-layer tablet.

70. A tablet according to claim 68 or 69, and according to any one of claims 1 to 67.

Images