System for oral delivery of active ingredients

Abstract

The present invention relates to a system for oral delivery of an active ingredient, the system comprising a mucosal adhesion layer and a backing layer containing the active ingredient.

Description

Technical Field

[0001] The present invention relates to a system for oral delivery of active ingredients such as nicotine, caffeine, or cannabinoids. The system is waste-free and achieves efficient transfer of the active ingredient through the user's oral mucosa.

Background Art

[0002] Various products for oral delivery of active ingredients are known. Examples include lozenges, instant films, chewing gums, and pouches. The drawback of such products is that the active ingredient contained therein is mainly delivered to the blood by absorption through the gastrointestinal tract after swallowing saliva, while only a small amount is transferred through the oral mucosa. Since many active ingredients are destroyed by the conditions in the user's gastrointestinal tract, known products do not achieve efficient systemic delivery of the active ingredient.

[0003] WO2011 / 137491A1 describes a trans mucosal delivery device comprising a solid core containing an active ingredient, a bioadhesive layer, and a backing layer. The surface of the core is exposed and the device can be placed on the oral mucosa surface with the exposed surface and the bioadhesive layer in contact with the oral mucosa surface. The bioadhesive layer does not contain the active ingredient. The drawback of the above device is that it has to have a large area in order to allow both sufficient transfer of the active agent through the exposed area of the core and sufficient contact between the bioadhesive layer and the mucosa so that the device can stay in place. This makes the use of the device inconvenient.

[0004] WO00 / 62764 relates to a gum pad for drug delivery to mucosal tissue. The gum pad is a laminate consisting of a backing layer configured to be held in place on gum in the mouth, an intermediate layer containing the drug, and a semipermeable outer layer. During use, saliva enters the semipermeable outer layer, dissolves the drug in the intermediate layer, and then diffuses outward to the mucosal tissue in the mouth. The disadvantage of the above gum pad is that it does not effectively prevent the absorption of the drug through the gastrointestinal tract after swallowing saliva. Furthermore, the backing layer of the gum pad is made of a material that does not dissolve in the oral cavity. Therefore, the gum pad must be removed from the mouth and discarded after use, and thus does not produce no waste.

[0005] US2021 / 0000161A1 describes an orally soluble film containing a nicotine activator, a binder, and a plasticizer. The film disintegrates rapidly in the user's mouth, and thus a significant proportion of the available nicotine is swallowed.

[0006] Therefore, there is a need for a system that does not produce waste and efficiently delivers active ingredients through the user's oral mucosa.

[0007] Objective of the present invention An object of the present invention is to provide a system for the delivery of active ingredients that achieves efficient delivery of the active ingredients. Another object of the present invention is to provide a system in which the active ingredients are completely dissolved after absorption, and therefore produce no waste whatsoever.

[0008] The oral delivery system described below fulfills the above objectives. [Overview of the Initiative]

[0009] In one embodiment, the present invention relates to a system for oral delivery of an active ingredient, the system comprising: a) a mucosal adhesion layer comprising a mucosal adhesion agent and an active ingredient; and b) a backing layer extending over the mucosal adhesion layer, wherein the backing layer comprises a bulk agent and optionally a flavoring agent; the active ingredient is selected from the group consisting of at least one cannabinoid such as nicotine, caffeine, anatabine, tetrahydrocannabinol, and combinations thereof; the delivery system is orally soluble; and the bulk agent is selected from the group consisting of at least one monosaccharide, disaccharide, and / or polysaccharide, at least one sugar alcohol, and combinations thereof.

[0010] In a preferred embodiment, the backing layer further comprises a binder. In a further preferred embodiment, the backing layer further comprises a dissolution accelerator. In a further preferred embodiment, the mucosal adhesion layer further comprises a penetration accelerator. In a further preferred embodiment, the backing layer does not contain the active ingredient. In a further preferred embodiment, the weight ratio of the active ingredient to the mucosal adhesion agent in the mucosal adhesion layer is about 1:1 to about 1:1000. In a further preferred embodiment, the weight ratio of the active ingredient in the mucosal adhesion layer to the weight ratio of the active ingredient in the backing layer is about 1:1 to about 1000:1, preferably about 10:1 to about 500:1, more preferably about 50:1 to about 300:1, and most preferably about 100:1 to about 250:1. In a further preferred embodiment, the mucosal adhesion agent is selected from the group consisting of gelatin, chitosan, carboxymethylcellulose (sodium), hydroxypropylmethylcellulose, polyvinyl alcohol, gellan gum, agar, agarose, and combinations thereof. In a preferred embodiment, the active ingredient is nicotine.

[0011] In a further embodiment, the present invention relates to a dosage form comprising a system according to the present invention. In a preferred embodiment, the dosage form is a tablet. In another embodiment, the present invention relates to a blister pack comprising a dosage form according to the present invention (e.g., a tablet). [Brief explanation of the drawing]

[0012] [Figure 1]A system for oral delivery according to one embodiment of the present invention. [Figure 2] A system for oral delivery according to another embodiment of the present invention. [Modes for carrying out the invention]

[0013] The present invention aims to provide a system for the efficient delivery of active ingredients and for the delivery of active ingredients without generating waste.

[0014] A system for oral delivery of an active ingredient comprises a) a mucosal adhesion layer containing a mucosal adhesion agent and the active ingredient, and b) a backing layer extending over the mucosal adhesion layer, wherein the backing layer comprises a bulk agent and optionally a flavoring agent, the active ingredient is selected from the group consisting of at least one cannabinoid such as nicotine, caffeine, anatabine, tetrahydrocannabinol, and combinations thereof, the delivery system is orally soluble, and the bulk agent is selected from the group consisting of at least one monosaccharide, disaccharide, and / or polysaccharide, at least one sugar alcohol, and combinations thereof.

[0015] During use, the oral delivery system according to the present invention is placed in the user's mouth so that the mucosal adhesion layer is in contact with the oral mucosa. The mucosal adhesion layer can adhere firmly to the oral mucosa, thereby preventing the swallowing of the active ingredient. The backing layer covers the surface of the mucosal adhesion layer opposite to the surface that is in contact with the oral mucosa. Thus, the backing layer prevents the active ingredient in the mucosal adhesion layer from coming into contact with saliva, ensuring that the active ingredient is not swallowed. Rather, the active ingredient is advantageously absorbed directly into the bloodstream through the oral mucosa.

[0016] Furthermore, the oral delivery system according to the present invention is orally soluble and therefore produces no waste.

[0017] Definitions and Terms Unless otherwise defined, all technical and scientific terms from this point forward have their commonly understood meanings.

[0018] Unless otherwise defined, any feature within any aspect or embodiment of the Invention may be combined with any feature within any other aspect or embodiment of the Invention, and those skilled in the art will understand that such combinations are encompassed within the original disclosure of this application. This also applies to the possibility of combinations of elements from a list of species within the definitions of broader terms that differ from one another, and the aforementioned possibilities of individualized combinations are expressly intended and within the direct and obvious disclosure of this application. This also applies particularly to all embodiments described in the sections relating to systems and their components with respect to other aspects, e.g., dosage forms of those systems. This also applies particularly, but not exclusively, to the endpoints of the scope disclosed herein. For example, if a given substance is disclosed as being present in a composition in a concentration range of XY% or AB%, it should be understood that this application expressly discloses not only the ranges XY% and AB%, but also the ranges XB%, AY%, and, numerically, YA% and BX%. Each of these ranges, and combinations of ranges, should be understood as contemplated and directly and obviously disclosed in this application.

[0019] Similarly, it should be understood that the section headings used throughout this application are solely for organizational purposes and do not give any exclusive character to the disclosure relating to aspects or embodiments of the invention referred to in any particular section heading. Therefore, the section headings do not preclude any combination of the disclosures within any one section heading to a corresponding or similar context provided under another section heading. In fact, such in-section disclosures are explicitly within the disclosures of this application.

[0020] As used herein, each of the terms "comprising," "having," and "containing," including their grammatical variations, is intended in a non-exclusive sense to mean "including," but not necessarily "composed of," and does not exclude elements in addition to those explicitly listed as being present. As used herein, the terms "comprising," "having," and "containing," and their grammatical variations, indicate that components other than those explicitly listed may be present, but are not essential. Thus, these terms, as a limiting case, include embodiments in which no elements other than those listed exist, for example, in the generally accepted sense of "consisting of."

[0021] As used herein, the phrase "consisting of," and its grammatically related variations, mean that no other elements other than those listed exist. Thus, considering the above definition of "comprising" (and grammatically and semantically related terms), the term "consisting of" means a limiting scenario within the meaning of "comprising."

[0022] Unless otherwise indicated, the percentages indicating the extent to which a particular component is included in a mixture or composition refer to weight / weight (w / w) percentages. Similarly, unless otherwise indicated, the ratios specified herein are weight ratios.

[0023] Unless otherwise stated, any range designation in this application using two bracket values ​​X and Y, or a hyphen ("-") separating two bracket ratios, should be understood as meaning and disclosing a specific range that includes both endpoint values ​​X and Y. The same applies to ranges expressed as "X to Y (X~Y)". Therefore, range expressions such as "XY", "X~Y", "X to Y (X~Y)", "XY", and "X to Y" should be understood as meaning and disclosing a range that includes the endpoint value X, all values ​​between X and Y, and the endpoint value Y.

[0024] As used herein, when "about" refers to a particular value, e.g., the endpoint of a range, the term "about" encompasses and discloses a certain variation in the vicinity of the specifically recited value itself in addition to the specifically recited value itself. Such variations can arise from normal measurement variations, for example, in the weighing or dispensing of various substances by methods known to those of ordinary skill in the art. The term "about" should be understood to encompass and disclose a range of variations above and below the indicated specific value, and the percentage values are relative to the specifically recited value itself as follows: The term "about" can encompass and disclose variations of ±5.0%. The term "about" can encompass and disclose variations of ±4.5%. The term "about" can encompass and disclose variations of ±4.0%. The term "about" can encompass and disclose variations of ±3.5%. The term "about" can encompass and disclose variations of ±3.0%. The term "about" can encompass and disclose variations of ±2.5%. The term "about" can encompass and disclose variations of ±2.0%. The term "about" can encompass and disclose variations of ±1.5%. The term "about" can encompass and disclose variations of ±1.0%. The term "about" can encompass and disclose variations of ±0.5%. In relation to a specifically recited value, the term "about" can encompass and disclose the exact specifically recited value itself regardless of any explicit reference to the inclusion of this exact specific value, and even in the absence of an explicit indication that the term "about" includes a particular exact recited value, this exact specific value is still included within the range of variations created by the term "about" and is thus disclosed in this application. Unless otherwise stated, when the term "about" is recited before the first endpoint of a numerical range but not before the second endpoint of that range, this term, and the variability it implies in the range and disclosure, refers to both the first endpoint and the second endpoint of the range. For example, an enumerated range of "about X to Y" should be read as " about X to about Y". The same applies to an enumerated range of ratios. For example, an enumerated weight ratio range of "about X:Y - A:B" should be read as a weight ratio of "(about X):(about Y) - (about A):(about B)".

[0025] As used herein, the term “the combination” refers to any combination in any proportion. That is, the term encompasses any combination of the enumerated features in any relative quantity (e.g., any two enumerated features, any combination of any three enumerated features, etc.). Those skilled in the art will readily be able to determine which quantities may be used in accordance with the intent of the invention.

[0026] As used herein, the term “for oral delivery” means that the product is adapted to deliver the active ingredient in the user’s mouth.

[0027] As used herein, the term "orally soluble" means a compound or composition that is completely soluble under conditions present in the user's mouth.

[0028] As used herein, the term “active ingredient” refers to a substance that has a modulating, for example, stimulating, effect on the user’s nervous system. In this invention, the active ingredient is selected in any proportion from the group consisting of nicotine, caffeine, anatabine, cannabinoids, and combinations thereof.

[0029] As used herein, the term “free of active ingredients” refers to the detectable absence of active ingredients.

[0030] As used herein, the term “nicotine” refers to a nicotine donor. A nicotine donor can be any nicotine compound. Such nicotine compounds include nicotine in its free base form (i.e., unprotonated form), nicotine in its salt form, as a complex, or as a solvated compound. Examples of nicotine complexes include nicotine resin complexes, in which nicotine is bound to an ion-exchange resin, such as nicotine polarilex. Examples of nicotine salts include hydrochloride, dihydrochloride, monotartrate, tartrate, sulfate, salicylate, citrate, stearate, glutarate, aspartate, palmitate, and lactate. Any combination thereof in any proportion is also possible and disclosed. Further possible forms of nicotine are discussed below.

[0031] As used herein, “nicotine content” refers to the amount of nicotine from a nicotine donor, calculated as free base nicotine in weight / weight (w / w) percentage, and is also referred to herein as “weight %”.

[0032] As used herein, the term “cannabinoid” refers to a diverse class of chemical compounds that act on cannabinoid receptors in cells that alter neurotransmitter release in the brain, also known as the endocannabinoid system. Ligands for these receptor proteins include endocannabinoids naturally produced in the bodies of animals, phytocannabinoids found in cannabis, and synthetic cannabinoids that are artificially produced. Cannabinoids found in cannabis include, but are not limited to, cannabigerol (CBG), cannabichromene (CBC), cannabidiol (CBD), tetrahydrocannabinol (THC), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevaline (CBCV), cannabigerovaline (CBGV), cannabigerol monomethyl ether (CBGM), cannabinerol acid, cannabidiolic acid (CBDA), cannabinol propyl variant (CBNV), cannabitriol (CBO), tetrahydrocannabinolic acid (THCA), and tetrahydrocannabivaric acid (THCV A). Any combination thereof in any proportion is also possible and is disclosed in the context of this invention. As used herein, the term “mucosal adhesive” means a natural or synthetic substance that can adhere to the mucous membrane of the subject.Non-limiting examples of mucosal adhesives include gelatin; starch; cellulose derivatives, e.g., carboxymethylcellulose (CMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose, sodium carboxymethylcellulose (Na CMC), etc.; agarose; chitosan, including chitosan derivatives such as trimethylchitosan (TMC) and chitosan glutamic acid; hyaluronic acid; polyvinylpyrrolidone (PVP); polyacrylates, e.g., polyacrylic acid (PAA, e.g., Carbopol®), polyhydroxyethyl methacrylate (PHEMA), etc.; polyvinyl alcohol (PVA); PVA, PAA, e.g., Carbopol®, PHEMA, HEC, HPC, HPMC, methylcellulose, Na CMC, which may be derivatized by one or more lectins, e.g., proteins or glycoproteins, e.g., polyethylene glycol (PEG); Examples include CMC; one or more thiolated polymers ("thiomers"); polyethylene glycol (PEG) (e.g., PEG-6 stearic acid and PEG-4000); sodium alginate; guar gum; karya gum; gellan gum; agar; leten; and tragacanth. Any combination thereof in any proportion is also possible and disclosed.

[0033] As used herein, the term “bulk agent” refers to a substance whose content is 50% by weight or more of the backing layer. In the present invention, the bulk agent may be selected from the group consisting of monosaccharides, disaccharides, and polysaccharides, as well as sugar alcohols. Non-limiting examples of bulk agents include, as possible monosaccharides, glucose, fructose, and galactose; as possible disaccharides, sucrose, lactose, maltose, and trehalose; as possible polysaccharides, starch (e.g., cassava starch); and as possible sugar alcohols, xylitol, sorbitol, erythritol, maltitol, isomalt, lactitol, and mannitol. Any combination thereof in any proportion is also possible and disclosed.

[0034] As used herein, the term “flavoring agent” is any flavored or aromatic substance that can alter the sensory properties of a compound or composition (e.g., sensory properties associated with the backing layer). Examples of sensory properties that can be modified by flavoring agents include taste (e.g., sweet, salty, sour, bitter), mouthfeel, moisture, coolness / heat, and / or aroma / fragrance. Flavoring agents may be natural or synthetic, and the flavor characteristics they impart may be described as fresh, sweet, salty, umami, herbal, confectionery, floral, fruity, or spicy. Specific types of flavors include, but are not limited to, vanilla, coffee, chocolate / cocoa, cream, mint, spearmint, menthol, peppermint, bracken, adzuki bean, ginseng, kelp, dwarf spicebush, eucalyptus, lavender, cardamom, nutmeg, cinnamon, clove, cascarilla, sandalwood, honey, jasmine, ginger, anise, sage, licorice, lemon, orange, apple, peach, lime, cherry, strawberry, and any combination thereof in any proportion. Flavoring agents also include components considered as humectants, coolants, or smoothing agents, such as eucalyptus. Flavoring agents can mask the flavors of other components in the composition (e.g., bitterness). Non-limiting examples of masking agents include compounds that can encapsulate sweeteners and flavoring agents (e.g., maltodextrin). Flavoring agents may contain at least one volatile flavor component. As used herein, “volatile” refers to a chemical substance that readily forms vapor at ambient temperature (i.e., a chemical substance that has a higher vapor pressure at a given temperature compared to a non-volatile substance). Typically, volatile flavor components have a molecular weight of less than approximately 400 Da and often contain at least one carbon-carbon double bond, a carbon-oxygen double bond, or both. Examples of volatile flavor components include alcohols, aldehydes, aromatic hydrocarbons, ketones, esters, terpenes, terpenoids, trigeminal sensates, or combinations thereof.Non-limiting examples of aldehydes include vanillin, ethyl vanillin, p-anisaldehyde, hexanal, furfural, isovaleraldehyde, cuminaldehyde, benzaldehyde, and citronellal. Non-limiting examples of ketones include 1-hydroxy-2-propanone and 2-hydroxy-3-methyl-2-cyclopentenone-1-one. Non-limiting examples of esters include allyl hexanoate, ethyl heptanoate, ethyl hexanoate, isoamyl acetate, and 3-methylbutyl acetate. Non-limiting examples of terpenes include sabinene, limonene, gamma-terpinene, beta-famecene, nerolidol, thujone, myrcene, geraniol, nerol, citronellol, linalool, and eucalyptol. Preferred flavorings include mint and fruit flavors. Any combination thereof in any proportion is also possible and disclosed.

[0035] In this invention, the system for oral delivery comprises a lining layer extending over the mucosal attachment layer. As used herein, the term “extending over” (or its grammatically related variations) means that the lining layer completely covers one of the surfaces of the mucosal attachment layer. The lining layer may also completely cover the sides of the mucosal attachment layer such that only the bottom surface (the surface in contact with the oral mucosa) of the mucosal attachment layer is exposed.

[0036] As used herein, the term “binder” means a substance that imparts structural integrity to a bulk agent (e.g., sucrose), as opposed to the bulk agent. Non-limiting examples of binders include carboxymethylcellulose (sodium) ((Na)CMC), (sodium) alginate, polyvinyl alcohol, polyethylene glycol (PEG), e.g., PEG-6 stearic acid or PEG-4000, microcrystalline cellulose, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, Carbopol®, guar gum, gelatin, karyagum gum, polyacrylic acid, acacia gum, and polyvinylpyrrolidone. Any combination thereof in any proportion is also possible and disclosed.

[0037] As used herein, the term “dissolution accelerator” means a substance that accelerates the dissolution of the backing layer (reduces the dissolution time). Non-limiting examples of dissolution accelerators include citric acid, sodium bicarbonate, agar, amorphous carbohydrates such as amorphous sugars, sodium starch glycolate, croscarmellose sodium, alginic acid, crospovidone, and calcium silicate. Any combination thereof in any proportion is also possible and disclosed.

[0038] As used herein, the term “gelling agent” refers to a substance that can form a gel when mixed with water. Non-limiting examples of gelling agents include sorbitol, glycerol, microcrystalline cellulose, and acacia gum. Any combination thereof in any proportion is also possible and disclosed.

[0039] As used herein, the term “penetration enhancer” refers to a substance that accelerates (reduces the absorption time of) the absorption of active ingredients into the bloodstream through the oral mucosa. Non-limiting examples of penetration enhancers include, for example, bile salts such as sodium glycodeoxycholate, one or more trihydroxy salts of sodium cholate, sodium glycocholate, sodium taurocholate, dihydroxy salts of sodium deoxycholate, sodium glycodeoxycholate, and sodium taurodeoxycholate; one or more fatty acids (e.g., oleic acid, lauric acid, cod liver oil, and one or more salts and esters thereof (e.g., sodium laurate, sodium caprate, glyceryl monostearate, one or more sucrose fatty acid esters, and diethylene glycol monoethyl ether); for example, laurocapra The material comprises one or more azetames such as 1 / 2; one or more surfactants such as sodium dodecyl(lauryl) sulfate; one or more polysorbates, one or more laureths, one or more brioci and benzalkonium chloride; one or more complexing agents such as one or more cyclodextrins (e.g., 2-hydroxypropyl beta-cyclodextrin or poly-beta-cyclodextrin), sodium edetate, ethylenediaminetetraacetic acid (EDTA), and one or more cosolvents such as sodium citrate, ethanol and propylene glycol; lecithin; and sodium fusidate. Any combination thereof in any proportion is also possible and is disclosed in the context of the present invention.

[0040] As used herein, the term “lubricant” means a substance that reduces irritation to the oral mucosa by forming a protective film.

[0041] System for oral delivery of active ingredients The present invention provides a system for oral delivery of an active ingredient, and the system is a) A mucosal adhesion layer containing a mucosal adhesive and an active ingredient, b) A backing layer extending over a mucosal adhesion layer, comprising a bulk agent and optionally a flavoring agent, The active ingredient is selected from the group consisting of at least one cannabinoid, such as nicotine, caffeine, anatabine, and tetrahydrocannabinol, and combinations thereof. The delivery system is orally soluble, The bulk agent is selected from the group consisting of at least one monosaccharide, disaccharide, and / or polysaccharide, at least one sugar alcohol, and combinations thereof.

[0042] The system for oral delivery of the active ingredient of the present invention is configured to enable efficient transmucosal delivery of the active ingredient. Furthermore, the delivery system is orally soluble.

[0043] The system comprises a mucosal adhesion layer and a backing layer. The active ingredient is contained in the mucosal adhesion layer. The backing layer typically does not contain the active ingredient and extends over the mucosal adhesion layer. The backing layer is water-permeable. During use, the system is placed in the user's mouth so that the mucosal adhesion layer is in contact with the oral mucosa. The mucosal adhesion layer can adhere firmly to the oral mucosa, thereby preventing the swallowing of the active ingredient. The backing layer covers the surface of the mucosal adhesion layer opposite to the surface in contact with the oral mucosa. Thus, the backing layer prevents the active ingredient in the mucosal adhesion layer from coming into contact with saliva, ensuring that the active ingredient is not swallowed. Rather, the active ingredient is advantageously absorbed directly into the bloodstream through the oral mucosa.

[0044] The bulk agent provides a taste (e.g., sweetness) and dissolves gradually over time. The thickness and composition of the backing layer can be selected to match the dissolution time of the mucosal adhesion layer. To avoid contact between the active ingredient and saliva, the dissolution time of the backing layer should be the same as or slightly longer (e.g., 10% longer) than that of the mucosal adhesion layer. Those skilled in the art will be familiar with the dissolution profiles of the compounds constituting the backing and mucosal adhesion layers of the present invention, and the thickness and composition of these layers can be easily adjusted to ensure a proper match in dissolution time.

[0045] The oral delivery system of the present invention may include additional layers, provided that they do not impair the functions of the mucosal adhesion layer and the backing layer. For example, a layer formed of a gelling agent may be present between the mucosal adhesion layer and the backing layer. Alternatively, or additionally, one or more coating layers may be formed on the surface of the backing layer opposite the mucosal adhesion layer.

[0046] a) Mucosal attachment layer The mucosal adhesion layer adheres to the user's oral mucosa. This ensures prolonged contact between the oral mucosa and the active ingredient, while avoiding contact between the active ingredient and saliva. As a result, the active ingredient is efficiently delivered through the user's oral mucosa. Delivery proceeds efficiently into the bloodstream, rather than inefficiently through the gastrointestinal tract, as would occur if the active ingredient were swallowed.

[0047] The mucosal adhesion layer contains a mucosal adhesive. Preferably, the mucosal adhesive is selected from the group consisting of gelatin; pectin; starch; cellulose derivatives, such as carboxymethylcellulose (CMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose, sodium carboxymethylcellulose (Na CMC), etc.; agarose; chitosan derivatives, such as trimethylchitosan (TMC) and chitosan glutamic acid, etc.; hyaluronic acid; polyvinylpyrrolidone (PVP); polyacrylates, such as polyacrylic acid (PAA, e.g., Carbopol®), etc.; polyhydroxyethyl methacrylate (PHEMA); polyvinyl alcohol (PVA); one or more lectins, such as proteins or glycoproteins; one or more thiolated polymers ("thiomers"); polyethylene glycol (PEG); sodium alginate; guar gum; karyja gum; gellan gum; agar; letene; tragacanth, and combinations thereof.

[0048] By using a combination of mucosal adhesives, a mucosal adhesion layer with good properties (adhesion strength, gel strength, and oral solubility) can be obtained.

[0049] In preferred embodiments, the mucosal adhesive is selected from the group consisting of gelatin, chitosan, carboxymethylcellulose (sodium), hydroxypropylmethylcellulose, polyvinyl alcohol, gellan gum, agar, agarose, and combinations thereof. These mucosal adhesives are advantageous in terms of adhesion strength and disintegration time. That is, these mucosal adhesives have excellent adhesion strength and retain the active ingredient for a sufficient time to be delivered transmucosally. At the same time, these mucosal adhesives have excellent oral solubility. More preferably, the mucosal adhesive is selected from the group consisting of gelatin, carboxymethylcellulose (sodium), hydroxypropylmethylcellulose, and combinations thereof. In preferred embodiments, the mucosal adhesive is a combination of CMC and gelatin. In another preferred embodiment, the mucosal adhesive is HPMC, Na CMC, gellan gum, chitosan, agarose, or a combination thereof.

[0050] To further improve the properties of the mucosal adhesion layer (adhesion strength, gel strength, oral solubility, elastic properties, density, color, etc.), the mucosal adhesion layer may also contain a gelling agent. In preferred embodiments, the gelling agent is selected from the group consisting of sorbitol, glycerol, microcrystalline cellulose, and acacia gum.

[0051] In a more preferred embodiment, the mucosal adhesive is HPMC and the gelling agent is glycerol. In the above embodiment, the weight ratio of HPMC to glycerol is preferably about 1:5 to about 5:1, more preferably about 1:2 to about 2:1, and the weight ratio of water to HPMC is preferably about 50:1 to about 10:1, more preferably about 30:1 to about 15:1.

[0052] The mucosal adhesion layer is prepared by mixing a mucosal adhesion agent, an active ingredient, and optional ingredients (e.g., gelling agent, penetration enhancer, etc.) with water. The components of the mucosal adhesion layer are dissolved in water. Dissolution can be achieved or accelerated by heating the mixture; that is, the mixture can be heated to completely dissolve its components. Heating can also be used to increase the viscosity of the mixture. Once the components are dissolved in water, the resulting paste / gel is cast onto a plate (e.g., a metal plate) and dried to obtain the mucosal adhesion layer.

[0053] The mucosal adhesion layer has a total content of water, mucosal adhesive, and gelling agent of at least about 50% by weight, preferably at least about 60% by weight, more preferably at least about 70% by weight, and most preferably at least about 80% by weight, based on the total weight of the mucosal adhesion layer.

[0054] The mucosal attachment layer is approximately 0.1 cm. 2 ~5cm 2 Preferably about 0.5 cm 2 ~3cm 2 More preferably about 0.8 cm 2 ~2cm 2 Most preferably about 0.9 cm 2 ~1.5cm 2 The film may have an area of ​​. In preferred embodiments, in combination with the embodiments described above or below, the film has a thickness of about 0.1 mm to 10 mm, preferably about 0.5 mm to 5 mm, more preferably about 0.7 mm to 3 mm, and most preferably about 1 mm to 2 mm. The shape of the mucosal adhesion layer is not particularly limited. In preferred embodiments, the mucosal adhesion layer has a substantially elliptical shape (e.g., circular shape) or a substantially rectangular shape (e.g., square shape).

[0055] The mucosal adhesion layer contains an active ingredient selected from the group consisting of at least one cannabinoid, such as nicotine, caffeine, anatabine, and tetrahydrocannabinol, and / or any combination thereof in any proportion. The weight ratio of the active ingredient to the mucosal adhesion agent in the mucosal adhesion layer is preferably about 1:1 to 1:1000, more preferably about 1:20 to 1:500, even more preferably about 1:50 to 1:200, and most preferably about 1:80 to 1:150.

[0056] In preferred embodiments, the active ingredient is nicotine, and its content in the mucosal adhesion layer is about 1% to 20% by weight, preferably about 2% to 15% by weight, more preferably about 5% to 12% by weight, and most preferably about 6% to 10% by weight, based on the total weight of the backing layer.

[0057] In a preferred embodiment, nicotine is a nicotine salt. The nicotine salt may be generated in situ during the preparation of the mucosal adhesion layer by mixing free nicotine base with an acidic counterpart (e.g., citric acid).

[0058] In a further preferred embodiment, nicotine may be in a liquid form (e.g., free nicotine base) that is encapsulated (e.g., by a cyclodextrin).

[0059] In preferred embodiments, nicotine is selected from the group consisting of nicotine bitartrate, nicotine polarilex, nicotine betadex (beta-cyclodextrin), nicotine o-salicylate, nicotine gentisinate, nicotine gallate, nicotine phthalate, nicotine isophthalate, nicotine acesulfame H, nicotine benzoate, nicotine fumarate, nicotine R-mandelate, nicotine hydrochloride, nicotine L-lactic acid, nicotine levulinate, nicotine phosphorate, nicotine ascorbate, nicotine ferulate, nicotine vanilate, nicotine picolinate, nicotine cumate, nicotine nicotinate, nicotine pyruvate, nicotine gamma-resorcylate, and combinations thereof.

[0060] In a more preferred embodiment, the active ingredient is caffeine.

[0061] In a more preferred embodiment, the active ingredient is anatabine.

[0062] The mucosal adhesion layer optionally contains an absorption enhancer. The absorption enhancer improves the transport of the active ingredient through the mucosa and therefore shortens the absorption time of the active ingredient. Therefore, if faster absorption of the active ingredient is desired, an absorption enhancer can be added to the mucosal adhesion layer. When an absorption enhancer is present, its content is typically about 1% to 5% by weight (preferably about 1% to 3% by weight, more preferably about 1.5% to 2% by weight) based on the total weight of the mucosal adhesion layer.

[0063] In preferred embodiments, the penetration enhancer is selected from the group consisting of bile salts such as sodium glycodeoxycholate, sodium trihydroxycholate, sodium glycocholate, sodium taurocholate, dihydroxy salt sodium deoxycholate, sodium glycodeoxycholate, and sodium taurodeoxycholate; fatty acids (e.g., oleic acid, lauric acid, cod liver oil) and their salts and esters (e.g., sodium laurate, sodium caprate, glyceryl monostearate, sucrose fatty acid esters, and diethylene glycol monoethyl ether); azones such as laurocapram; surfactants such as sodium dodecyl(lauryl) sulfate, polysorbate, bridi, and benzalkonium chloride; complexing agents such as cyclodextrin, sodium edetate, ethylenediaminetetraacetic acid (EDTA), and sodium citrate; cosolvents such as ethanol and propylene glycol; lecithin; and sodium fusidate. In a more preferred embodiment, the penetration enhancer is selected from the group consisting of bile salts such as sodium glycodeoxycholate, sodium trihydroxycholate, sodium glycocholate, sodium taurocholate, sodium dihydroxydeoxycholate, sodium glycodeoxycholate, and sodium taurodeoxycholate; fatty acids (e.g., oleic acid, lauric acid, cod liver oil) and their salts and esters (e.g., sodium laurate, sodium caprate, glyceryl monostearate, sucrose fatty acid esters, and diethylene glycol monoethyl ether); and azones such as laurocaprum. Combinations of the above penetration enhancers may also be used.

[0064] The mucosal adhesion layer may also contain a lubricant. In a preferred embodiment, the lubricant is selected from the group consisting of at least one polysaccharide, acid, gum arabic, phenol, honey, marshmallow (root), ghee, licorice, slippery elm, and at least one essential oil, such as sage, thyme, tea tree, eucalyptus, oregano, chamomile, peppermint, ginger, echinacea, and / or silk cotton seed oil, as well as combinations thereof. In another preferred embodiment, optionally combined with the embodiments described above or below, the lubricant content is about 1% to 10% by weight, preferably about 1% to 7% by weight, more preferably about 2% to 5% by weight, and most preferably about 2% to 4% by weight, based on the total weight of the mucosal adhesion layer.

[0065] The mucosal adhesion layer may further contain one or more analgesics such as menthol, capsaicin (e.g., derived from cayenne pepper), oleocanthal, sodium bicarbonate, butter, phenol, Arkovox® (Arkopharma), amylmethacresol, dichlorobenzyl alcohol, hexylresorcinol, benzocaine, dextromethorphan, lidocaine, paracetamol, and ibuprofen, or any combination thereof.

[0066] In a preferred embodiment, the total amount of lubricant and analgesic in the mucosal adhesion layer is about 1 to 10% by weight, preferably about 1 to 7% by weight, more preferably about 2 to 5% by weight, and most preferably about 2 to 4% by weight, based on the total weight of the mucosal adhesion layer.

[0067] The mucosal adhesion layer may also contain a dissolution accelerator. The content of the dissolution accelerator in the mucosal adhesion layer is about 0% to 20% by weight of the total weight of the mucosal adhesion layer, preferably about 1% to 15% by weight, more preferably about 2% to 10% by weight, and most preferably about 3% to 5% by weight based on the total weight of the mucosal adhesion layer. The dissolution accelerator shortens the dissolution time of the mucosal adhesion layer.

[0068] b) Backing layer The oral delivery system of the present invention comprises a backing layer extending over a mucosal adhesion layer. The backing layer contains a bulk agent and optionally a flavoring agent. The bulk agent is selected from the group consisting of monosaccharides, disaccharides, and polysaccharides, sugar alcohols, and combinations thereof in any proportion. In a preferred embodiment, the bulk agent is selected from the group consisting of glucose, fructose, galactose, sucrose, lactose, maltose, trehalose, starch, xylitol, sorbitol, erythritol, mannitol, and combinations thereof. In another preferred embodiment, the bulk agent is xylitol, erythritol, or a combination thereof. In a further preferred embodiment, the bulk agent is a combination of xylitol and erythritol in a weight ratio of about 1:5 to 5:1, preferably about 1:2 to 2:1, more preferably about 1:1.5 to 1.5:1, and most preferably about 1:1.

[0069] Because the lining layer extends over the mucosal adhesion layer, it provides a physical barrier between the active ingredient in the mucosal adhesion layer and saliva, thus preventing contact between the active ingredient present in the mucosal adhesion layer and saliva. Consequently, swallowing of the active ingredient is avoided, and the transport of the active ingredient via the transmucosal route is increased. The transmucosal route allows for more efficient delivery of the active ingredient than the gastrointestinal route.

[0070] The backing layer may consist of a bulk agent. The bulk agent may be in a compressed form (e.g., tablet form). Since the bulk agent generally has a sweet flavor, the backing layer also improves the user experience of the system by providing a pleasant sweet flavor while the system of the present invention is in the mouth for oral delivery. The bulk agent is orally soluble and disintegrates in the user's mouth.

[0071] The backing layer may optionally contain flavorings. Flavorings may include vanilla, coffee, chocolate / cocoa, cream, mint, spearmint, menthol, peppermint, dwarf spicebush, eucalyptus, lavender, cardamom, nutmeg, cinnamon, clove, cascarilla, sandalwood, honey, jasmine, ginger, anise, sage, licorice, lemon, orange, apple, peach, lime, cherry, strawberry, and combinations thereof. The flavoring content in the backing layer is typically 0% to 30% by weight, preferably about 1% to 20% by weight, more preferably about 5% to 15% by weight, and most preferably about 7% to 12% by weight, based on the total weight of the backing layer. Additionally, a small amount of nicotine (e.g., nicotine salts such as nicotine stearate or nicotine palmitate) may be added to the backing layer (about 0% to 2% by weight of the total weight of the backing layer) to give the backing layer a nicotine flavor.

[0072] In a preferred embodiment, the flavoring agent is in powder (solid) form. In another preferred embodiment, the flavoring agent is an enclosed liquid fragrance.

[0073] The lining layer may contain a binder. Depending on the bulk material used, the addition of a binder can improve the mechanical strength of the lining layer. Furthermore, the addition of a binder allows the lining layer to be prepared without applying excessive mechanical pressure. As a result, a lower-density lining layer can be obtained that can disintegrate more quickly in the user's mouth. The binder can also improve the bond between the lining layer and the mucosal adhesion layer. The binder content in the lining layer is about 0% to 20% by weight based on the total weight of the lining layer, preferably about 1% to 15% by weight based on the total weight of the lining layer, more preferably about 2% to 10% by weight based on the total weight of the lining layer, and most preferably about 3% to 5% by weight based on the total weight of the lining layer.

[0074] In preferred embodiments, the binder may be selected from the group consisting of carboxymethylcellulose (sodium), guar gum, gelatin, (sodium) alginate, polyvinyl alcohol, polyethylene glycol, microcrystalline cellulose, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, Carbopol®, Kalya gum, polyacrylic acid, acacia gum, polyvinylpyrrolidone, and any combination thereof. These binders can reduce the dissolution time of the backing layer to about 15 to 45 minutes (e.g., about 20 to 30 minutes), which is highly desirable.

[0075] The backing layer may also contain a dissolution accelerator. The content of the dissolution accelerator in the backing layer is about 0% to 20% by weight of the total weight of the backing layer, preferably about 1% to 15% by weight, more preferably about 2% to 10% by weight, and most preferably about 3% to 5% by weight based on the total weight of the backing layer. The dissolution accelerator shortens the dissolution time of the backing layer. The dissolution accelerator may be present in the backing layer instead of or in addition to the binder. In a preferred embodiment, the backing layer contains a binder and a dissolution accelerator, and the total weight of the binder and dissolution accelerator in the backing layer is about 2% to 20% by weight, preferably about 5% to 15% by weight, and more preferably about 7% to 10% by weight based on the total weight of the backing layer.

[0076] In preferred embodiments, the dissolution accelerator is selected from citric acid, sodium bicarbonate, sodium starch glycolate, croscarmellose sodium, alginic acid, crospovidone, calcium silicate, or any combination thereof, and may be optionally combined with any of the embodiments described above or below.

[0077] The lining layer has an area at least equal to the area of ​​the mucosal attachment layer. Preferably, the area of ​​the lining layer is about 0-20% larger than the area of ​​the mucosal attachment layer. More preferably, the area of ​​the lining layer is approximately equal to the area of ​​the mucosal attachment layer.

[0078] The thickness of the backing layer can be appropriately selected based on the thickness of the mucosal adhesion layer to ensure that the active ingredients are completely absorbed before the backing layer dissolves. In one embodiment, the thickness of the backing layer is about 10% to about 500% greater than the thickness of the mucosal adhesion layer, for example, about 20% to about 200% greater.

[0079] Preparation of a system for oral delivery according to the present invention The oral delivery system of the present invention can be prepared by the following method.

[0080] The backing layer is prepared by mixing all the components of the backing layer and pressing the mixture into a mold to obtain a backing layer of the desired shape.

[0081] The mucosal adhesion layer is prepared as described herein. The surface of the mucosal adhesion layer is moistened to create an adhesive effect so that the backing layer can be placed on the mucosal adhesion layer and fixed thereon.

[0082] Figure 1 shows one embodiment of the system of the present invention. The system (11) comprises a backing layer (12) and a mucosal adhesion film (3) made of a pressed powder mixture (tablet). The mucosal adhesion film (13) contains an active ingredient. The backing layer (12) extends over the upper surface of the mucosal adhesion layer (13). The system (11) is placed in the user's mouth such that the exposed surface of the mucosal adhesion film (13) is in contact with the gingival mucosa (14).

[0083] During use, the system (11) is placed in the user's mouth so that the mucosal adhesion film (13) is in contact with the gingival mucosa (14). The mucosal adhesion film (13) adheres firmly to the gingival mucosa, thereby preventing the swallowing of the active ingredients. The lining layer (12) covers the surface of the mucosal adhesion film (13) opposite to the surface that is in contact with the gingival mucosa. Thus, the lining layer (12) prevents the active ingredients in the mucosal adhesion layer (13) from coming into contact with saliva, ensuring that the active ingredients are not swallowed. Rather, the active ingredients are advantageously absorbed directly into the bloodstream through the oral mucosa.

[0084] Figure 2 shows another embodiment of the system of the present invention. The system (21) comprises a backing layer (22) and a mucosal adhesion film (23) made of a pressed powder mixture (tablet). The mucosal adhesion film (23) contains an active ingredient. The backing layer (22) completely covers all three sides (upper, left, and right in Figure 2) of the mucosal adhesion layer (23) such that only the bottom side (the side in contact with the gingival mucosa (24)) of the mucosal adhesion layer (23) is exposed. The system (21) is placed in the user's mouth so that the mucosal adhesion film (23) is in contact with the gingival mucosa (24).

[0085] In one embodiment, the mucosal adhesive is selected from the group consisting of gelatin, carboxymethylcellulose (sodium), hydroxypropylmethylcellulose, and combinations thereof, the active ingredient is nicotine, the mucosal adhesive content is 60% to 80% by weight based on the total weight of the mucosal adhesive layer, the nicotine content is 5% to 12% by weight based on the total weight of the mucosal adhesive layer, the bulk agent is xylitol, erythritol, or a combination thereof, and the flavoring agent is vanilla, coffee, chocolate / cocoa, cream, mint, spearmint, menthol, peppermint, or a combination thereof.

[0086] In further embodiments, the mucosal adhesive is selected from the group consisting of gelatin, carboxymethylcellulose (sodium), hydroxypropylmethylcellulose, and combinations thereof; the active ingredient is a nicotine salt selected from the group consisting of nicotine lactate, nicotine aspartate, nicotine glutarate, nicotine citrate, and combinations thereof; the mucosal adhesive content is 60% to 80% by weight based on the total weight of the mucosal adhesive layer; the nicotine content is about 5% to 10% by weight based on the total weight of the mucosal adhesive layer; the bulk agent is a combination of xylitol and erythritol; and the flavoring agent is coffee, chocolate / cocoa, peppermint, or a combination thereof.

[0087] In further embodiments, in combination with any of the above embodiments, the mucosal adhesion layer comprises an analgesic selected from menthol, capsaicin, oleocanthal, sodium bicarbonate, phenol, Arkovox®, amylmethacresol, dichlorobenzyl alcohol, hexylresorcinol, benzocaine, dextromethorphan, lidocaine, paracetamol, ibuprofen, or any combination thereof, and a lubricant selected from sage oil, thyme, tea tree oil, eucalyptus oil, oregano oil, chamomile oil, peppermint oil, or a combination thereof, wherein the total amount of lubricant and analgesic in the mucosal adhesion layer is about 2% to 5% by weight, based on the total weight of the mucosal adhesion layer.

[0088] Dosage form In another embodiment, the present invention relates to a dosage form comprising a system for oral delivery of the present invention. In a preferred embodiment, the dosage form is a tablet. The shape of the tablet is not particularly limited. In a preferred embodiment, the tablet is generally round, for example, having an oval or circular shape. In another preferred embodiment, in combination with any of the embodiments described above or below, the dosage form is packaged in a blister pack. In another preferred embodiment, the dose of the active ingredient in the dosage form is about 0.1 g to 5 g, preferably about 0.5 g to 2 g, more preferably about 0.7 g to 1.2 g.

[0089] The present invention also covers the following embodiments.

[0090] Embodiment 1. A system for oral delivery of the active ingredient, a) A mucosal adhesion layer containing a mucosal adhesive and an active ingredient, b) A backing layer extending over a mucosal adhesion layer, comprising a bulk agent and optionally a flavoring agent, The active ingredient is selected from the group consisting of at least one cannabinoid, such as nicotine, caffeine, anatabine, and tetrahydrocannabinol, and combinations thereof. The delivery system is orally soluble, The bulk agent is selected from the group consisting of at least one monosaccharide, disaccharide, and / or polysaccharide, at least one sugar alcohol, and combinations thereof. Embodiment 2. The system according to Embodiment 1, wherein the backing layer further comprises a binder. Embodiment 3. The system according to Embodiment 2, wherein the binder is selected from the group consisting of carboxymethylcellulose (sodium), guar gum, gelatin, (sodium) alginate, polyvinyl alcohol, polyethylene glycol, microcrystalline cellulose, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, Carbopol®, Kalya gum, polyacrylic acid, acacia gum, polyvinylpyrrolidone, and any combination thereof. Embodiment 4. The system according to Embodiment 2 or 3, wherein the binder content in the backing layer is about 1% to 15% by weight based on the total weight of the backing layer, preferably about 2% to 10% by weight based on the total weight of the backing layer, and more preferably about 3% to 5% by weight based on the total weight of the backing layer. Embodiment 5. The system according to any one of Embodiments 1 to 4, wherein the backing layer further comprises a dissolution accelerator. Embodiment 6. The system according to Embodiment 5, wherein the content of the dissolution accelerator in the backing layer is about 1% to 15% by weight of the total weight of the backing layer, preferably about 2% to 10% by weight of the total weight of the backing layer, and more preferably about 3% to 5% by weight based on the total weight of the backing layer. Embodiment 7. The system according to Embodiment 1 or 3, wherein the backing layer comprises a binder and a dissolution accelerator, and the total weight of the binder and dissolution accelerator in the backing layer is about 2% to 20% by weight, preferably about 5% to 15% by weight, and more preferably about 7% to 10% by weight, based on the total weight of the backing layer. Embodiment 8. The system according to any one of embodiments 5 to 7, wherein the dissolution accelerator is selected from the group consisting of citric acid, sodium bicarbonate, sodium starch glycolate, croscarmellose sodium, alginic acid, crospovidone, calcium silicate, and combinations thereof. Embodiment 9. The system according to any one of Embodiments 1 to 8, wherein the mucosal adhesive is selected from the group consisting of gelatin; pectin; starch; cellulose derivatives, e.g., carboxymethylcellulose (CMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose, sodium carboxymethylcellulose (Na CMC), etc.; agarose; chitosan, including chitosan derivatives (e.g., trimethylchitosan (TMC), or chitosan glutamic acid); hyaluronic acid; polyvinylpyrrolidone (PVP); polyacrylate (e.g., polyacrylic acid (PAA, e.g., Carbopol®)); polyhydroxyethyl methacrylate (PHEMA); polyvinyl alcohol (PVA); one or more lectins (e.g., proteins or glycoproteins); one or more thiolated polymers; polyethylene glycol (PEG); sodium alginate; guar gum; karyja gum; gellan gum; agar; letene; tragacanth; and combinations thereof. Embodiment 10. The system according to Embodiment 9, wherein the mucosal adhesive is selected from the group consisting of gelatin, chitosan, carboxymethylcellulose (sodium), hydroxypropylmethylcellulose, polyvinyl alcohol, gellan gum, agar, agarose, and combinations thereof, and preferably the mucosal adhesive is selected from the group consisting of gelatin, carboxymethylcellulose (sodium), hydroxypropylmethylcellulose, and combinations thereof. Embodiment 11. The system according to Embodiment 10, wherein the mucosal adhesive is a combination of CMC and gelatin. Embodiment 12. The system according to Embodiment 10, wherein the mucosal adhesive is HPMC, Na CMC, gellan gum, chitosan, agarose, or a combination thereof. Embodiment 13. The system according to any one of Embodiments 1 to 12, wherein the mucosal adhesion layer further comprises a gelling agent. Embodiment 14. The system according to Embodiment 14, wherein the gelling agent is selected from the group consisting of sorbitol, glycerol, microcrystalline cellulose, and acacia gum. Embodiment 15. The system according to Embodiment 13 or 14, wherein the mucosal adhesive is HPMC and the gelling agent is glycerol. Embodiment 16. The system according to Embodiment 15, wherein the weight ratio of HPMC to glycerol is about 1:5 to about 5:1, preferably about 1:2 to about 2:1, and the weight ratio of water to HPMC is about 50:1 to about 10:1, preferably about 30:1 to about 15:1. Embodiment 17. The system according to any one of Embodiments 1 to 16, wherein the mucosal adhesion layer has a total content of at least about 50% by weight, preferably at least about 60% by weight, more preferably at least about 70% by weight, and most preferably at least about 80% by weight of water, mucosal adhesion agent, and gelling agent, based on the total weight of the mucosal adhesion layer. Embodiment 18. The system according to any one of Embodiments 1 to 17, wherein the mucosal adhesion layer contains an active ingredient selected from the group consisting of at least one cannabinoid such as nicotine, caffeine, anatabine, and tetrahydrocannabinol, and combinations thereof. Embodiment 19. The system according to Embodiment 18, wherein the weight ratio of the active ingredient to the mucosal adhesive in the mucosal adhesion layer is about 1:1 to 1:1000, preferably about 1:20 to 1:500, more preferably about 1:50 to 1:200, and most preferably about 1:80 to 1:150. Embodiment 20. The system according to any one of Embodiments 1 to 19, wherein the active ingredient is nicotine. Embodiment 21. The system according to Embodiment 20, wherein the nicotine content of the mucosal adhesion layer is about 1% to 20% by weight, preferably about 2% to 15% by weight, more preferably about 5% to 12% by weight, and most preferably about 6% to 10% by weight, based on the total weight of the backing layer. Embodiment 22. The system according to embodiment 20 or 21, wherein nicotine is a nicotine salt. Embodiment 23. The system according to Embodiment 20 or 21, wherein the nicotine is in a liquid form of nicotine (e.g., free nicotine base) that is encapsulated (e.g., by cyclodextrin). Embodiment 24. The system according to Embodiment 20 or 21, wherein nicotine is selected from the group consisting of nicotine betartrate, nicotine betadex (beta-cyclodextrin), nicotine o-salicylate, nicotine gentisinate, nicotine gallate, nicotine phthalate, nicotine isophthalate, nicotine-acesulfame H, nicotine benzoate, nicotine fumarate, nicotine R-mandelate, nicotine hydrochloride, nicotine L-lactic acid, nicotine levulinate, nicotine phosphorate, nicotine ascorbate, nicotine ferulate, nicotine vanilate, nicotine picolinate, nicotine cumate, nicotine nicotinate, nicotine pyruvate, nicotine gamma-resorcylate, and combinations thereof. Embodiment 25. The system according to any one of Embodiments 1 to 19, wherein the active ingredient is caffeine. Embodiment 26. The system according to any one of Embodiments 1 to 19, wherein the active ingredient is anatabine. Embodiment 27. The system according to any one of Embodiments 1 to 26, wherein the mucosal adhesion layer further comprises a penetration enhancer. Embodiment 28. The system according to Embodiment 27, wherein the content of the penetration enhancer is in the range of about 1% to 5% by weight, preferably about 1% to 3% by weight, and more preferably about 1.5% to 2% by weight, based on the total weight of the mucosal adhesion layer. Embodiment 29. The system according to Embodiment 27 or 28, wherein the penetration enhancer is selected from the group consisting of bile salts such as sodium glycodeoxycholate, sodium trihydroxycholate, sodium glycocholate, sodium taurocholate, dihydroxy salt sodium deoxycholate, sodium glycodeoxycholate, and sodium taurodeoxycholate; fatty acids (e.g., oleic acid, lauric acid, cod liver oil), and their salts and esters (e.g., sodium laurate, sodium caprate, glyceryl monostearate, sucrose fatty acid esters, and diethylene glycol monoethyl ether); azones such as laurocaprum; surfactants such as sodium dodecyl(lauryl) sulfate, polysorbate, laureths, bridi, and benzalkonium chloride; complexing agents such as cyclodextrin, sodium edetate, ethylenediaminetetraacetic acid (EDTA), and sodium citrate; cosolvents such as ethanol and propylene glycol; lecithin; and sodium fusidate. Embodiment 30. The system according to any one of Embodiments 1 to 29, wherein the mucosal adhesion layer further comprises a lubricant. Embodiment 31. The system according to Embodiment 30, wherein the lubricant is selected from the group consisting of at least one polysaccharide, galacturonic acid, gum arabic, phenol, honey, marshmallow (root), ghee, licorice, slippery elm, and at least one essential oil, such as sage, thyme, tea tree, eucalyptus, oregano, chamomile, peppermint, ginger, echinacea, and / or silk cotton seed oil essential oils, and combinations thereof. Embodiment 32. The system according to Embodiment 31 or 32, wherein the lubricant content is in the range of about 1% to 10% by weight, preferably about 1% to 7% by weight, more preferably about 2% to 5% by weight, and most preferably about 2% to 4% by weight, based on the total weight of the mucosal adhesion layer. Embodiment 33. The system according to any one of Embodiments 1 to 32, wherein the mucosal adhesion layer further comprises one or more analgesics such as menthol, capsaicin (e.g., derived from cayenne pepper), oleocanthal, sodium bicarbonate, butter, phenol, Arkovox® (Arkopharma), amylmethacresol, dichlorobenzyl alcohol, hexylresorcinol, benzocaine, dextromethorphan, lidocaine, paracetamol, and ibuprofen, or any combination thereof. Embodiment 34. The system according to Embodiment 33, wherein the total amount of lubricants and analgesics in the mucosal adhesion layer is, in all ranges, about 1 to 10% by weight, preferably about 1 to 7% by weight, more preferably about 2 to 5% by weight, and most preferably about 2 to 4% by weight, based on the total weight of the mucosal adhesion layer. Embodiment 35. The system according to any one of Embodiments 1 to 34, wherein the mucosal adhesion layer further comprises a dissolution accelerator. Embodiment 36. The system according to Embodiment 35, wherein the content of the dissolution accelerator in the mucosal adhesion layer is about 1% to 20% by weight of the total weight of the mucosal adhesion layer, preferably about 1% to 15% by weight of the total weight of the mucosal adhesion layer, more preferably about 2% to 10% by weight of the total weight of the mucosal adhesion layer, and most preferably about 3% to 5% by weight based on the total weight of the mucosal adhesion layer. Embodiment 37. The system according to any one of Embodiments 1 to 35, wherein the backing layer does not contain a pharmaceutical active ingredient. Embodiment 38. The system according to any one of Embodiments 1 to 35, wherein the weight ratio of the active ingredient in the mucosal adhesion layer to the weight ratio of the active ingredient in the backing layer is 1:1 to 1000:1. Embodiment 39. The system according to any one of Embodiments 1 to 38, wherein the weight ratio of the active ingredient to the mucosal adhesive in the mucosal adhesion layer is approximately 1:1 to 1:1000. Embodiment 40. The system according to any one of Embodiments 1 to 39, wherein the backing layer further contains a flavoring agent. Embodiment 41. The system according to Embodiment 40, wherein the flavoring agents are vanilla, coffee, chocolate / cocoa, cream, mint, spearmint, menthol, peppermint, dwarf spicebush, eucalyptus, lavender, cardamom, nutmeg, cinnamon, clove, cascarilla, sandalwood, honey, jasmine, ginger, anise, sage, licorice, lemon, orange, apple, peach, lime, cherry, strawberry, and combinations thereof. Embodiment 42. The system according to Embodiment 40 or 41, wherein the flavoring agent content in the backing layer is in the range of 0.5% to 30% by weight, preferably about 1% to 20% by weight, more preferably about 5% to 15% by weight, and most preferably about 7% to 12% by weight, all based on the total weight of the backing layer. Embodiment 43. The system according to any one of Embodiments 40 to 42, wherein the flavoring agent is in powder (solid) form. Embodiment 44. The system according to any one of embodiments 40 to 42, wherein the flavoring agent is an enclosed liquid fragrance. Embodiment 45. The system according to any one of Embodiments 1 to 44, wherein the backing layer has an area at least equal to the area of ​​the mucosal adhesion layer, and preferably the area of ​​the backing layer is about 0 to 20% larger than the area of ​​the mucosal adhesion layer. Embodiment 46. The system according to Embodiment 45, wherein the area of ​​the backing layer is approximately equal to the area of ​​the mucosal adhesion layer. Embodiment 47. The system according to any one of embodiments 1 to 46, wherein the mucosal attachment layer has a single exposed surface, and the remaining surface is covered by a backing layer. Embodiment 48. A dosage form comprising the system described in any one of Embodiments 1 to 47. Embodiment 49. The dosage form according to Embodiment 48, which is in the form of a tablet. Embodiment 50. A blister pack containing the dosage form described in Embodiment 48 or 49. [Examples]

[0091] Example 1: Preparation of the mucosal attachment layer The nicotine / lactic acid solution was obtained by mixing 100 μl of free nicotine base with 51 μl of lactic acid (target molar ratio 1:1). Separately, 5g of CMC was dissolved in 45g of water. Then, nicotine / lactic acid solution was added to the CMC solution. The resulting mixture was heated to dissolve all the solids and obtain a gel. The resulting gel was cast onto a plate and dried to obtain a mucosal adhesion layer. Example 2: Preparation of the mucosal attachment layer 80 mg of aspartic acid was dissolved in 10 g of water by heating. 100 μl of nicotine was added to the aspartic acid solution. Separately, 5 g of CMC was dissolved in 35 g of water. Then, a nicotine / aspartic acid solution was added to the CMC solution and heated to obtain a gel. The obtained gel was cast onto a plate and dried to obtain a mucosal adhesion layer. Example 3: Preparation of the backing layer The powder was prepared by mixing equal parts erythritol and xylitol, and flavorings and active ingredients (e.g., anatabine) were added. The mixture was pressed into a mold using a commercially available apparatus (e.g., Roltgen Table Press Flexitab S) to obtain the desired shape (e.g., tablets). [Explanation of Symbols]

[0092] 11, 21 Systems for Oral Delivery 12, 22 Backing layer 13, 23 Mucosal adhesion film 14, 24 Gingival mucosa

Claims

1. A system for oral delivery of active ingredients, a) A mucosal adhesion layer containing a mucosal adhesion agent and an active ingredient, b) A backing layer extending on the mucosal adhesion layer, comprising a bulk agent and optionally a flavoring agent, The active ingredient is selected from the group consisting of at least one cannabinoid such as nicotine, caffeine, anatabine, and tetrahydrocannabinol, and combinations thereof. The delivery system is orally soluble, A system in which the bulk agent is selected from the group consisting of at least one monosaccharide, disaccharide, and / or polysaccharide, at least one sugar alcohol, and combinations thereof.

2. The system according to claim 1, wherein the backing layer further comprises a binder.

3. The system according to claim 1 or 2, wherein the backing layer further comprises a dissolution accelerator.

4. The system according to any one of claims 1 to 3, wherein the mucosal adhesion layer further comprises a penetration enhancer.

5. The system according to any one of claims 1 to 4, wherein the backing layer does not contain a pharmaceutical active ingredient.

6. The system according to any one of claims 1 to 4, wherein the weight ratio of the active ingredient in the mucosal adhesion layer to the weight ratio of the active ingredient in the backing layer is 1:1 to 1000:

1.

7. The system according to any one of claims 1 to 4, wherein the weight ratio of the active ingredient to the mucosal adhesive in the mucosal adhesion layer is about 1:1 to 1:1000.

8. The system according to any one of claims 1 to 7, wherein the mucosal adhesive is selected from the group consisting of gelatin, chitosan, carboxymethylcellulose (sodium), hydroxypropylmethylcellulose, polyvinyl alcohol, gellan gum, agar, agarose, and combinations thereof.

9. The system according to any one of claims 1 to 8, wherein the active ingredient is nicotine.

10. A dosage form comprising the system described in any one of claims 1 to 9.

11. The dosage form according to claim 10, which is in the form of a tablet.

12. A blister pack comprising the dosage form according to claim 10 or 11.

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