Solid mucoadhesive composition

Abstract

A solid mucoadhesive composition comprising or consisting of (a) at least one active agent, preferably at least one perfume or fragrance molecule; (b) at least one carrier; and (c) at least one mucoadhesive polymer, wherein the carrier is selected from the group comprising silicon dioxide, silica and silicates.

Description

Invention Field

[0001] This invention relates to the field of oral care preparations and to novel solid mucosal adhesion compositions, manufacturing methods, and uses thereof. Background Technology

[0002] Fragrances and flavorings often exhibit unfavorable adhesion and release properties on physiological surfaces. Therefore, to improve the intensity and / or duration of taste or odor, or further sensory perception, the concentration of the substance used is increased, or highly effective agents are employed.

[0003] However, the problem of being able to control sensory perception only to a limited extent remains. Furthermore, the duration and intensity of perception can only be painstakingly measured within the body.

[0004] Related existing technologies

[0005] WO 2002 002085 A2(LTS) relates to a dosage form, particularly in the form of tablets, which rapidly disintegrates or dissolves in an aqueous environment for the rapid release of an active ingredient in the oral cavity, body orifice, or body cavity, wherein the dosage form comprises a matrix containing one or more water-soluble polymers as a base substance and containing at least one active ingredient, characterized in that the dosage form has spaces or cavities present in the polymer matrix, the content of which differs from that of the matrix in terms of polymerization state.

[0006] WO 2003 011247 A2(LTS) refers to a form of drug delivery applied to the skin or mucous membrane, comprising a carrier matrix and at least one active substance, characterized in that the carrier matrix has a plurality of particles having open pores or containing capillary spaces, the particles serving as reservoirs for the active substance and containing at least one active substance.

[0007] EP 2347796 A2 (EVONIK) describes functional composite particles for use in the field of oral care, more particularly for toothpaste and mouthwash, which are filled with active ingredients that ensure long-term antimicrobial or antibacterial effects in the oral cavity, thereby reducing plaque formation and halitosis. This invention also relates to methods for producing these composite particles and their use in the production of oral hygiene products.

[0008] US 5,700,478 (CYGNUS) covers water-soluble pressure-sensitive adhesives containing a water-soluble polymer that becomes viscous at room temperature by adding a water-soluble plasticizer miscible with the polymer. Suitable polymers are solids at room temperature; and have a hydrophilicity greater than about 25% by weight, as measured by water absorption; they are liquids at room temperature with a boiling point above about 80°C. The adhesives according to the invention can be conveniently provided in dry film form. Preferred water-soluble pressure-sensitive adhesives of the invention can adhere to mucosal surfaces as well as to a variety of materials that can form part of a device or prosthesis for retention in a body cavity with a mucosal lining.

[0009] US 2004 0156794 A1 (BARKALOW) relates to bioadhesive and bioerosive confectionery products and methods of their preparation and use; more specifically, the invention provides delivery systems for extended release of flavorings, sweeteners, cooling agents, and active ingredients to consumers. Furthermore, these confectionery products can also provide consumers with a place to mask the taste and bitterness of drugs or other active ingredients.

[0010] US 2006 0182786 A1 (RADEMACHER) relates to a film-like delivery form for administering an active substance to a human or animal via a mucosa. The delivery form is characterized by a pH value of the base substance used in its production being adapted to or close to the physiological pH of the mucosa to which the delivery form will be applied. The base substance comprises a solvent or a mixture of a solvent, at least one matrix-forming polymer, and at least one active substance. The invention also includes methods for preparing such formulations and their use as delivery forms, particularly for pharmaceutically active substances, such that mucosal irritation is reduced or even prevented when the resulting delivery form is used.

[0011] US Patent 2014 / 0234212 A1 (MIT) discloses an oral delivery device comprising a mucosal adhesive polymer matrix, nanoparticles dispersed therein, and an impermeable backing layer, wherein an active substance is loaded within the nanoparticles. In application, the oral delivery device is placed on a mucosal layer and adheres to the oral epithelium via mucosal adhesion, where the nanoparticles penetrate the mucosa and controllably release the loaded active substance. The nanoparticles used are produced in solutions containing the active substance and a corresponding polymer.

[0012] US 2013 / 0337022 A1 (UNIVERSITY OF THE WITWATERSRAND) relates to a pharmaceutical dosage form comprising a mucosal adhesion layer, a water-insoluble layer, and an intermediate layer loaded with an active substance, wherein the active substance is in the form of a microstructure and / or nanostructure and is incorporated into the intermediate layer by directed dissolution, suspension, or emulsion. The mucosal adhesion of the dosage form is assessed using a texture analyzer by measuring the tension required to separate the dosage form film from a simulated gastric lining.

[0013] US 20110028431 A1 (ZERBE et al.) relates to a direct compressed formulation produced by mixing a mucosal adhesion polymer, a pharmaceutically active substance, a disintegrant, and other components, followed by compression to obtain a blend. The resulting compressed formulation can be further formulated into solid oral dosage forms. By administering these dosage forms, the absorption of the active substance through the oral mucosa is enhanced, and the intake of the active substance is reduced.

[0014] US 2010 / 0063110 A1 (MEYER et al.) discloses an oral disintegrating membrane containing an alkaline substance that disintegrates and adheres to the buccal mucosa within 1 to 10 minutes in the oral cavity. The mucosal adhesion of the membrane was tested using a tensile strength tester.

[0015] US 2009 / 0110717 A1 (SINGH et al.) relates to a transmucosal tablet comprising two compartments for administering an active substance, preferably with the active substance in the inner compartment and a mucosal adhesive in the outer compartment. In application, portions of the inner and outer compartments adhere to the mucosa to deliver the active substance via the buccal mucosa. After achieving the desired effect of the active substance, the tablet can be easily peeled off.

[0016] US 2017 / 0071988 A1 (SYMRISE) relates to mucosal adhesive active compositions and corresponding mucosal adhesive dosage forms that can deliver active substances in the oral cavity, particularly oral dispersible tablets for delivering probiotics.

[0017] Purpose of the invention

[0018] Therefore, the object of the present invention is to provide novel mucosal adhesion compositions and, in particular, to identify suitable carriers of active agents, preferably aromatic molecules, such as fragrances, aromatic agents, and physiological cooling / warming agents, for use in oral care, having improved properties, such as higher strength and / or longer duration and / or elimination of odor upon contact with human mucosa. Summary of the Invention

[0019] The first object of the present invention refers to a solid adhesive film composition comprising or consisting of the following substances

[0020] (a) at least one active agent, preferably at least one fragrance or aroma agent molecule;

[0021] (b) at least one carrier; and

[0022] (c) at least one mucosal adhesion polymer,

[0023] The carrier is selected from the group consisting of silica, silica gel, and silicates.

[0024] Surprisingly, silica, silicates, and certain types of silica have been found to be suitable carriers for certain surfactants, ensuring both long-term storage stability and easy delivery to mucous membranes.

[0025] Solid adhesive film composition

[0026] The active agent constituting component (a) of the composition according to the invention represents an agent commonly used in oral care preparations and causing sensation upon contact with mucous membranes. These agents are generally selected from the group comprising fragrances, aromatics, physiological cooling agents, physiological warming agents, and mixtures thereof.

[0027] Fragrance and aroma compounds

[0028] Suitable fragrance and aroma compounds can be selected from synthetic fragrance liquids and / or oils derived from plant leaves, flowers, fruits, etc., and combinations thereof. Representative fragrance liquids include: artificial, natural, or naturally occurring flavorings such as eucalyptus oil, lemon oil, orange oil, banana oil, grape oil, white lemon oil, almond oil, and grapefruit oil; fruit flavorings including apple, strawberry, cherry, orange, pineapple, etc.; flavorings derived from legumes and nuts such as coffee, cocoa, cola, peanut, almond, etc.; and root-derived flavorings such as licorice or ginger.

[0029] Fragrance preparations preferably consist of essential oils and extracts, tinctures and balms, such as fennel oil, basil oil, bergamot oil, bitter almond oil, camphor oil, lemongrass oil, lemon oil; lemon eucalyptus oil, eucalyptus oil, fennel oil, grapefruit oil, chamomile oil, peppermint oil, artemisia oil, white lemon oil, orange oil, nutmeg oil, myrrh oil, clove oil, clove flower oil, orange oil, oregano oil, parsley (seed) oil, peppermint oil, rosemary oil, sage oil (fragrant sage oil, Dalmatian or Spanish sage oil), star anise oil, thyme oil, vanilla extract, cypress oil (especially juniper berry oil), wintergreen oil, cinnamon leaf oil, cinnamon oil and their fractions, or components separated from them.

[0030] Particularly advantageous is that the fragrance composition of the present invention contains at least one, preferably two, three, four, five, six, seven, eight or more fragrance preparations selected from the group consisting of: menthol (preferably L-menthol and / or racemic menthol), anethole, anethole ether, anisaldehyde, anisol, (racemic) neomenthol, eucalyptol (1,8-eucalyptol), menthone (preferably L-menthone), isomenthone (preferably D-isomenthone), isomenthone, menthyl acetate (preferably L-menthone), menthyl propionate, carvone (preferably (-)-carvone, optionally as a component of spearmint oil), methyl salicylate (optionally as a component of wintergreen oil), eugenol acetate, isoeugenol methyl ether, β-cyclocitral, eugenol, isobutyraldehyde, 3-octanol, dimethyl sulfide, hexanol, hexanal, trans-2-hexanal, cis-3-hexenol, 4-terpineol, menthone, linalool Alcohols, 8-ocimene acetate, isoamyl alcohol, isovaleraldehyde, α-pinene, β-pinene, limonene (preferably D-limonene, optional as a component of the essential oil), menthone, trans-hydrated sapindus mucilage, mentha furan, caryophyllene, geraniol D, cinnamaldehyde, menthol, thymol, γ-octyl lactone, γ-nonanolactone, γ-decyl lactone, (1,3E,5Z)-undecanetriene, 2-butanone, ethyl formate, 3-octyl acetate, isoamyl isovalerate, Cis- and trans-carvyl acetate, p-cymene, damascone, damascone, cis-rosinone, trans-rosinone, frankinc, acetaldehyde diethyl acetal, 1-ethoxyethyl acetate, cis-4-heptenal, cis-jasmone, methyl dihydrojasmonic acid, 2'-hydroxyphenylacetone, menthyl methyl ether, myrtyl acetate, 2-phenylethanol, 2-phenylethyl isobutyrate, 2-phenylethyl isovalerate, geraniol, nerol, and chlorophyllol.

[0031] The particularly preferred fragrance or aromatic compounds contain menthol, eucalyptol, eugenol, thymol, cinnamaldehyde, peppermint oil, spearmint oil, eucalyptus oil, thyme oil, cinnamon oil, clove oil, spruce needle oil, fennel oil, sage oil, anise oil, star anise oil, chamomile oil, and artemisia oil, and mixtures thereof.

[0032] spices

[0033] Flavors may be used as a single component or in more or less complex mixtures; the flavors may be obtained from natural sources or prepared through organic synthesis.

[0034] Natural aromatic oils include extracts from flowers (lily, lavender, rose, jasmine, orange blossom, ylang-ylang), stems and leaves (geranium, patchouli, bitter orange), fruits (fennel, coriander, cilantro, juniper), peels (bergamot, lemon, orange), roots (nutmeg, angelica, celery, cardamom, costus root, iris, calamus), woods (pine, sandalwood, guaiac, cedar, rosewood), herbs and grasses (tarragon, lemongrass, sage, thyme), pine needles and branches (spruce, fir, pine, dwarf pine), resins and balsams (galbanum, elemi, benzoin, myrrh, frankincense, red myrrh). Animal ingredients, such as civet and castoreum, may also be used.

[0035] Synthetic fragrances typically represent aldehydes, ketones, alcohols, ethers, esters, hydrocarbons, and mixtures thereof. These types of fragrances are illustrated below but are not limited to the examples:

[0036] Aldehydes. Suitable fragrance examples displaying aldehyde structures include melon aldehyde, triplal, ligustral, adoxal, anisaldehyde, cymal, ethyl vanillin, anthocyanin, senna aldehyde, neojasmine aldehyde, piperaldehyde, hydroxycitronellol, Koavon, lauryl, canthoxal, neolichal, lily aldehyde, adoxal, anisaldehyde, cumal, methylnonylacetaldehyde, citronellol, citronelloloxyacetaldehyde, cyclamen aldehyde, bourgeonal, p,t-bucinal, phenylacetaldehyde, undecenal, vanillin; 2,6,10-trimethyl-9-undecenal, 3-dodecen-1- Aldehydes, α-n-pentylcinnamaldehyde, 4-methoxybenzaldehyde, benzaldehyde, 3-(4-tert-butylphenyl)propanal, 2-methyl-3-(p-methoxyphenyl)propanal, 2-methyl-4-(2,6,6-trimethyl-2(1)-cyclohexen-1-yl)butanal, 3-phenyl-2-propenal, cis / trans-3,7-dimethyl-2,6-octadien-1-aldehyde, 3,7-dimethyl-6 -Octen-1-aldehyde, [(3,7-dimethyl-6-octenyl)oxy]acetaldehyde, 4-isopropylbenzylaldehyde, 1,2,3,4,5,6,7,8-octahydro-8,8-dimethyl-2-naphthaldehyde, 2,4-dimethyl-3-cyclohexene-1-carboxaldehyde, 2-methyl-3-(isopropylphenyl)propanal, decanal, 2,6-dimethyl-5-heptenal; 4-(tricyclo[5.2.1.][0(2,6)]decylidene-8-ene)butanal; octahydro-4,7-methylene-1H-indenealdehyde; 3-ethoxy-4-hydroxybenzaldehyde, p-ethyl-α,α-dimethylhydrocinnamaldehyde, α-methyl-3,4-(methylenedioxy)-hydrocinnamaldehyde, 3,4-methylenedioxybenzaldehyde, α-n-hexylcinnamaldehyde, meso-cymene-7-carboxaldehyde, α-methylphenylacetaldehyde, 7-hydroxy-3,7-dimethyloctanal, undecenal, 2,4,6-trimethyl-3-cyclohexene-1-carboxaldehyde, 4-(3)(4-methyl-3-pentenyl)-3-cyclohexenecarboxaldehyde, 1-dodecaldehyde, 2,4-dimethylcyclohexene-3-carboxaldehyde, 4-(4-hydroxy-4-methylpentyl)-3-cyclohexenecarboxaldehyde Hexen-1-carboxaldehyde, 7-methoxy-3,7-dimethyloct-1-aldehyde, 2-methylundecaldehyde, 2-methyldecanaldehyde, 1-nonanal, 1-octanal, 2,6,10-trimethyl-5,9-undecadienal, 2-methyl-3-(4-tert-butyl)propanal, 3-(4-ethylphenyl)-2,2-dimethylpropanal, 3-(4-methoxyphenyl)-2-methylpropanal, methylnonylacetaldehyde, 2-phenylpropan-1-aldehyde, 3-phenylpropan-2-en-1-aldehyde, 3-phenyl-2-pentylpropan-2-en-1-aldehyde, 3-phenyl-2-hexylpropan-2-enal, 3-(4-isopropylphenyl)-2-methylpropan-1-aldehyde, 3-(4-ethylphenyl)-2,2-dimethylpropan-1-aldehyde 3-(4-tert-butylphenyl)-2-methylpropanal, 3-(3,4-methylenedioxyphenyl)-2-methylprop-1-aldehyde, 3-(4-ethylphenyl)-2,2-dimethylpropanal, 3-(3-isopropylphenyl)but-1-aldehyde, 2,6-dimethylhept-5-en-1-aldehyde, dihydrocinnamaldehyde, 1-methyl-4-(4-methyl-3-pentenyl)-3-cyclohexene-1-carboxaldehyde, 5- or 6-methoxyhexahydro-4,7-methyleneindenyl-1- or -2-carboxaldehyde, 3,7-dimethyloct-1-aldehyde, 1-undecane-1-aldehyde, 10-undecene-1-aldehyde, 4-hydroxy-3-methoxybenzaldehyde, 1-methyl-3-(4-methylpentyl)-3-cyclohexenecarboxaldehyde, 7-hydroxy-3 ,7-Dimethyloctanal; trans-4-decenal, 2,6-nonadiene, p-tolylacetaldehyde; 4-methylphenylacetaldehyde, 2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butenal, o-methoxycinnamonaldehyde, 3,5,6-trimethyl-3-cyclohexenecarboxaldehyde, 3,7-dimethyl-2-methylene-6-octenal, phenoxyacetaldehyde; 5,9-dimethyl-4,8-decadienal, paeonaldehyde (6,10-dimethyl-3-oxa-5,9-undecadien-1-aldehyde), hexahydro-4,7-methyleneindenyl-1-carboxaldehyde, octanal, 2-methyloctanal, α-methyl-4-(1-methylethyl)phenylacetaldehyde, 6,6-dimethyl-bicyclo[3.1].1]-Hept-2-en-2-propanal, p-methylphenoxyacetaldehyde, 2-methyl-3-phenyl-2-propen-1-aldehyde, 3,5,5-trimethylhexanal, hexahydro-8,8-dimethyl-2-naphthal, 3-propylbicyclo[2.2.1]hept-5-en-2-carboxal, 9-decenal, 3-methyl-5-phenyl-1-pentanal, methylnonylacetaldehyde, 1-p-menthene-q-carboxal, citral and mixtures thereof, lily aldehyde, citral, 1-decanal, undecanoal, dodecanal, anthocyanin, 2,4-dimethyl-3-cyclohexene-1-carboxal, 4-methoxybenzaldehyde, 3-methoxy-4-hydroxybenzaldehyde, 3-ethoxy-4-hydroxybenzaldehyde, 3,4-methylenedioxybenzaldehyde and 3,4-dimethoxybenzaldehyde and mixtures thereof.

[0037] As described above, the ketone or aldehyde may exhibit aliphatic, alicyclic, aromatic, olefinic unsaturated structures, or mixtures of these elements. Components may also include heteroatoms or exhibit polycyclic structures. Suitable substituents for all these structures are hydroxyl and / or amino groups. Further fragrances are compiled in the following document: Steffen Arctander, published in 1960 and 1969 respectively, Reprinted 2000 ISBN: Aroma Chemicals Vol. 1: 0-931710-37-5, Aromatic Chemicals Vol. 2: 0-931710-38-3, which is incorporated herein by reference.

[0038] Ketones. Suitable examples of fragrances exhibiting ketone structures include buccoxime, isojasmone, methyl-β-naphthone, musconeinone, tuna musk / musca, α-damascone, β-damascone, δ-damascone, isodamacone, damascenone, damarose, methyl dihydrojasmonate, menthone, carvone, camphor, fentanyl, α-ionone, β-ionone, dihydro-β-ionone, γ-methylionone (so-called), heptacyclopentanone, dihydrojasmone, cis-jasmone, ambroxanone (Iso-E-Super), methyl-cedryenyl-ketone or methyl-cedryenone, acetophenone, methyl acetophenone, p-methoxy-acetophenone, methyl-β-naphthone, benzylacetone, dibenzo[a]benzyl[b]acetone, etc. Ketones, p-hydroxyphenylbutanone, celery ketone or livescone, 6-isopropyldecahydro-2-naphthone, dimethyl-octenone, Freskomenthe, 4-(1-ethoxyvinyl)-3,3,5,5-tetramethylcyclohexanone, methyl-heptenone, 2-(2-(4-methyl-3-cyclohexen-1-yl)propyl)-cyclopentanone, 1-(p-menthene-6(2)-yl)-1-propanone, 4-(4-hydroxy-3-methoxyphenyl)-2-butanone, 2-acetyl-3,3-dimethyl-norbornane, 6,7-dihydro-1,1,2,3,3-pentamethyl-4(5H)-indanone, 4-damarol, Dulcinyl Cassion, gelsone, hexalone, isocyclemone E, methyl cyclohexane, methyl-Lavender-ketone, orrivone, p-tert-butylcyclohexanone, verdone, 2-tert-butylhexyl ester, 2-pentylcyclopentane, muscone, plicaton, velouton, 2,4,4,7-tetramethyloct-6-en-3-one, tertramerane, hedione, and mixtures thereof. The ketones may preferably be selected from α-damascone, δ-damascone, isodamacone, carvone, γ-methylionone, ambroxanone, 2,4,4,7-tetramethyloct-6-en-3-one, benzylacetone, β-damascone, damasneone, methyl dihydrojasmone, methyl cypressone, methyl dihydrojasmone, and mixtures thereof.

[0039] Alcohols. Suitable examples of fragrances displaying alcohol structures include 10-undecen-1-ol, 2,6-dimethylhept-2-ol, 2-methylbutanol, 2-methylpentanol, 2-phenoxyethanol, 2-phenylpropanol, 2-tert-butylcyclohexanol, 3,5,5-trimethylcyclohexanol, 3-hexanol, 3-methyl-5-phenylpentanol, 3-octanol, 1-octen-3-ol, 3-phenylpropanol, 4-heptenol, 4-isopropylcyclohexanol, 4-tert-butylcyclohexanol, 6,8-dimethyl-2-nonanol, 6-nonen-1-ol, 9-decen-1-ol, α-methylbenzyl alcohol, α-terpineol, amyl salicylate, benzyl alcohol, benzyl salicylate, β-terpineol. Alcohols, butyl salicylate, citronellol, cyclohexyl salicylate, decanol, dihydrogeraniol, dimethylbenzyl alcohol, dimethylheptanol, dimethyloctanol, ethyl salicylate, ethyl vanillin, anethole, eugenol, geraniol, heptanol, hexyl salicylate, isoborneol, isoeugenol, isomenthyl alcohol, linalool, menthol, myrtol, n-hexanol, nerol, nonanol, octanol, p-menth-7-ol, phenylethyl alcohol, phenol, phenyl salicylate, tetrahydrogeraniol, tetrahydrolinalool, thymol, trans-2-cis-6-nonadienol, trans-2-nonen-1-ol, trans-2-octenal, undecyl alcohol, vanillin, cinnamaldehyde, and mixtures thereof.

[0040] Esters. Examples of suitable fragrances having an ester structure include benzyl acetate, phenoxy isobutyrate, tert-butyl cyclohexyl acetate, linaloyl acetate, dimethyl benzyl acetate (DMBCA), ethyl acetate, benzyl acetate, ethyl methylphenylglycine, allyl cyclohexylpropionate, styrax ester propionate, benzyl salicylate, cyclohexyl salicylate, Floramat, melusat, jasmacyclatat, and mixtures thereof.

[0041] Ethers. Examples of suitable fragrances possessing an ether structure include benzyl ethyl ether or ambergris.

[0042] Hydrocarbons. Examples of suitable flavorings from hydrocarbons include terpenes, such as limonene and pinene.

[0043] physiological cooling agents and warming agents

[0044] Physiological cooling agents are preferably selected from the following list: menthol and menthol derivatives (e.g., L-menthol, D-menthol, racemic menthol, isomenthol, neo-isomenthol, neomenthol), menthyl ethers (e.g., (I-menthoxy)-1,2-propanediol, (L-menthoxy)-2-methyl-1,2-propanediol, L-menthyl-methyl ether), menthyl esters (e.g., menthyl formate, menthyl acetate, menthyl isobutyrate, menthyl lactate, L-lactic-L-menthyl, D-lactic-L-menthyl, menthyl-(2-methoxy)-ethyl Menthyl esters, menthol (2-methoxyethoxy) acetate, menthol pyroglutamic acid menthol), menthyl carbonate (e.g., menthyl propylene glycol carbonate, menthyl ethylene glycol carbonate, menthyl glycerol carbonate or mixtures thereof), half-esters of menthol with dicarboxylic acids or their derivatives (e.g., menthyl succinate, menthyl glutarate, menthyl malonic acid, O-menthyl succinate-N,N-(dimethyl)amide, O-menthyl succinate amide), menthane carboxylic amides (preferably menthane carboxylic acid-N-acetamide [WS3] or N... α -(menthol carbonyl)glycine ethyl ester [WS5], as described in US 4,150,052, menthol carboxylic acid-N-(4-cyanophenyl)amide or menthol carboxylic acid-N-(4-cyanomethylphenyl)amide, as described in WO 2005049553A1, menthol carboxylic acid-N-(alkoxyalkyl)amide), menthone and menthone derivatives (e.g., L-menthol glycerol acetal / ketal), 2,3-dimethyl-2-(2-propyl)-butyric acid derivatives (e.g., 2,3-dimethyl-2-(2-propyl)-butyric acid N-methylamide [WS23]), isoprene alcohol or its esters (I-(-)-isomenthol, I-(-)-isomenthol acetate), menthol derivatives (e.g., p-menthol-3,8-diol), cubebol or synthetic or natural mixtures containing cubebol, pyrrolidone derivatives of cycloalkyl dione derivatives (e.g., 3-methyl) -2(1-pyrrolidinyl)-2-cyclopenten-1-one or tetrahydropyrimidin-2-one (e.g., iciline or related compounds, as described in WO2004 / 026840), other formamides (e.g., N-(2-(pyridin-2-yl)-3-p-menthaneformamide or related compounds), (1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(1-isopropyl)cyclohexaneformamide [WS12], oxalates (preferably those described in EP2033688A2) and [(1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl]2-(ethylamino)-2-oxo-acetic acid ester (XCool).

[0045] Physiological warming agents can be selected from a group including capsaicin, dihydrocapsaicin, nordihydrocapsaicin, high capsaicin, high dihydrocapsaicin, N-vanillylnonivamide, and chili extract.

[0046] carrier

[0047] The carrier used to form component (b) of the oral active agent as defined above is selected from silica, silica gel, and silicates. In a first preferred embodiment, the carrier is silica gel, which is an amorphous and porous form of silica, consisting of an irregular three-dimensional framework of alternating silicon and oxygen atoms with nanoscale voids and pores. The voids may contain water or some other liquid, or may be filled by gas or vacuum. In the latter case, the material is aptly referred to as silica desiccant. Silica desiccant with an average pore size of 2.4 nanometers has a strong affinity for water molecules and is widely used as a desiccant. It is hard and translucent, but much softer than bulk quartz glass or quartz; and remains hard even when saturated with water. Silica desiccant is generally commercially available in the form of coarse particles or beads with a diameter of a few millimeters.

[0048] A particularly preferred option is that it can be obtained from Evonik under the trademark. The purchased product. It represents a group of precipitated silicas specifically developed for toothpaste applications. For example, 8, 9, or 22s indicates a high-hardness, low-viscosity abrasive or thickening silica used in toothpaste formulations, providing improved cleaning efficiency. This product can be used in clear toothpaste formulations. It can be marketed under a trade name. (For example FP 244, Grace) or For example, composed of mesoporous SiO2 particles 300 (Evonik) has an alternative product.

[0049] All these products exhibit particle sizes of approximately 3 to approximately 60 μm, pore volumes of approximately 1 to approximately 3 ml / g, pore diameters of approximately 15 to 60 nm, and pore sizes of approximately 200 nm to approximately 500 nm. 2 / gram of surface area.

[0050] Also useful are silicates, especially aluminosilicates, which are commonly used as supports for metal catalysts. In the process of this invention, suitable silicates have the general formula [SiO₂]. (4-2x)- 4-x ] n Where 0 ≤ x < 2. This group includes orthosilicate SiO₂. 4- 4(x=0), metasilicate SiO 2- 3 (x = 1) and pyrosilicon Si2O 6-7 (x = 0.5, n = 2). This name is also used for any salt of this type of anion, such as sodium metasilicate; or any ester containing the corresponding chemical group, such as tetramethyl orthosilicate. Suitable aluminosilicates follow the formula Al₂O₃*SiO₂, where the silica content ranges from 50 to 75% by weight.

[0051] Mucosal adhesion polymers

[0052] "Mucosal adhesion" is a material property that enables it to adhere to human mucous membranes. The mucosal adhesion polymer forming component (c) is preferably used in this invention, including hydrophilic polymers and natural gums. Examples of preferred hydrophilic polymers are cellulose polymers of the hydroxyalkyl cellulose type, such as hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulose and their salts, and mixtures of two or more of these; vinyl polymers, such as polyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidone; and acrylic polymers and copolymers, such as poly(meth)acrylic acid and its salts, polycarboxylic acid, etc. Natural gums are polysaccharides of natural origin. Examples of some natural gums are carrageenan, konjac, sodium and calcium alginate, agarose, guar gum, pectin, tragacanth gum, gum arabic, gum arabic, dextran, gellan gum, xanthan gum, sclerotium dextran, hyaluronic acid, chitosan, fenugreek gum, locust bean gum, etc. The above-mentioned combinations of mucosal adhesion polymers can also be used. Other mucosal adhesion polymers or combinations of mucosal adhesion polymers can also be used.

[0053] The most preferred adhesive polymer in this invention is selected from the group including polyacrylic acid, for example... 971P NF, low-methylcellulose or hydroxypropyl methylcellulose (HPMC), for example 65SH50, and chitosan.

[0054] Composition

[0055] Preferably, the surfactant is incorporated into a carrier, and the carrier is coated with a mucosal adhesion polymer. Typically, the carrier is loaded with about 1 to about 50% by weight, preferably about 2 to about 15% by weight, and more particularly about 5 to about 10% by weight of the surfactant, calculated based on the carrier. The loading depends on the individual loading capacity of a particular carrier.

[0056] Once the carrier is loaded, it is coated with about 1 to 25% by weight, preferably about 3 to 15% by weight, and more particularly about 5 to 10% by weight of a mucosa-adhesive polymer, based on the carrier.

[0057] Preparation method

[0058] Another object of the present invention relates to a first method (so-called wet method) for preparing a solid adhesive film composition, comprising or consisting of the following steps:

[0059] (i) Provide at least one active agent;

[0060] (ii) Providing at least one carrier selected from silica, silica gel, silica and silicates, and

[0061] (iii) Provide at least one mucosal adhesion polymer,

[0062] (iv) Loading the surfactant onto a carrier, via

[0063] (iv-a) Contact the support with an active agent optionally dissolved in a solvent, then remove the solvent to obtain the supported support; or

[0064] (iv-b) Contact the support with the solid surfactant, and then melt the surfactant to obtain the supported support;

[0065] (v) The load carrier is coated by contacting the product of step (iv) with a suspension of at least one mucosa-adhesive polymer in water or a lipophilic solvent.

[0066] In the "wet process," the carrier is typically wetted or impregnated with an active agent (which may be solid or liquid) in a solution or dispersion in a suitable solvent such as water, ethanol, or oil. This step can be carried out at room temperature, preferably under vigorous stirring. The solvent is then separated by filtration or—preferably—evaporation.

[0067] In the next step, the loaded carrier is coated with a polymer. Typically, the carrier is placed in a mixer, and a solution or dispersion of the polymer in a suitable solvent is added dropwise under vigorous stirring. The solvent can be water, but lipids have been found to exhibit excellent properties in terms of coating stability. Therefore, preferred solvents for the coating material are triglycerides, such as triglycerides or sunflower oil, or the active agent (preferably a lipophilic fragrance or flavoring agent) itself, provided that they are lipophilic liquids.

[0068] Another object of the present invention relates to a second method (so-called dry / hot melt method) for preparing solid adhesive film compositions, comprising or consisting of the following steps:

[0069] (i) Provide at least one active agent;

[0070] (ii) Providing at least one carrier selected from silica, silica, silica gel, and silicates, and

[0071] (iii) Provide at least one mucosal adhesion polymer,

[0072] (iv) Loading the surfactant onto a carrier, via

[0073] (iv-a) Contact the support with the surfactant dissolved in the solvent, then remove the solvent to obtain the supported support; or

[0074] (iv-b) The support is brought into contact with a solid surfactant, and then the two solids are melted to obtain a loaded support;

[0075] (v) The load carrier is coated by contacting the product of step (iv) with at least one substantially mucosa-adhesive polymer and mixing the two components under high shear.

[0076] The second method differs from the first in that the coating occurs within the substance (“powder coating”), meaning the polymer is not dissolved or dispersed in a solvent but is added directly to the carrier. Coating is achieved by vigorous stirring of the two components under high shear, preferably using a high-shear mixer, in the presence of another non-adhesive polymer with a melting point of about 30 to about 60°C, such as a solid polyethylene glycol ether (e.g., PEG-1000). The amount of the second polymer added is about 5 to about 25% by weight – calculated based on the mixture. Alternatively, high-shear mixing is carried out at a temperature above the melting point of the second polymer.

[0077] Oral Composition

[0078] Another object of the present invention relates to oral formulations comprising a mucosal adhesion composition as defined above, preferably in a content of about 0.1 to about 10% by weight, more preferably about 1 to about 8% by weight, and most preferably about 2 to about 5% by weight.

[0079] Oral formulations may be selected from a group including (hard heat-treated) candies, compressed tablets, chewing gum, and toothpaste, more specifically...

[0080] Tooth powder;

[0081] • Toothpaste tablets;

[0082] • Teeth cleaning foam;

[0083] • Semi-solid dosage forms for oral administration;

[0084] Sublingual tablets and oral tablets;

[0085] Mucosal adhesives;

[0086] • Melt film;

[0087] • Tablets (with and without coating, with and without improved sustained-release formulation, chewable tablets, lyophilized products for ingestion);

[0088] • Sugar-coated pills (with and without coating, with and without improved sustained-release formulation);

[0089] • Capsules (hard or soft gelatin capsules with or without modified sustained release);

[0090] • Granules (with and without modified sustained release); and

[0091] • Powder (with and without modified sustained release).

[0092] The preparation and composition of the oral composition are described below:

[0093] candy

[0094] According to the invention, preferred confectionery is so-called hard high-temperature cooked confectionery. Its substrate is typically prepared from a mixture of sugars and other carbohydrates and maintained in an amorphous or vitreous state. This form can be considered as a solid syrup of sugars typically containing up to about 4.5% by weight of water, based on the weight of the sugar substrate, preferably about 0.5% to about 2.5% by weight, and most preferably about 1.0% to about 1.5% by weight. Such materials typically contain up to about 65% by weight of corn syrup, up to 80% by weight of sugar, and 0.1% to 5.0% by weight of water. Typically, the ratio between sugar (or other sweeteners suitable for sugar formulations) and corn syrup is in the range of about 70:25 to about 45:55, preferably about 60:40. The syrup components are typically prepared from high-fructose corn syrup, but may also include other materials. Other ingredients may also be added, such as flavorings, sweeteners, acidulants, colorings, etc.

[0095] Hard, high-temperature boiled candy bases can also be prepared from non-fermentable sugars such as sorbitol, mannitol, xylitol, maltitol, hydrogenated starch hydrolysate, hydrogenated corn syrup, and mixtures thereof. The candy base may contain up to about 95% by weight of sorbitol, a mixture of sorbitol and mannitol in a ratio of about 9.5 to 0.5 and up to about 7.5 to 2.5, and a syrup component of up to about 55% hydrogenated corn syrup.

[0096] Compressed tablets

[0097] The oral formulation according to the invention is a compressed tablet, which typically contains about 0.1 to about 0.6% by weight, and preferably about 0.5% by weight, of liquid flavoring.

[0098] chewing gum

[0099] Chewing gum typically consists of water-insoluble substrate components, water-soluble components, and additives that provide, for example, a specific flavor.

[0100] Water-insoluble substrates, also known as "colloidal bases," typically contain natural or synthetic elastomers, resins, fats and oils, plasticizers, fillers, softeners, dyes, and optionally waxes. The substrate typically comprises 5 to 95% by weight in the total formulation, preferably 10 to 50% by weight, and particularly 20 to 35% by weight. In a typical embodiment of the invention, the substrate consists of 20 to 60% by weight of synthetic elastomers, 0 to 30% by weight of natural elastomers, 5 to 55% by weight of plasticizers, 4 to 35% by weight of fillers, and small amounts of additives such as dyes, antioxidants, etc., provided that these small amounts are water-soluble.

[0101] Suitable synthetic elastomers are, for example, polyisobutylene, isobutylene / isoprene copolymers (“butyl elastomers”), styrene / butadiene copolymers (styrene:butadiene ratio, for example, 1:3 to 3:1), and polyvinyl acetate, polyisoprene, polyethylene, vinyl acetate / vinyl laurate copolymers and mixtures thereof, with an average molecular weight (according to GPC) of 10,000 to 100,000, and preferably 50,000 to 80,000, according to GPC. Suitable examples of natural elastomers are rubbers, such as smoked latex or liquid latex or guar gum, and natural rubbers such as jelutong, lechi caspi, perillo, sorva, massaranduba balata, massaranduba chocolate, nispero, roseindinha, gum syrup, gutta-percha, and mixtures thereof. The selection of synthetic and natural elastomers and their mixing ratios are primarily based on whether the chewing gum produces bubbles (“bubblegum”). Elastomer mixtures containing jelutong, lechi caspi, sorva, and sorva are preferred.

[0102] In most cases, elastomers are too stiff or lack the plasticity for satisfactory processing; therefore, it has been found advantageous to use specific plasticizers, which, of course, must specifically meet all the requirements permitted for use as food additives. Esters of resin acids, such as low-fatty alcohols or polyols, with fully or partially cured monomers or oligomeric resin acids are particularly suitable in this regard. Methyl, glycerol, or pentaerythritol esters, or mixtures thereof, are used specifically for this purpose. Alternatively, terpene resins derived from α-pinene, β-pinene, δ-limonene, or mixtures thereof may also be used.

[0103] Suitable fillers or thickeners are magnesium carbonate or calcium carbonate, ground foam rock, silicates, especially magnesium silicate or aluminum silicate, clay, alumina, talc, titanium dioxide, monocalcium phosphate, dicalcium and tricalcium phosphate, and cellulose polymers.

[0104] Suitable softeners or emulsifiers are tallow, hardened tallow, hardened or partially hardened vegetable oils, cocoa butter, metaglycerides, lecithin, triacetin, and saturated or unsaturated fatty acids containing 6 to 22, preferably 12 to 18 carbon atoms, and mixtures thereof.

[0105] Suitable dyes and bleaching agents include, for example, FD and C-type plant and fruit extracts permitted for use in food coloring, as well as titanium dioxide. The gum base may contain wax or not.

[0106] Besides the water-insoluble gum base, chewing gum compositions typically contain water-soluble components, such as softeners, sweeteners, fillers, flavoring substances, taste enhancers, emulsifiers, dyes, acidifiers, antioxidants, etc., provided that these components are at least sufficiently water-soluble. Depending on the water solubility of a particular representative substance, a single component may belong to either the water-insoluble or water-soluble phase. However, a combination of, for example, water-soluble and water-insoluble emulsifiers can be used, where the single representative substance is located in a different phase. Typically, the water-insoluble component constitutes 5 to 95% by weight of the formulation, and preferably about 20 to 80% by weight.

[0107] Water-soluble softeners or plasticizers are added to chewing gum compositions to improve chewability and chewing sensation, and are typically used in the mixture at a rate of 0.5 to 15% by weight. Typical examples are glycerin, lecithin, and aqueous solutions of sorbitol, hardened starch hydrolysate, or corn syrup.

[0108] Specifically, for the production of low-calorie chewing gum, suitable fillers are selected from polydextrose, raftilose, inulin, NutraFlora, palatinoseoligosaaccharides, guar gum hydrolysate, and dextrin.

[0109] In addition, chewing gum can contain other aids and additives suitable for dental care, especially for combating plaque and gingivitis, such as chlorhexidine, CPC, or triclosan. It may also contain pH adjusters (such as buffers or urea), anti-caries active substances (such as phosphates or fluoride), and bioactive ingredients (antibodies, enzymes, caffeine, plant extracts), provided that these substances are permitted for use in food and do not react with each other in an undesirable manner.

[0110] toothpaste

[0111] Toothpaste generally refers to a paste-like preparation containing water, thickeners, humectants, abrasives or polishing agents, surfactants, sweeteners, flavorings, deodorants, and active agents that combat oral and dental diseases. In the toothpaste according to the invention, any conventional polishing agent can be used, such as chalk, dicalcium phosphate, insoluble sodium metaphosphate, aluminum silicate, calcium pyrophosphate, fine-particle synthetic resin, silica, alumina, and alumina trihydrate. Polishing agents particularly suitable for the toothpaste of the invention are fine-particle dry gel silica, hydrogel silica, precipitated silica, alumina trihydrate, and fine-particle α-alumina, or mixtures of these polishing agents. The amount of such polishing agent is preferably about 15-40% by weight of the toothpaste. Preferred humectants used in the toothpaste according to the invention include low molecular weight polyethylene glycol, glycerin, sorbitol, or mixtures thereof, in amounts up to about 50% by weight of the toothpaste. Among known thickeners used in the toothpaste of the present invention, particularly preferred are thickening, fine-grained gel silica and nonionic hydrocolloids, such as hydroxyethyl cellulose, hydroxypropyl guar gum, hydroxyethyl starch, polyvinylpyrrolidone, high molecular weight polyethylene glycol, and plant gums such as tragacanth gum, agar, carrageenan, gum arabic, and xanthan gum. The desired flavor and aroma of the formulation according to the invention can be obtained by adding components (a) and / or (b) and optionally (c). It is also advantageous to add caries inhibitors in the form of alkali metal salts, such as alkali metal fluorides, alkali metal monofluorophosphonates, or organophosphonic acids, to the oral formulation. Furthermore, the oral formulation according to the invention may contain other standard adjuvants, such as dyes, preservatives, and opacifiers, such as titanium dioxide.

[0112] additive

[0113] Oral preparations according to the invention may include additional additives, such as sweeteners or vitamins, in amounts from about 0.001 to about 10% by weight. These additives may also be components of the corresponding medicine.

[0114] sweeteners

[0115] Suitable sweeteners, including natural sources of these substances (component e5), such as sweet carbohydrates or sugars (e.g., sucrose), trehalose, lactose, maltose, melizitose, raffinose, palaginose, lactulose, D-fructose, D-glucose, D-galactose, L-rhamnose, D-sorbose, D-mannose, D-tagatose, D-arabinose, L-arabinose, D-ribose, D-glyceraldehyde, maltodextrin, or plant preparations primarily containing these carbohydrates (e.g., from sugar beets (Betavulgaris ssp., sugars, syrups, molasses), from sugarcane (Saccharum officinarum ssp., molasses, syrups), from maple syrup (Acer syrup)). ssp.), derived from agave (agave concentrate), synthetic / enzymatic hydrolysis products of starch or sucrose (e.g., invert sugar syrup, high-concentration fructose made from corn starch), fruit concentrates (e.g., derived from apples or pears, apple syrup, pear syrup), sugar alcohols (e.g., erythritol, threitol, arabinitol, ribitol, xylitol, sorbitol, mannitol, eurythritol, lactitol), proteins (e.g., kiwifruit protein, monetin, sweet protein, curculigo protein, brazzein), sweeteners (magap, sodium cyclohexylsulfamate, acesulfame potassium, neohesperidin dihydrochalcone, sodium saccharin), Super-aspartame, neotame, alitame, sucralose, steviol glycosides, rabodiin, lugduname, carrelame, sucrononate, sucrooctate, monatin, folate, certain sweet-tasting amino acids (glycine, D-leucine, D-threonine, D-aspartic acid, D-phenylalanine, D-tryptophan, L-proline), other sweet-tasting small molecules (e.g., hernandulcin, dihydrochalcone glycosides, glycyrrhizin, glycyrrhizic acid ammonium salt or other glycyrrhizic acid derivatives, licorice extract (Glycyrrhizza glabra ssp.), Lippia dulcis extract, Momordicassp. extract or single substances (especially Momordica grosvenori [monk fruit] and mogroside derived therefrom), Hydrangea dulcis or Stevia ssp. (e.g., stevia) extract or single substance.

[0116] Vitamins

[0117] In another embodiment of the invention, the composition may contain a vitamin (component e1). Vitamins possess various biochemical functions. Some function as hormone-like regulators of mineral metabolism (e.g., vitamin D) or regulators of cell and tissue growth and differentiation (e.g., some forms of vitamin A). Others function as antioxidants (e.g., vitamin E and sometimes vitamin C). Most vitamins (e.g., B-complex vitamins) act as precursors to enzyme cofactors, assisting enzymes as catalysts for metabolism. In this role, vitamins may be tightly bound to enzymes as part of a prosthesis: for example, biotin is part of an enzyme involved in the production of fatty acids. Vitamins may also act as coenzymes, not tightly bound to enzyme catalysts, functioning as separable molecules that carry chemical groups or electrons between molecules. For example, folic acid carries various forms of carbon groups—methyl, formyl, and methylene—in cells. While these roles in assisting enzyme-substrate reactions are the most well-known functions of vitamins, other vitamin functions are equally important. Suitable vitamins in this invention are selected from the group comprising...

[0118] Vitamin A (retinol, retinaldehyde, beta-carotene),

[0119] Vitamin B1 (thiamine),

[0120] Vitamin B2 (riboflavin),

[0121] Vitamin B3 (niacin, niacinamide),

[0122] Vitamin B5 (pantothenic acid),

[0123] Vitamin B6 (pyridoxine, pyridoxamine, pyridoxal),

[0124] Vitamin B7 (Biotin),

[0125] Vitamin B9 (folic acid, folinic acid),

[0126] Vitamin B 12 (Cyanocobalamin, Hydroxycobalamin, Methylcobalamin)

[0127] Vitamin C (ascorbic acid),

[0128] Vitamin D (cholecalciferol),

[0129] Vitamin E (tocopherol, tocotrienol), and

[0130] • Vitamin K (phylloquinone, menaquinone).

[0131] Preferred vitamins are ascorbic acid and tocopherol. The vitamins are present in the food composition at a concentration of about 0.001% to about 5% by weight, and preferably about 0.5% to about 1% by weight.

[0132] Industrial applications

[0133] Another object of the present invention relates to the use of the mucosal adhesion composition described above in the preparation of oral formulations, particularly toothpaste. To avoid ambiguity, it is stated that all preferred embodiments, scopes, mixtures, and applications described above should also be applied to specific uses and therefore need not be repeated. Example

[0134] Examples 1 to 4

[0135] Stability of the load carrier

[0136] A liquid flavor mixture consisting of anethole, carvone, and eucalyptol in a weight ratio of 60:30:10 (“ LIQUID) or a liquid flavor mixture consisting of menthol, thymol, and camphor in a weight ratio of 60:30:10 ("OPTA-"). Various types of silica were treated with SOLID and stored in sealed glass bottles, protected from light at 20°C, and the samples were heated from -5°C to 40°C over 24 hours, then cooled to -5°C. After 6 months, the amount of fragrance residue on each carrier was determined by high-performance liquid chromatography (HPLC). The results are summarized in Table 1.

[0137] Table 1

[0138] stability test of the carrier

[0139]

[0140] Examples 1 to 3 were carried out using a flavor carrier (products 1 to 3) loaded with approximately 100% by weight of its capacity. Experiments showed that the loading remained almost constant throughout storage. Example 4 was carried out using an overloaded carrier (product 4; loading limit: 3.4% by weight), meaning that approximately 1.2% by weight of the flavor agent was not encapsulated within the carrier but bound only to the outer surface. Storage with this carrier showed that only the portion of the flavor agent adhering to the outer surface of the carrier was released.

[0141] Examples 5 to 6

[0142] Stability of liquid-coated load carriers

[0143] To coat the support carrier with the polymer for mucosal adhesion, Product 2 was placed in a mixer at 20°C, and a suspension of 10% by weight of hydroxypropyl methylcellulose (HPMC) in sunflower oil (Product 5) was added dropwise over 2 minutes with vigorous stirring. Once the polymer was added, the solution was stirred for another 5 minutes. Another method is to suspend the polymer (HPMC) in... The liquid flavoring agent was simultaneously loaded with and coated with an unloaded carrier (Product 6), wherein the process was carried out as described in Product 5. The coated carrier was again stored in sealed vials at 20°C, and then again according to the temperature gradient of the previous examples, with polymer content determined by HPLC over a period of up to 6 months. The results are summarized in Table 2.

[0144] Table 2

[0145] Stability testing of the coated carrier

[0146]

[0147]

[0148] In particular, when coating is performed from an oil-containing suspension or by a one-step process with a suspended polymer in a liquid flavoring agent, a coating carrier is obtained in which the polymer content remains almost unchanged even after 6 months.

[0149] Examples 7 to 8

[0150] Stability of the coating carrier – dry & hot melt coating

[0151] In the first experiment (Product 7), Product 2 was added to a high-shear mixer containing 3 wt% HPMC and then homogenized for approximately 2 minutes at speeds of 400, 1500, and 3000 rpm, respectively. In the second experiment (Product 8), Product 2 containing 5 wt% HPMC was homogenized again for 5 minutes in a high-shear mixer, first at 400 rpm and then at 1500 rpm. Then 10 wt% PEG-1000 was added, and the mixture was heated to 45°C above the melting point of polyethylene glycol ether, homogenized at 400 rpm for 5 minutes, and then homogenized at 1500 rpm for 25 minutes. The mixture was then slowly cooled to 20°C with a stirring speed of 1500 rpm. The coating carrier ( Loadings (10.39 and 9.52 wt%) were stored again in sealed vials at 20°C, and then again according to the temperature gradient in the previous examples. The polymer was measured by HPLC over a period of up to 6 months. The results are summarized in Table 3.

[0152] Table 3

[0153] Stability testing of the coated carrier

[0154]

[0155]

[0156] Dry high-shear mixing and the hot-melt method using PEG also represent reliable methods for obtaining stable coated carriers.

[0157] Examples 9 to 10

[0158] Mucosal adhesion test

[0159] A porcine mucosa approximately 2 mm thick and 2.5 cm in diameter was prepared and placed on a metal disk within the mucosa adhesion unit. The sample was placed on the mucosa, and its surface was moistened with artificial saliva droplets from the container (AS) using an HPLC pump (P) at a flow rate of 0.5 ml / min. The cells and container were placed in the same water bath to ensure the same temperature of 37°C, as shown in Figure 1. The used artificial saliva was prepared according to Matzker / Schreiber 1972 (CaCl2-free), and its composition is listed in Table 4 below:

[0160] Table 4

[0161] artificial saliva

[0162]

[0163] Recovered from collected saliva at 2, 4, 6, 8, 10, and 12 minutes, and additionally from mucosa at 12 minutes. The retained carrier was removed from the mucosa using a cotton swab and 1 ml of EtOH. The swab was extracted with 5 ml of EtOH and analyzed by HPLC. The results are summarized in Table 5. The examples show that, compared with the ordinary carrier (Product 2), the addition of 3-4% by weight of HPMC as a mucosal adhesive has significantly improved mucosal adhesion by 2 to 3 times.

[0164] Table 5

[0165] Mucosal adhesion

[0166]

[0167] Examples 11 to 12

[0168] Mucosal adhesion test with optimized polymer content

[0169] Mucosal adhesion tests with increased polymer content were conducted using a flavor carrier containing 10% by weight HPMC according to Product 5 (Product 9), and a flavor carrier containing 10% by weight HPMC and 10% by weight PEG-1000 according to Product 8 (Product 10). The results are shown in Table 6. The examples demonstrate that, compared to a conventional carrier (Product 2), the addition of 10% by weight HPMC as a mucosal adhesive significantly improved mucosal adhesion by 4 to 8 times.

[0170] Table 6

[0171] Optimize the adhesive properties of the polymer content

[0172]

[0173]

[0174] Examples 13 to 14

[0175] Mucosal adhesion test of alternative polymers

[0176] use Mucosal adhesion tests of chitosan as a polymer alternative to HPMC were conducted using products 5 containing 10% by weight. The flavor carrier of 971P NF (Product 11) was used with the flavor carrier containing 6% by weight of food-grade chitosan according to Product 5 (Product 12). The results are shown in Table 7. The examples show that the mucosal adhesion of Product 12 is doubled compared with the ordinary carrier (Product 2), while the mucosal adhesion of Product 11 is significantly increased by 9 times.

[0177] Table 7

[0178] Mucosal adhesion of alternative polymers

[0179]

[0180] Examples 15 to 17

[0181] Mucosal adhesion test of alternative carrier

[0182] In addition, using 9. Mucosal adhesion tests were conducted using the product as a carrier. The flavoring carrier was prepared as described in Product 4. 8% by weight of HPMC from sunflower oil (Product 13) and 8% by weight of HPMC from sunflower oil were used respectively, according to Product 5. (Product 14) was formulated using 10 wt% HPMC and 10 wt% PEG-1000 polymers, based on Product 8. The results are shown in Table 8. Examples demonstrate that, compared to a conventional carrier (Product 4), Product 13 exhibits a significantly increased film adhesion by 2.5 times, and Product 14 exhibits a 4-fold increase in film adhesion. Compared to a conventional carrier, Product 15 shows only a slight increase in film adhesion.

[0183] Table 8

[0184] Mucosal adhesion of alternative carriers

[0185]

[0186] Examples 18 to 19

[0187] Mucosal adhesion test using triacetin as solvent

[0188] Alternatively, for sunflower oil, triacetin was tested as a solvent for polymer adhesives, and a mucosal adhesion test was also performed here. 10% by weight HPMC was used according to Product 9 (Product 16) and 10% by weight was used according to Product 11, respectively. (Product 17) Samples were prepared, but triacetin was used instead of sunflower oil as the solvent. The results of the mucosal adhesion test are shown in Table 9. The examples show that, compared to the ordinary carrier (Product 2), Product 16 exhibited 4.5 times increased mucosal adhesion, and Product 17 exhibited 7.5 times increased adhesion.

[0189] Table 9

[0190] Mucosal adhesion with triacetin as solvent

[0191]

[0192]

[0193] Examples 20 to 23

[0194] Long-lasting mucosal adhesion

[0195] For some carriers, in addition to the 12-minute test, mucosal adhesion was also measured after 30 and 60 minutes. Table 10 shows that the amount of fragrance adhering to the mucosa decreased over time for all mucosal adhesion carriers. However, all mucosal adhesion examples showed significantly better adhesion to the mucosa compared to ordinary carriers.

[0196] Table 10

[0197] Long-lasting mucosal adhesion

[0198]

[0199] Formulation Examples

[0200] Tables I through III below provide various examples of oral compositions; all quantities are given in weight percent.

[0201] Table I

[0202] chewing gum

[0203]

[0204] Table II

[0205] toothpaste

[0206]

[0207] Table III

[0208] Hard high temperature boiled candy

[0209]

Claims

1. A solid adhesive film composition comprising or consisting of the following substances (a) At least one active agent, which includes at least one fragrance or aroma agent molecule; (b) at least one support, said support being silicon dioxide; and (c) At least one mucosal adhesion polymer, The mucosal adhesion polymer is selected from the group consisting of poly(meth)acrylic acid, hydroxyalkyl methyl cellulose, and chitosan. The surfactant is incorporated into the carrier and the carrier is coated with the mucosal adhesion polymer, wherein the solvent used for the coating material is triacetate or sunflower oil, and The carrier described herein exhibits one or both of the following properties: Particle sizes ranging from 3 to 60 μm, 1 to 3 ml / g pore volume, Apertures ranging from 15 to 60 nm, and 200 to 500 m 2 / gram of surface area.

2. The composition according to claim 1, wherein the solvent used for the coating material is sunflower oil.

3. The composition according to claim 1 or 2, wherein the active agent is selected from the group consisting of fragrances, aromatics, physiological cooling agents, physiological warming agents, and mixtures thereof.

4. The composition according to claim 1 or 2, wherein the carrier is loaded with 1 to 15% by weight of the active agent, based on the carrier calculation.

5. The composition according to claim 1 or 2, wherein the load carrier is coated with 1 to 15% by weight of a mucosal adhesion carrier, based on calculations of the load carrier.

6. A method for preparing a solid adhesive film composition according to any one of claims 1-5, comprising or consisting of the following steps: (i) Provide at least one active agent; (ii) Providing at least one carrier selected from silica, and (iii) Provide at least one mucosal adhesion polymer, (iv) Loading the surfactant onto the carrier in any of the following ways: (iv-a) Contact the support with the surfactant dissolved in the solvent, then remove the solvent to obtain the supported support; or (iv-b) The support is brought into contact with a solid surfactant, and then the two solids are melted to obtain a loaded support; (v) The loading carrier is coated by contacting the product of step (iv) with a suspension of at least one mucosal adhesion polymer in a lipophilic solvent. The mucosal adhesion polymer is selected from the group consisting of poly(meth)acrylic acid, hydroxyalkyl methylcellulose, and chitosan. The lipophilic solvent is characterized as triacetin or sunflower oil.

7. The method according to claim 6, wherein the lipophilic solvent is sunflower oil.

8. An oral preparation comprising the mucosal adhesion composition according to claim 1 or 2.

9. The formulation according to claim 8, wherein the product is selected from the group consisting of... toothpaste; Dental cleaning foam; Semi-solid preparations for oral use; Mucosal adhesion preparations; Melt film; tablet; dragee; capsule; Granules; powder; and candy.

10. The formulation according to claim 8, comprising 0.1 to 25% by weight of a mucosal adhesion composition.

11. The formulation according to claim 8, wherein the formulation is tooth powder, oral tablets or chewing gum.

12. The formulation according to claim 8, wherein the formulation is a toothpaste tablet.

13. The formulation according to claim 8, wherein the formulation is a sublingual tablet.

14. Use of the mucosal adhesion composition according to claim 1 or 2 in the preparation of oral formulations.

15. The use according to claim 14, wherein the oral preparation is toothpaste.

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