WO2021228358A1 - Composition mucoadhésive solide - Google Patents

Composition mucoadhésive solide Download PDF

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Publication number
WO2021228358A1
WO2021228358A1 PCT/EP2020/063027 EP2020063027W WO2021228358A1 WO 2021228358 A1 WO2021228358 A1 WO 2021228358A1 EP 2020063027 W EP2020063027 W EP 2020063027W WO 2021228358 A1 WO2021228358 A1 WO 2021228358A1
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WIPO (PCT)
Prior art keywords
carrier
mucoadhesive
active agent
percent
composition
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PCT/EP2020/063027
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English (en)
Inventor
Ulrike SÖPPER
Rolf Daniels
Anja Hoffmann
Jörg Thilo Fischer
Arnold Machinek
Marcus Rudolf Götz
Original Assignee
Symrise Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Symrise Ag filed Critical Symrise Ag
Priority to PCT/EP2020/063027 priority Critical patent/WO2021228358A1/fr
Priority to CN202080100702.0A priority patent/CN115843240A/zh
Priority to JP2022567189A priority patent/JP2023525987A/ja
Priority to EP20726027.4A priority patent/EP4149419A1/fr
Publication of WO2021228358A1 publication Critical patent/WO2021228358A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/25—Silicon; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/347—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/35—Ketones, e.g. benzophenone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/731—Cellulose; Quaternized cellulose derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/736—Chitin; Chitosan; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
    • A61K8/8141—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
    • A61K8/8147—Homopolymers or copolymers of acids; Metal or ammonium salts thereof, e.g. crotonic acid, (meth)acrylic acid; Compositions of derivatives of such polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A61K9/0058—Chewing gums
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5063—Compounds of unknown constitution, e.g. material from plants or animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses

Definitions

  • a solid mucoadhesive composition A solid mucoadhesive composition
  • the present invention refers to the area of oral care preparations and concerns new solid mucoadhesive compositions, a method for production and their use.
  • Flavors and fragrances generally exhibit an unfavorable adhesion and release profile on physiological surfaces. For this reason, in order to improve the intensity and/or duration of taste or odour or further sensory perceptions, the concentration of the substances used is increased or highly effective agents are used.
  • WO 2002 002085 A2 concerns a dosage form which is, in particular, sheet-like and rapidly disintegrating or soluble in an aqueous environment for rapid release of active ingredients in the oral cavity, in body orifices or in body cavities, where the dosage form comprises a matrix which comprises one or more water-soluble polymers as base substances, and comprises at least one active ingredient, is characterized in that the dosage form is provided with spaces or cavities which are present in the polymeric matrix and whose contents differ in terms of the state of aggregation from the matrix.
  • WO 2003 011247 A2 refers to administration forms for application to the skin or mucosa, comprising a carrier matrix and at least one active substance, are characterized in that the carrier matrix has a plurality of particles having open pores or containing capillary spaces, said particles serving as active substance reservoir and containing at least one active substance.
  • EP 2347796 A2 (EVONIK) describes functional composite particles for the oral care sector, more particularly for toothpastes and mouthwashes, which are charged with active ingredients which ensure a long-term antimicrobial or antibacterial effect in the oral cavity and hence reduce the formation of plaque and halitosis.
  • the invention further relates to a process for producing these composite particles and also to their use for producing oral hygiene articles.
  • US 5,700,478 covers water-soluble pressure-sensitive adhesives include a water-soluble polymer that is made tacky at room temperature by addition of a water- soluble plasticizer that is miscible with the polymer.
  • Suitable polymers are solid at room temperature; and have a hyd rophilicity as measured by water uptake greater than about 25 wt. -percent; they are liquid at room temperature and have a boiling point higher than about 80 °C.
  • the adhesives according to the invention may conveniently be provided in dry film form.
  • Preferred water-soluble pressure-sensitive adhesives of the invention adhere both to mucosal surfaces and to a variety of materials that may constitute a part of a device or prosthesis to be held in a body cavity that has a mucosal lining.
  • US 2004 0156794 A1 (BARKALOW) concerns both bioadhesive and bioerodible confectionery formulations and methods of making and using the same; more specifically, the present invention provides delivery systems to release flavors, sweeteners, cooling agents, active ingredients and the like to consumer for an extended period of time. Further, these confectionery products may also provide a venue to mask off notes and bitter flavors of drugs or other active ingredients to consumers.
  • US 2006 0182786 A1 claims film-shaped administration forms for trans-mucosal administration of active substances to the human or animal body.
  • the administration forms are characterized by an adaptation or approximation of the pH value of the base mass intended for the production of the administration form to the physiological pH value of the mucosa to which the administration form is to be applied, said base mass comprising a solvent or a mixture of solvents, at least one matrix-forming polymer and at least one active substance.
  • the invention further comprises a process for the production of such preparations, and the use thereof as administration forms, particularly for pharmaceutical active substances, such that when the resultant administration forms are used, an irritation of the mucous membrane is reduced or even prevented.
  • US 2014/0234212 A1 (MASSACHUSETTS INSTITUTE OF TECHNOLOGY) disclosed an oral delivery device comprising a mucoadhesive polymer matrix, nanoparticles dispersing therein and an impermeable backing layer, wherein the active substances are loaded in the nanoparticles.
  • the oral delivery device should be placed onto the mucus layer and through the mucoadhesion adhere to the oral epithelium, where the nanoparticles penetrate in the mucosa and controlled release the loaded active substance.
  • the applied methods of the nanoparticles production are all carried out in a solution comprising active substance and the corresponding polymers.
  • US 2013/0337022 A1 (UNIVERSITY OF THE WITWATERSRAND) referred to a pharma ceutical dosage form comprising a mucoadhesive layer, a water-insoluble layer and an intermediate layer loading active substance, wherein the active substance are in the form of micro- and/or nanostructures and by directed dissolution, suspended or in an emulsion form incorporated into the intermediate layer.
  • the mucoadhesion of the dosage form was evaluated with Texture Analyser by measuring the tensile force required to separate the dosage membrane from a simulated gastric membrane.
  • US 20110028431 A1 (ZERBE ET AL) related to a direct compression formulation produced by blending a mucoadhesive polymer, a pharmaceutically active substance, a disintegrant and other components, then compressing the obtained blend.
  • the obtained compressed formulation can be further made into a solid oral dosage form.
  • US 2010/0063110 A1 published oral disintegrable films comprising alkaline substances, which can disintegrate in the mouth within 1 to 10 minutes and adhere to the buccal mucosa.
  • the mucoadhesiveness of the films were tested with a tensile strength tester.
  • US 2009/0110717 A1 concerned a trans-mucosal disk containing two compartments for administration of an active substance, preferably the active substance is in the inner compartment and the mucoadhesive agent is in the outer compartment.
  • the partial inner compartment and partial outer compartment adhered to the mucosal membrane to deliver the active substance through the buccal mucosa. After the desired effect of the active substance has been achieved, the disk could be easily peeled off.
  • US 2017/0071988 A1 (SYMRISE) relates to mucoadhesive active composition and corresponding mucoadhesive dosage form, which can deliver an active substance within the oral cavity, especially an oro-dispersible tablet for delivering probiotic substance.
  • a first object of the present invention refers to a solid mucoadhesive composition comprising or consisting of
  • At least one mucoadhesive polymer wherein said carrier is selected from the group consisting of silicon dioxide, silica gels and silicates.
  • the active agents forming component (a) of the compositions according to the pre sent invention represent agents which are typically used in oral care preparations and caus ing a sensation when brought into contact with mucous membranes. These agents are typi cally selected from the group consisting of flavors, fragrances, physiological cooling agents, physiological warming agents and mixtures thereof.
  • Suitable aromas and flavors can be chosen from synthetic flavoring liquids and/or oils derived from plants leaves, flowers, fruits and so forth, and combinations thereof.
  • Rep resentative flavoring liquids include: artificial, natural or nature identical flavors such as eu calyptus, lemon, orange, banana, grape, lime, apricot and grapefruit oils and fruit essences including apple, strawberry, cherry, orange, pineapple and so forth; bean and nut derived flavors such as coffee, cocoa, cola, peanut, almond and so forth; and root derived flavors such as licorice or ginger.
  • the flavoring agent is preferably selected from the group consisting of essential oils and extracts, tinctures and balsams, such as, for example, anise oil, basil oil, bergamot oil, bitter almond oil, camphor oil, citronella oil, lemon oil; Eucalyptus citriodora oil, eucalyptus oil, fennel oil, grapefruit oil, camomile oil, spearmint oil, caraway oil, lime oil, mandarin oil, nutmeg oil, myrrh oil, clove oil, clove blossom oil, orange oil, oregano oil, parsley (seed) oil, peppermint oil, rosemary oil, sage oil (clary sage, Dalmatian or Spanish sage oil), star aniseed oil, thyme oil, vanilla extract, juniper oil (in particular juniper berry oil), wintergreen oil, cinnamon leaf oil; cinnamon bark oil, and fractions thereof, or constituents isolated therefrom.
  • the flavored composition according to the invention comprises at least one flavoring agent, preferably two, three, four, five, six, seven, eight or more flavoring agents chosen from the following group: menthol (preferably l-menthol and/or racemic menthol), anethole, anisole, anisaldehyde, anisyl alcohol, (racemic) neomen thol, eucalyptol (1,8-cineol), menthone (preferably L-menthone), isomenthone (preferably D-isomenthone), isopulegol, menthyl acetate (preferably L-menthyl acetate), menthyl propi- onate, carvone (preferably (-)-carvone, optionally as a constituent of a spearmint oil), methyl salicylate (optionally as a constituent of a wintergreen oil), eugenol acetate, isoeugenol me thyl ether,
  • menthol preferably l-ment
  • aroma or flavouring compounds encompass menthol, cineol, eugenol, thymol, cinnamic aldehyde, peppermint oil, spearmint oil, eucalyptus oil, thyme oil, cinnamon oil, clove oil, spruce needle oil, fennel oil, sage oil, aniseed oil, star anise oil, chamomile oil, and caraway oil, and their mixtures.
  • the fragrances can be used as single components or in the form of more or less com plex mixtures; said fragrances may be obtained from natural sources or prepared by organic synthesis.
  • Natural perfumes include the extracts of blossoms (lily, lavender, rose, jasmine, nero- li, ylang-ylang), stems and leaves (geranium, patchouli, petitgrain), fruits (anise, coriander, caraway, juniper), fruit peel (bergamot, lemon, orange), roots (nutmeg, angelica, celery, car damom, costus, iris, calmus), woods (pinewood, sandalwood, guaiac wood, cedarwood, rosewood), herbs and grasses (tarragon, lemon grass, sage, thyme), needles and branches (spruce, fir, pine, dwarf pine), resins and balsams (galbanum, elemi, benzoin, myrrh, oliba- num, opoponax). Animal raw materials, for example civet and beaver, may also be used.
  • the synthetic fragrances represent aldehydes, ketones, alcohols, ethers, esters, hydrocarbons and their mixtures.
  • these types of fragrances are illus trated but not limited by examples:
  • Aldehydes examples for suitable fragrances showing an aldehyde structure encom pass melonal, triplal, ligustral, adoxal, anisaldehyde, cymal, ethylvanillin, florhydral, flo- ralozon, helional, heliotropin, hydroxycitronellal, koavon, laurinaldehyde, canthoxal, lyral, lilial, adoxal, anisaldehyde, cumal, methyl-nonyl-acetaldehyde, citronellal, citronellyloxy- acetaldehyde, cyclamenaldehyde, bourgeonal, p-tert.-bucinal, phenylacetaldehyde, un- decylenaldehyde, vanillin; 2,6,10-trimethyl-9-undecenal, 3-dodecen-l-al,
  • said ketones or said aldehydes may show an aliphatic, cycloali phatic, aromatic, ethylenically unsaturated structure or a mixture of these elements.
  • the components may also include heteroatoms or show a polycyclic structure. Suitable substitu ents for all these structures are hydroxyl and/or amino groups.
  • Further fragrances are com piled in the following document: Steffen Arctander « Published 1960 and 1969 respectively, Reprinted2000 ISBN: Aroma Chemicals Vol. 1: 0-931710-37-5, Aroma Chemicals Vol. 2: 0- 931710-38-3", which is hereby incorporated by reference.
  • Ketones Examples for suitable fragrances showing a ketone structure encompass buccoxime, iso jasmone, methyl-3-naphthyl ketone, moschus indanone, tonalid/moschus plus, a-damascone, b-damascon, d-damascone, Iso-damascone, damascenone, damarose, methyl-dihydrojasmonate, menthone, carvone, campher, fenchone, a-lonen, b-iononw, di- hydro-b-Iohohq, y-methylionone, fleuramone, dihydrojasmone, cis-Jasmon, iso-E-Super, me thyl cedrenylk etone, or methyl cedrylon, acetophenone, methyl aceto phenone, p- methoxyacetophenone,
  • the preferred ketones are selected from the group comprising a-damascone, d- damascone, iso-damascone, carvone, y-methyl ionone, Iso-E-Super, 2,4,4,7-tetramethyl-oct- 6-en-3-one, benzylacetone, b-damascone, damascenone, methyl dihydrojasmonate, methyl cedrylone, hedione and their mixtures
  • fragrance alcohols encompass for example 10-undecen-l-ol, 2,6- dimethylheptan-2-ol, 2-methylbutanol, 2-methylpentanol, 2-phenoxyethanol, 2- phenylpropanol, 2-tert-Butycyclohexanol, 3,5,5-trimethylcyclohexanol, 3-hexanol, 3-methyl- 5-phenylpentanol, 3-octanol, l-octen-3-ol, 3-phenylpropanol,4-heptenol, 4- isopropylcyclohexanol, 4-tert-butycyclohexanol, 6,8-dimethyl-2-nonanol,6-nonen-l-ol, 9- decen-l-ol, a-methyl benzylalcohol, a-terpineol, amylsalicylat, benzyl alcohol, benzyl alcohol, benzyl
  • Esters examples include ben zyl acetate, phenoxyisobutyrate, p-tert.-butylcyclohexylacetate, linalylacetate, dimethylben- zylcarbinylacetate (DMBCA), phenylethylacetate, benzylacetate, ethylmethylphenylglycinate, allylcyclohexylpropionate, styrallylpropionate, benzylsalicylate, cyclohexylsalicylate, flora- mat, melusat, jasmacyclatat and their mixtures.
  • DMBCA dimethylben- zylcarbinylacetate
  • Ethers examples include ben- zylethyl ether or ambroxan.
  • Hydrocarbons examples for suitable fragrances representing hydrocarbons encom pass terpenes, e.g. limonen and pinen.
  • Physiological cooling agents are preferably selected from the following list: menthol and menthol derivatives (for example L-menthol, D-menthol, racemic menthol, isomenthol, neoisomenthol, neomenthol) menthylethers (for example (l-menthoxy)-l,2-propandiol, (I- menthoxy)-2-methyl-l,2-propandiol), menthone glyceryl acetal, menthone glyceryl ketal or mixtures of both, menthylesters (for example menthylformiate, menthyhydroxyisobutyrat, menthyllactates, L-menthyl-L-lactate, L-menthyl-D-lactate, menthyl-(2-methoxy)acetate, menthyl-(2-methoxyethoxy)acetate, menthylpyroglutamate), menthylcarbonates (for exam ple menthyl
  • Physiological warming agents can be selected from the group consisting of capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin nonivamid, and chili extracts.
  • CARRIERS CARRIERS
  • the carriers for the above defined oral active agents forming component (b) are se lected from silicon dioxide, silica gels and silicates.
  • the carri er is silica gel, which is an amorphous and porous form of silicon dioxide (silica), consisting of an irregular tridimensional framework of alternating silicon and oxygen atoms with nanome ter-scale voids and pores.
  • the voids may contain water or some other liquids, or may be filled by gas or vacuum.
  • the material is properly called Silica xerogel.
  • Silica xerogel with an average pore size of 2.4 nanometers has a strong affinity for water mole cules and is widely used as a desiccant. It is hard and translucent, but considerably softer than massive silica glass or quartz; and remains hard when saturated with water.
  • Silica xero gel is usually commercialized as coarse granules or beads, a few millimeters in diameter.
  • SIDENT ® a product commercialized under the trademark SIDENT ® , obtainable from Evonik. It stands for a group of precipitated silica specially developed for toothpaste applications. For example SIDENT ® 8, 9 or 22s represent abrasive or thickening silica with high hardness and low thickening for toothpaste formulations with improved cleaning efficiency. The product enables transparent toothpaste formulations.
  • Alternative products can be obtained under the tradename SYLOID ® (for example SYLOID ® FP 244, Grace), AEROSIL ® or AEROPERL ® , for example AEROPERL ® 300 (Evonik) which consists of mesoporous S1O 2 granules.
  • All these products show particles sizes between about 3 to about 60 pm, pore vol umes of from about 1 to about 3 ml/g, pore diameters of from about 15 to 60 nm and sur face areas of from about 200 to about 500 m 2 /g.
  • silicates particularly alumosilicates, which typically find use as carri ers for metal catalysts.
  • suitable silicates share the general formula [SiO (4_2x) 4-x] n, where 0 ⁇ x ⁇ 2.
  • the name is also used for any salt of such anions, such as sodium metasilicate; or any ester containing the corre sponding chemical group, such as tetramethyl orthosilicate.
  • Suitable alumosilicates follow the formula AhC ⁇ SiC wherein the silica content ranges from 50 to 75 wt. -percent.
  • Mucoadhesive/Mucoadhesion is a property of a material that has the ability to adhere to mucosal membranes in the human body.
  • Mucoadhesive polymers, forming com ponent (c) are preferably used in this invention include hydrophilic polymers and natural gums.
  • hyd rophilic polymers are cellulosic polymers of the hydroxy alkyl cellulose type such as hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, ethylhyd roxyethyl cellulose, carboxymethyl cellulose and its salts and mixtures of two or more thereof; vinyl polymers such as polyvinyl acetate, polyvinyl alcohol, polyvinyl pyrrolidone; and acrylic acid polymers and copolymers such as poly(meth)acrylic acid(s) and its salts, polycarbophil etc.
  • Natural gums are polysaccharides of natural origin.
  • Examples of some natural gums are carrageenan, konjac, sodium and calcium alginate, agarose, guar, pectin, tragacanth, acacia, arabic, dex- tran, gellan, xanthan, scleroglucan, hyaluronic acid, chitosan, fenugreek gum, locust bean gum etc. Combinations of the above mucoadhesive polymers may also be employed. Other mucoadhesive polymers or combinations of mucoadhesive polymers may also be used.
  • the most preferable mucoadhesive polymer in the present invention is selected from the group consisting of polyacrylic acids such as for example Carbopol ® 971P NF, hypo- melloses or hydroxypropyl methylcelluloses (HPMC) such as for example Metolose ® 65SH50, and chitosan.
  • polyacrylic acids such as for example Carbopol ® 971P NF
  • hypo- melloses or hydroxypropyl methylcelluloses (HPMC)
  • HPMC hydroxypropyl methylcelluloses
  • the active agent is incorporated into the carrier and the carrier is coated by the mucoadhesive polymer.
  • the carrier is loaded with about 1 to about 50 wt.- percent, preferably about 2 to about 15 wt. -percent and more particularly about 5 to about 10 wt. -percent of active agents - calculated on the carrier. Loading depends on the individu al loading capacity of the specific carrier.
  • the carrier is loaded it is coated with about 1 to about 25 wt. -percent, prefera bly about 3 to about 15 wt. -percent and more particularly about 5 to 10 wt. -percent of mu coadhesive polymers - calculated on the carrier.
  • Another object of the present invention refers to a first process (so called wet- process) for making solid mucoadhesive compositions, comprising or consisting of the fol lowing steps:
  • step (iv-b) bringing the carrier into contact with a solid active agent, and subsequently melt ing the active agent to obtain the loaded carrier; (v) coating the loaded carrier by bringing the product of step (iv) into contact with a sus pension of the at least one mucoadhesive polymer in water or a lipophilic solvent.
  • the carrier is typically wetted or impregnated with a solution or dispersion of the active agent (which can be solid or liquid) in a suitable solvent, such as for example water, ethanol or an oil body.
  • a suitable solvent such as for example water, ethanol or an oil body.
  • the step can be conducted at room tem perature, preferably under vigorous stirring. Subsequently the solvent is separated off, ei ther by filtration or - preferred - evaporation.
  • the loaded carrier is coated with the polymers.
  • 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, however it has been found that lipids behave superior when it comes to stability of the coating. Therefore, preferred sol vents for the coating material are triglycerides such as for example triacetin or sunflower oil, or the active agents (preferably lipophilic fragrances or flavors) themselves, on condition that they represent lipophilic liquids.
  • Another object of the present invention refers to a second process (so called dry/hot- melt process) for making solid mucoadhesive compositions, comprising or consisting of the following steps:
  • step (v) coating the loaded carrier by bringing the product of step (iv) into contact with a at least one mucoadhesive polymer in substance and mixing both components under high shear.
  • the second process differs from the first one in that coating takes place in substance ("powder coating"), which means that the polymers are not dissolved or dispersed in a sol vent, but added to the carrier directly.
  • Coating takes place by vigorous stirring of the two components under high shear, for example using an High Shear mixer preferably, the mixing takes place in the presence of another non-mucoadhesive polymer having a melting point ranging from about 30 to about 60 °C, such as for example a solid polyglycolether (e.g. PEG- 1000).
  • the second polymer is added in amounts of from about 5 to about 25 wt. -percent - calculated on the mixture.
  • high-shear mixing is carried out at a tempera ture above the melting point of the second polymer.
  • Another object of the present invention refers to an oral preparation comprising the mucoadhesive composition as defined above, preferably in amounts of from about 0.1 to about 10 wt. -percent, more preferably from about 1 to about 8 wt. -percent and most pref erably from about 2 to about 5 wt. -percent.
  • the oral preparations may be chosen from the group consisting of (hard boiled) can dies, compressed tablets, chewing gums, and toothpastes, and more particularly
  • capsules hard or soft gelatin capsules with modified release and without
  • the preferred candies are so-called hard-boiled candies.
  • Their bases are usually prepared from a mixture of sugar and other carbohydrates that are kept in an amorphous or glassy condition.
  • This form can be considered a solid syrup of sugars generally having up to about 4.5 wt. -percent moisture, based on the weight of the candy base, with about 0.5 to about 2.5 wt. -percent being preferred and about 1.0 to about 1.5 wt. -percent being most preferred.
  • Such materials normally contain up to 65 wt. -percent corn syrup, up to 80 wt. -percent sugar and from 0.1 to 5.0 wt. -percent water.
  • the ratio of sugar (or other sweetener suitable for candy formulation) to corn syrup is within the range of about 70:25 to about 45:55 with about 60:40 being preferred.
  • the syrup compo nent generally is prepared from corn syrups high in fructose, but may include other materi als. Further ingredients such as flavorings, sweeteners, acidulants, colorants and so forth may also be added.
  • Hard boiled candy bases may also be prepared from non-fermentable sugars such as sorbitol, mannitol, xylitol, maltitol, hydrogenated starch hydrolysate, hydrogenated corn syrup and mixtures thereof.
  • the candy bases may contain up to about 95 wt. -percent sorbi tol, a mixture of sorbitol and mannitol at a ratio of about 9.5 to 0.5 up to about 7.5 to 2.5 and hydrogenated corn syrup up to about 55 wt. -percent of the syrup component.
  • the oral compositions can represent compressed tablets, comprising the liquid flavor in amounts of typically about 0.1 to about 0.6 wt.- percent and preferably about 0.5 wt. -percent
  • Chewing gums typically consist of a water- insoluble base component, a water- soluble component and additives providing for example a specific flavor.
  • the water-insoluble base typically comprises natural or synthetic elastomers, resins, fats and oils, plasticizers, fillers, softeners, dyes and optionally waxes.
  • the base normally makes up 5 to 95 wt. -percent, preferably 10 to 50 wt.- percent and more particularly 20 to 35 wt. -percent of the composition as a whole.
  • the base consists of 20 to 60 wt. -percent synthetic elastomers, 0 to 30 wt. -percent natural elastomers, 5 to 55 wt. -percent plasticizers, 4 to 35 wt. -percent fillers, 5 to 35 wt. -percent softeners and small amounts of additives, such as dyes, antioxidants and the like, with the proviso that they are soluble in water at best in small quantities.
  • Suitable synthetic elastomers are, for example, polyisobutylenes with average mo lecular weights (as measured by GPC) of 10,000 to 100,000 and preferably 50,000 to 80,000, isobutylene/isoprene copolymers ("butyl elastomers”), styrene/butadiene copolymers (sty- rene:butadiene ratio, for example, 1:3 to 3:1).
  • suitable natural elastomers are rubbers, such as for example smoked or liquid latex or guayuls, and natural gums, such as jelutong, lechi caspi, perillo, sorva, massaranduba bal- ata, massaranduba chocolate, nispero, rosindinba, chicle, gutta hang kang and mixtures thereof.
  • the choice of the synthetic and natural elastomers and their mixing ratios essential ly depends on whether or not bubbles are to be produced with the chewing gums (bubble gums). Elastomer mixtures containing jelutong, chicle, sorva and massaranduba are prefera bly used.
  • plasticizers are, above all, esters of resin acids, for example esters of lower aliphatic alcohols or polyols with completely or partly hydrogenated, mono meric or oligomeric resin acids.
  • esters of resin acids for example esters of lower aliphatic alcohols or polyols with completely or partly hydrogenated, mono meric or oligomeric resin acids.
  • the methyl, glycerol or pentaerythritol esters or mixtures thereof are used for this purpose.
  • terpene resins which may be de rived from a-pinene, b-pinene, d-limonene or mixtures thereof, could also be used.
  • Suitable fillers or texturizers are magnesium or calcium carbonate, ground pumice stone, silicates, especially magnesium or aluminium silicates, clays, aluminium oxides, tal cum, titanium dioxide, mono-, di- and tricalcium phosphate and cellulose polymers.
  • Suitable softeners or emulsifiers are tallow, hydrogenated tallow, hydrogenated or partly hydrogenated vegetable oils, cocoa butter, partial glycerides, lecithin, triacetin and saturated or unsaturated fatty acids containing 6 to 22 and preferably 12 to 18 carbon atoms and mixtures thereof.
  • Suitable dyes and whiteners are, for example, the FD&C types, plant and fruit ex tracts permitted for coloring foods and titanium dioxide.
  • the gum bases may also contain waxes or may be wax-free
  • chewing gum preparations regularly contain a water-soluble component which is formed, for example, by softeners, sweeteners, fillers, flavors, flavor enhancers, emulsifiers, dyes, acidifiers, antioxidants and the like, with the proviso that the constituents have at least adequate solubility in water. Accordingly, in dividual constituents may belong both to the water-insoluble phase and to the water-soluble phase, depending on the water solubility of the special representatives. However, combina tions may also be used, for example a combination of a water-soluble and a water-insoluble emulsifier, in which case the individual representatives are present in different phases.
  • the water-insoluble component usually makes up 5 to 95 wt. -percent and preferably 20 to 80 wt. -percent of the preparation.
  • Water-soluble softeners or plasticizers are added to the chewing gum compositions to improve chewability and the chewing feel and are present in the mixtures in quantities of typically 0.5 to 15 wt. -percent. Typical examples are glycerol, lecithin and aqueous solutions of sorbitol, hydrogenated starch hydrolysates or corn sirup.
  • Fillers are particularly suitable for the production of low-calorie chewing gums and may be selected, for example, from polydextrose, raftilose, raftilin, fructo-oligosaccharides (NutraFlora), palatinose oligosaccharides, guar gum hydrolyzates (Sun Fiber) and dextrins.
  • the chewing gums may additionally contain auxiliaries and additives which are suita ble, for example, for dental care, more particularly for controlling plaque and gingivitis, such as for example chlorhexidine, CPC or triclosan. They may also contain pH adjusters (for ex ample buffer or urea), anti-caries agents (for example phosphates or fluorides), biogenic agents (antibodies, enzymes, caffeine, plant extracts, probiotic bacteria), providing these substances are permitted in foods and do not undesirably interact with one another.
  • auxiliaries and additives which are suita ble, for example, for dental care, more particularly for controlling plaque and gingivitis, such as for example chlorhexidine, CPC or triclosan. They may also contain pH adjusters (for ex ample buffer or urea), anti-caries agents (for example phosphates or fluorides), biogenic agents (antibodies, enzymes, caffeine, plant extracts, probiotic bacteria), providing these substances are permitted in foods and do not undesirably interact with one
  • Toothpastes or tooth creams are generally understood to be paste-like preparations of water, thickeners, humectants, abrasives or polishes, surfactants, sweeteners, flavorings, deodorizing agents and agents active against oral and dental diseases.
  • any of the usual polishes may be used, such as chalk, dicalcium phosphate, insoluble sodium metaphosphate, aluminium silicates, calcium pyrophosphate, finely particulate synthetic resins, silicas, aluminium oxide and aluminium oxide trihydrate.
  • polishes for toothpastes according to the invention are finely particulate xerogel silicas, hydrogel silicas, precipitated silicas, aluminium oxide trihydrate and finely particulate a-alumina, or mixtures of these polishes. Such polishes are preferably used in quantities of from about 15 to 40 wt. -percent of the toothpaste.
  • Preferred humectants used for toothpastes according to the invention include low molecular weight polyethylene gly cols, glycerol, sorbitol or mixtures thereof in quantities of up to about 50 wt. -percent of the toothpaste.
  • the thickening, finely particulate gel silicas and nonionic hy drocolloids such as hydroxy ethyl cellulose, hydroxy propyl guar, hydroxy ethyl starch, poly vinyl pyrrolidone, high molecular weight polyethylene glycol and vegetable gums, such as tragacanth, agaragar, carrageen moss, gum arabic and xanthan gum.
  • the desired flavor and aroma for preparations in accordance with the invention may be obtained by adding the components (a) and/or (b) and optionally also (c).
  • the oral preparations ac cording to the invention may contain other standard auxiliaries, such as dyes, preservatives and opacifiers, for example titanium dioxide.
  • compositions of the present invention may include additional additives as for examples sweeteners or vitamins; in amounts of from about 0.001 to about 10 wt.- percent These additives may also represent components of the respective medicaments.
  • Suitable sweet-tasting substances including natural sources of these substances (component e5), such as for example sweet-tasting carbohydrates or sugars (e.g. sucrose (synonymous with saccharose), trehalose, lactose, maltose, melizitose, raffinose, palatinose, 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 vegetable preparations containing predominantly these carbohydrates (e.g.
  • sugar beet Beta vul garis ssp., sugar fractions, sugar syrup, molasses
  • sugar cane Sacharum officinarum ssp., e.g. molasses, sugar syrups
  • sugar maple Acer ssp.
  • agave agave thick juice
  • synthetic/enzymatic hydrolysates of starch or sucrose e.g. invert sugar syrup, highly enriched fructose syrups made from corn starch
  • fruit concentrates e.g. from apples or pears, apple syrup, pear syrup
  • sugar alcohols e.g.
  • erythritol erythritol, threitol, arabitol, ribitol, xyli- tol, sorbitol, mannitol, dulcitol, lactitol), proteins (e.g.
  • sweeteners magap, sodiumcyclamate, acesulfame K, neohesperidin dihydro- chalcone, saccharin sodium salt, aspartame ® , superaspartame, neotame, alitame, sucralose, stevioside, rebaudioside, lugduname, carrelame, sucrononate, sucrooctate, monatin, phyl- lodulcin), certain sweet-tasting amino acids (glycine, D-leucine, D-threonine, D-asparagine, D-phenylalanine, D-tryptophan, L-proline), other sweet-tasting low-molecular substances (e.g.
  • hernandulcin dihydrochalcone glycosides, glycyrrhizin, glycyrrhetinic acid ammonium salt or other glycyrrhetinic acid derivatives), liquorice extracts (Glycyrrhizza glabra ssp.), Lip- pia dulcis extracts, Momordica ssp. extracts or individual substances (in particular Momordi- ca grosvenori [Luo Han Guo] and the mogrosides obtained therefrom), Hydrangea dulcis or Stevia ssp. (e.g. Stevia rebaudiana) extracts or individual substances.
  • the compositions may include vita mins (component el).
  • Vitamins have diverse biochemical functions. Some have hormone like functions as 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 antioxi dants (e.g., vitamin E and sometimes vitamin C).
  • vitamins e.g. B complex vitamins
  • Vitamins may also be less tightly bound to enzyme catalysts as coenzymes, detachable mole cules that function to carry chemical groups or electrons between molecules.
  • folic acid carries various forms of carbon group - methyl, formyl, and methylene - in the cell.
  • suitable vitamins are selected from the group consisting of
  • Vitamin A retinol, retinal, b-carotene
  • Vitamin B2 (riboflavin)
  • Vitamin B3 (niacin, niacinamide),
  • Vitamin B5 panthothenic acid
  • Vitamin Be (pyridoxine, pyridoxamine, pyridoxal),
  • Vitamin B7 (biotin)
  • Vitamin Bg folic acid, folinic acid
  • Vitamin B12 (cyanobalamin, hydroxocobalamin, methylcobalamin),
  • Vitamin C ascorbic acid
  • Vitamin D cholesterol
  • Vitamin E tocopherols, tocotrienols
  • Vitamin K phytoquinone, menaquinone
  • the preferred vitamins are ascorbic acid and tocopherols. Said vitamins may be pre sent in the food composition in amounts of about 0.001 to about 5 wt. -percent, and prefer ably about 0.5 to about 1 wt. -percent
  • Another object of the present invention refers to the use of the mucoadhesive com positions as described above for making oral preparations, particular tooth pastes. To avoid ambiguities it is stated that all preferred embodiments, ranges, mixtures and applications as explained above shall also apply for the specific use, and thus no repetition is necessary.
  • Examples 1 to 3 were carried out with carriers that were loaded to about 100 wt.- percent of their capacity with flavors (Products 1 to 3). The experiments show that the load remains practically unchanged over the entire storage period.
  • Example 4 was carried out with a carrier that was overloaded (Product 4; load limit: 3.4 wt.-percent), i.e. about 1.2 wt.- percent of the flavors were not entrapped within the carrier but only bound to the outer surface. Storage of this carrier showed that only the fraction of flavors adhering to the outer surface of the carrier were released.
  • product 2 was placed in a mixer at 20 °C and a 10 wt. -percent suspension of hydroxy propyl methylcellulose (HPMC) in sunflower oil was added drop by drop for 2 minutes under strict stirring at 400 to 600 rpm (Product 5). Once the polymer was added the solution was stirred for another 5 minutes.
  • Another method is the simultaneous loading and coating of the unloaded carrier by suspend ing the polymer (HPMC) in the Optamint ® liquid flavor (Product 6), in which the procedure is performed as described for Product 5.
  • the coated carriers were again stored in a closed vial once at 20 °C and again according to the temperature gradient as in the previous examples and the polymer content was determined by HPLC over a period of up to 6 months.
  • the re sults are summarized in Table 2.
  • coated carriers were obtained in which the polymer content was practically unchanged even after 6 months.
  • product 7 In a first experiment (product 7), product 2 was added to a High-shear mixer with 3 wt. -percent HPMC and then homogenized for about 2 minutes at 400, 1,500 and 3,000 rpm respectively.
  • product 8 In the second experiment (product 8), product 2 with 5 wt. -percent HPMC was again homogenized in an High-shear mixer over 5 minutes, first at 400 and then at 1,500 rpm. Then 10 wt. -percent PEG-1000 was added, the mixture was heated to 45 °C above the melting point of the polyglycol ether, homogenized for 5 minutes at 400 rpm and then for 25 minutes at 1,500 rpm.
  • a piece of porcine mucosa with a thickness of about 2 mm and a diameter of 2.5 cm was prepared and placed on a metal disc within a mucoadhesion cell.
  • a sample was placed on the mucosa and its surface was wetted with drops of artificial saliva from a container (AS) using a HPLC pump (P) with a flow rate of 0.5 ml/min.
  • Cell and container were placed in the same water bath to ensure same temperatures of 37 °C as shown in Figure 1.
  • the used arti ficial saliva was prepared according to Matzker/Schreiber 1972 (without CaCh) and its com position was listed in the following Table 4:
  • Optamint ® was recovered after 2, 4, 6, 8, 10 and 12 minutes from the collected saliva and after 12 minutes additionally from the mucosa.
  • the retained carrier was removed from the mucosa with a swab and 1 ml EtOH.
  • the swab was extracted with 5 ml EtOH and the analysis conducted via HPLC.
  • the results are compiled in Table 5.
  • the examples show that compared to the plain carrier (Product 2) mucoadhesion has been seriously increased by a factor 2 to 3 by the addition of 3-4 wt. -percent HPMC as mucoadhesive agent.

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Abstract

L'invention concerne une composition mucoadhésive solide comprenant ou consistant en (a) au moins un agent actif ; (b) au moins un excipient ; et (c) au moins un polymère mucoadhésif, ledit excipient étant choisi dans le groupe constitué par du dioxyde de silicium, de la silice et des silicates.
PCT/EP2020/063027 2020-05-11 2020-05-11 Composition mucoadhésive solide WO2021228358A1 (fr)

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CN202080100702.0A CN115843240A (zh) 2020-05-11 2020-05-11 固体粘膜粘附组合物
JP2022567189A JP2023525987A (ja) 2020-05-11 2020-05-11 固体粘着性組成物
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