Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K6/00—Preparations for dentistry
  • A61K6/20—Protective coatings for natural or artificial teeth, e.g. sealings, dye coatings or varnish
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K6/00—Preparations for dentistry
  • A61K6/80—Preparations for artificial teeth, for filling teeth or for capping teeth
  • A61K6/831—Preparations for artificial teeth, for filling teeth or for capping teeth comprising non-metallic elements or compounds thereof, e.g. carbon
  • A61K6/838—Phosphorus compounds, e.g. apatite
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
  • A61K8/0208—Tissues; Wipes; Patches
• • 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
• • 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
  • A61K9/0063—Periodont
• • 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
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7007—Drug-containing films, membranes or sheets

Definitions

• the invention relates to an adhesive film which has a certain adhesion to the tooth surface or on the gums and is soluble or swellable in water and in which a finely divided calcium salt which is sparingly soluble in water is incorporated as a remineralizing active ingredient.
• EP 0 381 193 A2 discloses films for application to the oral mucosa which contain a topical active ingredient, e.g. can also contain sodium fluoride or potassium nitrate.
• WO 95/33441 A1 describes phosphate-free compositions which contain finely divided (colloidal) metal compounds, e.g. of yttrium, cerium, aluminum or zirconium for the treatment of hypersensitive teeth and which should also be applied in the form of oral adhesive plasters.
• finely divided (colloidal) metal compounds e.g. of yttrium, cerium, aluminum or zirconium
• a dental adhesive film for local, remineralizing dental treatment consisting of a water-soluble or swellable carrier material which adheres to the tooth and active ingredients embedded therein, the active ingredients being a finely divided calcium salt which is sparingly soluble in water, selected from phosphates and fluorides , Fluorophosphates and mixtures thereof, which may optionally also comprise hydroxyl, carbonate or chloride ions.
• the carrier film can consist of any solid, flexible, water-soluble or swellable material. Suitable materials are preferably natural or synthetic polymers that are plasticized with water and / or water-miscible solvents. An example of such a material is, for example according to US Pat. No. 3,444,858, a gelatin softened by water and glycerol.
• suitable carrier materials are, for example, pullulan, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium alginate, xanthan gum, tragacanth, guar, acacia gum, gum arabic, amylose, hydroxypropyl starch, dextrin, pectin, chitin, chitosan, levan, collagen, zein, gluten, soy protein, casein, polyvinyl pyrrolidone, poly , Polyethylene glycol, polyacrylic acid, methyl methacrylate acrylic acid copolymer and mixtures thereof.
• the carrier component is a water-soluble or water-swellable natural or synthetic polymer material selected from vegetable and microbial gums, gelatin, cellulose ethers, copolymers of acrylic or methacrylic acid and esters of acrylic or methacrylic acid, polyvinyl alcohol, partially saponified polyvinyl acetate, polyvinylpyrrolidone and Mixtures of them included.
• the active substances are released from the carrier in a controlled manner over a longer period of time, that is to say that the carrier material in the mouth does not disintegrate too quickly under the action of the saliva or dissolve too quickly and the active substance is swallowed before it has an effect on the tooth or gums.
• the disintegration or dissolution of the carrier material can be delayed by various measures and the release of the active substances can thus be controlled in a targeted manner.
• measures are e.g. the crosslinking of the water-soluble polymers, the addition of less water-soluble polymers, the addition of hydrophobic components, e.g. Magnesium stearate, or, as suggested in WO 99/04764 A1, the use of proteins or cellulose ethers crosslinked with tannic acids or tannin.
• Carrier films are produced from a suitable carrier material by known processes by preparing a solution of the polymer or the polymer mixture, dissolving or dispersing the active substances therein and drying this solution or dispersion in a thin layer on a non-adhesive, for example a silicone-coated, base , After the solvent has evaporated, the finished film can be removed from the base and, if necessary, cut into a size suitable for application to the teeth.
• Calcium salts which are sparingly soluble in water are to be understood as those salts which are less than 0.1% by weight (1 g / l) soluble in water at 20 ° C.
• Such suitable salts are, for example, calcium hydroxyphosphate (Ca 5 [OH (P0 4 ) 3 ]) or hydroxyapatite, calcium fluorophosphate (Ca 5 [F (P0) 3 ]) or fluoroapatite, fluorine-doped hydroxyapatite with the composition Ca 5 (P0 4 ) 3 ( OH, F) and calcium fluoride (CaF 2 ) or fluorite or fluorspar as well as other calcium phosphates such as di-, tri- or tetracalcium phosphate
• a finely divided calcium salt which is sparingly soluble in water and which is selected from hydroxyapatite, fluoroapatite and mixtures thereof is preferably suitable as the remineralizing active ingredient, since the tooth material, the restoration of which is the aim of remineralization, consists of approximately 95% hydroxyapatite.
• Calcium salts which are not very soluble in water and have an average particle size of 10-300 nm (nanometer) have proven to be particularly advantageous. Particle fineness is to be understood here as the diameter of the particles in the direction of their greatest linear expansion. The average particle fineness relates to a volume-averaged value.
• Such calcium salts can e.g. according to the process known from DE 19858 662 A1 in the form of rod-shaped primary particles with thicknesses of 5-50 nm and lengths of 10-150 nm.
• hydroxylapatite attaches itself in an orderly manner to the protein matrix in the tooth or bone, which mainly consists of collagen.
• the formation of the hard and resilient mineral structure is controlled by so-called matrix proteins, which are formed from collagen and other proteins that attach to the collagen and thus cause a controlled mineralization process, the so-called biomineralization. Proteins also serve as protective colloids, which are adsorbed onto the surface of the nanoparticles and prevent them from coagulating and agglomerating and slowing crystal growth.
• matrix proteins which are formed from collagen and other proteins that attach to the collagen and thus cause a controlled mineralization process, the so-called biomineralization.
• Proteins also serve as protective colloids, which are adsorbed onto the surface of the nanoparticles and prevent them from coagulating and agglomerating and slowing crystal growth.
• crystal growth should be slowed down and controlled by proteins as a protective colloid, so that a dense and sufficiently solid crystal structure can be formed.
• the dental adhesive film according to the invention further contains a protein component selected from proteins, protein degradation products and derivatives of proteins or protein degradation products.
• proteins all proteins come into question regardless of their origin, i.e. both animal and vegetable proteins.
• Suitable animal proteins are e.g. Collagen, fibroin, elastin, keratin, albumin and casein.
• Suitable vegetable proteins are e.g. Wheat and wheat germ proteins (gluten), rice protein, soy protein, oat protein, pea protein, almond protein and potato protein. Also single cell proteins such as Yeast protein or bacterial proteins are suitable.
• Proteins preferred according to the invention are animal products such as collagen, keratin and casein.
• the protein can come from a vegetable or marine source.
• Protein degradation products are understood to mean those products which are obtainable by hydrolytic, oxidative or reductive degradation of water-insoluble proteins to give oligo- and polypeptide structures with a lower molecular weight and with improved water solubility.
• hydrolytic breakdown of water-insoluble proteins is the most important breakdown method; it can be under the catalytic influence of acids, alkalis or of enzymes. Those protein degradation products which are not degraded further than what is required to achieve water solubility are particularly suitable.
• the less degraded protein hydrolyzates include, for example, the gelatin preferred in the context of the present invention, which can have molar masses in the range from 15,000 to 250,000 D.
• Gelatin is a polypeptide that is primarily obtained by hydrolysis of collagen under acidic (gelatin type A) or alkaline (gelatin type B) conditions.
• the gel strength of the gelatin is proportional to its molecular weight, i.e. that is, a more hydrolyzed gelatin gives a lower viscous solution.
• the gel strength of the gelatin is given in Bloom numbers. When the gelatin is cleaved enzymatically, the polymer size is greatly reduced, which leads to very low Bloom numbers.
• Derivatives of proteins and protein degradation products are understood to mean chemically modified proteins or protein hydrolyzates which e.g. by acylation of free amino groups, by addition of ethylene or propylene oxide and hydroxyl, amino or carboxyl groups or by alkylation of hydroxyl groups of the protein or protein degradation product or a hydroxyalkyl derivative thereof, e.g. with epoxypropyl-trimethylammonium chloride or 3-chloro-2-hydroxypropyl-trimethylammonium chloride.
• the protein component is selected from gelatin, casein, their hydrolyzates and mixtures thereof.
• the dental adhesive film according to the invention can, for example, consist predominantly of a protein component, for example of gelatin or collagen, as the carrier material.
• a different material e.g. a plant gum, a single-cell biopolymer (xanthan gum, pullulan), a cellulose or starch ether, a polyvinylpyrrolidone or a mixture of cellulose ether, polyvinyl acetate and polyacrylic acid, then one should be preferred Protein component contained therein in an amount of at least 1% by weight, preferably 1-20% by weight.
• the active substance is a composite material consisting of the calcium salt, which is sparingly soluble in water, and a protein component selected from proteins, protein degradation products and derivatives of proteins or protein degradation products.
• Composite materials are understood to be composites which comprise the sparingly soluble calcium salts and the protein components and which are microscopically heterogeneous, macroscopically but homogeneous aggregates in which the primary particles of the calcium salts are associated with the structure of the protein component.
• the proportion of protein components in such composite materials is between 0.1 and 60% by weight, but preferably between 1.0 and 20% by weight, based on the weight of the composite material.
• hydroxyapatite particles present there have a particle size of 2-10 nm and therefore belong to the range of amorphous or partially X-ray amorphous substances. Hydroxyapatite nanoparticles which have a clearly recognizable crystalline morphology and whose particle fineness is therefore in the range from 10 to 300 nm are more suitable.
• Composite materials are also more suitable, in which the finely divided, poorly soluble calcium salts with particle finenesses of 10-300 nm together with finely divided proteins, protein hydrolyzates or derivatives thereof form a spatial structure in such a way that the finely divided calcium salts of the protein structure are deposited, virtually depicting them spatially.
• Composite materials consisting of such preferably suitable nanoparticulate calcium salts and protein components lead to particularly effective biomineralization.
• Composite materials suitable according to the invention can be prepared by precipitation from aqueous solutions of water-soluble calcium salts with aqueous solutions of water-soluble phosphate and / or fluoride salts in the presence of protein components.
• the protein components in pure, dissolved or colloidal form of the alkaline aqueous phosphate and / or fluoride salt solution or the alkaline solution of the calcium salt before Precipitation reaction can be added.
• the protein components can be presented in pure, dissolved or colloidal form and then the alkaline calcium salt solution and the alkaline phosphate and / or fluoride salt solution are added in succession in any order or simultaneously.
• the individual components can in principle be put together in all possible orders.
• Ammonia is preferably used as the alkalizing agent.
• Another variant of the production process is that the precipitation from an acidic solution of a water-soluble calcium salt together with a stoichiometric amount of a water-soluble phosphate and / or fluoride salt or from an acidic solution of hydroxyapatite with a pH below 5, preferably at pH below 3, by raising the pH with aqueous alkali or ammonia to a value above 5 in the presence of the protein components.
• nanoparticulate calcium salts in pure or dispersed form or by precipitation reactions from aqueous solutions of water-soluble calcium salts and aqueous solutions of water-soluble phosphate and / or fluoride salts are mixed with the protein components, the latter preferably in dissolved or dispersed form , whereby any order can be chosen when adding.
• the solution or dispersion of the protein component is preferably introduced and a dispersion of the nanoparticulate calcium salt is added.
• the resulting dispersion of the composite material can, if required, be known by processes known to those skilled in the art, such as, B. filtration or centrifugation, separated from the solvent and the other constituents of the reaction mixture and by subsequent drying, for. B. by freeze-drying, isolated in solvent-free form.
• Water is preferably used as the solvent in all manufacturing processes, but organic solvents such as, for. B. alcohols with 1 to 4 carbon atoms or glycerol can be used.
• the fine-particle calcium salt primary particles or the fine-particle calcium salt primary particles present in the composite materials can be enveloped by one or more surface modification agents.
• the surface modification agent is adsorbed onto the surface of the nanoparticles and changes them in such a way that the dispersibility of the calcium salt increases and the agglomeration of the nanoparticles is prevented.
• the structure of the composite materials and the loading of the protein component with the nanoparticulate calcium salt can be influenced by a surface modification. In this way, when using the composite materials in remineralization processes, it is possible to influence the course and speed of the remineralization process.
• Surface modification agents are understood to mean substances which physically adhere to the surface of the finely divided particles, but which do not react chemically with them.
• the individual molecules of the surface modification agents adsorbed on the surface are essentially free of intermolecular bonds with one another.
• Dispersants are also known to the person skilled in the art under the terms surfactants and protective colloids. Suitable surfactants or polymeric protective colloids can be found in German patent application DE 198 58 662 A1.
• the composite materials according to the invention in which the primary particles of the calcium salts are surface-modified, can be produced by analogous precipitation processes as described above, but the precipitation of the nanoparticulate calcium salts or of the composite materials takes place in the presence of one or more surface modification agents.
• the active ingredient that is to say the finely divided calcium salt which is sparingly soluble in water or preferably the composite material composed of the sparingly soluble calcium salt and a protein component
• the active ingredient is added to the still liquid solution of the carrier material in water or aqueous alcohol.
• the active ingredient can be used as a water- and solvent-free powder or as an aqueous or aqueous-alcoholic dispersion.
• the resulting dispersion is dried in a thin layer on a non-stick surface.
• the amount added depends on how much of the active ingredient is to be contained in the finished dental adhesive film.
• the active ingredient is contained in an amount of 0.1-10% by weight in the ready-to-use dental adhesive film.
• Caries-inhibiting fluorine compounds for example sodium fluoride, tin fluoride or sodium monofluorophosphate
• Anti-tartar active ingredients for example organophosphonates such as 1-hydroxyethane-1,1-diphosphonic acid, phosphonopropane-1,2,3-tricarboxylic acid (Na salts), 1-azacycloheptane-2,2-diphosphonic acid (Na salt),
• Aroma and synthetic aroma oils such as Peppermint oil, spearmint oil, eucalyptus oil, anise oil, fennel oil, caraway oil, fruit aroma and synthetic aroma oils,
• sweeteners such as sodium saccharin, acesulfame-K, aspartame ®, sodium cyclamate, stevioside, thaumatin, sucrose, lactose, maltose, fructose or glycyrrhizin,
• type B gelatin (gelatin obtained by alkaline hydrolysis of bovine skin) were mixed with 100 ml of water and boiled once using a microwave.
• the pH was 10.4 at the start of the dropping time and was kept at a value of about 10 by adding ammonia solution. After a reaction time of 20 hours (25 ° C., with stirring), the pH of the aqueous suspension had dropped to 9.5.
• the precipitated composite material was centrifuged off at 5000 rpm, washed with demineralized water at about 30-40 ° C. and freeze-dried. 2.2 g of composite material were obtained, the elemental analysis of which showed a carbon content of 2.3%; this corresponds to a content of protein material of 5.6% by weight, based on the total amount of the composite material.
• solutions A and B were prepared separately.
• Solution A 25.4 g calcium nitrate tetrahydrate and 8.50 g diammonium hydrogen phosphate were each dissolved in 100 g deionized water. Both solutions were combined to form a white precipitate. After adding 10 ml of 37% by weight HCl, a clear solution was obtained.
• Solution B 200 ml of deionized water, 200 ml of 25 wt .-% aqueous ammonia solution and 20 g of Plantacare ® 1200 were added together and cooled to 0 ° C in an ice bath.
• Solution A was added to solution B with vigorous stirring to form a precipitate of hydroxyapatite. After removing excess ammonia, the dispersion was purified by dialysis. The dispersion was then concentrated on a rotary evaporator by determining the amount of water separated to such an extent that the solids content in the dispersion, calculated as hydroxylapatite, was 7.5% by weight.
• This dispersion was added at room temperature to 100 ml of a 10% by weight aqueous solution of gelatin Bloom 300 (manufacturer: Fluka) prepared as in Example 1.1, then heated to 80 ° C. and stirred at this temperature for 5 minutes. The mass was then allowed to solidify at room temperature to form the composite material.
• gelatin Bloom 300 manufactured as in Example 1.1
• the dispersion was poured into a 2 m thick layer on a silicone-coated base and dried. An approximately 0.2 mm thick film was obtained which was cut into 1 cm wide strips.
• the dispersion was poured onto a silicone-coated base in a 2 mm thick layer and dried. An approximately 0.2 mm thick film was obtained, which was cut into approximately 1 cm wide strips.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Oral & Maxillofacial Surgery (AREA)
• Epidemiology (AREA)
• Birds (AREA)
• Plastic & Reconstructive Surgery (AREA)
• Inorganic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Biomedical Technology (AREA)
• Dental Preparations (AREA)
• Cosmetics (AREA)
• Adhesives Or Adhesive Processes (AREA)
• Medicinal Preparation (AREA)

Priority Applications (9)

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Related Child Applications (1)

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Cited By (13)

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Citations (8)

Family Cites Families (9)

• 2000
  • 2000-12-20 DE DE10063945A patent/DE10063945A1/de not_active Ceased
• 2001
  • 2001-12-11 EP EP01271194A patent/EP1343450B1/de not_active Expired - Lifetime
  • 2001-12-11 BR BR0116331-0A patent/BR0116331A/pt not_active Application Discontinuation
  • 2001-12-11 JP JP2002550922A patent/JP2004536032A/ja active Pending
  • 2001-12-11 MX MXPA03005482A patent/MXPA03005482A/es unknown
  • 2001-12-11 WO PCT/EP2001/014512 patent/WO2002049578A1/de not_active Ceased
  • 2001-12-11 AT AT01271194T patent/ATE385760T1/de active
  • 2001-12-11 AU AU2002219172A patent/AU2002219172A1/en not_active Abandoned
  • 2001-12-11 DE DE50113612T patent/DE50113612D1/de not_active Expired - Lifetime
  • 2001-12-11 CA CA2432456A patent/CA2432456C/en not_active Expired - Fee Related
• 2003
  • 2003-06-19 US US10/465,157 patent/US20030219388A1/en not_active Abandoned
• 2007
  • 2007-01-04 US US11/649,637 patent/US20070128130A1/en not_active Abandoned

Patent Citations (8)

Non-Patent Citations (1)

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