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
  • 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
  • A61K8/55—Phosphorus compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• Polyphosphonate derivatives for toothpaste compositions are Polyphosphonate derivatives for toothpaste compositions.
• the invention relates to a polyphosphonate compound used as a medicament, in particular for oral hygiene, an oral hygiene composition comprising such a bisphophonate compound, the use of such a compound for the preparation of a medicament more specifically intended for the prevention of the appearance and development of dental plaque.
• the oral bacterial flora is made up of very many taxa in association, and organized in the form of a multigeneric biofilm commonly called dental plaque. This flora is associated with the development of carious and periodontal pathology. Certain species such as Streptococcus mutans, S. sobrinus and Lactobacillus, identifiable in this biofilm, are cariogenic and constitute the primary colonizing species of dental surfaces by interaction with molecules of salivary origin.
• the bacterial species of the oral flora express virulence factors the effects of which are observable locally and certain from a distance: colonization factors (adhesins), persistence (aggressors, stress proteins ...), and tissue destruction (aggins, protease activities ).
• Streptococci in the oral cavity colonize tooth surfaces via adhesins, which are protein components of the bacterial wall.
• S. mutans plays a key role both in the initiation and the development of the carious process thanks to its homofermentative metabolism, but also to its capacity to produce homopolymers of glucose in particular (soluble dextrans), synthesized by glucosyltransferases (GTFs).
• GTFs participate in the adhesion capacities of cariogenic streptococci via glucose polymers.
• Decay can affect the enamel, dentin and pulp of the tooth. Symptoms can range from simple demineralization to complete destruction of the tooth.
• Dental plaque adheres to the very thin layer that surrounds each tooth and that includes salivary proteins.
• a 5-day plaque if not brushed off, can form a thick layer up to about 60 micrometers.
• a cariogenic plaque can often include 2x10 8 S. mutans bacteria / mg of dry weight and can quickly releasing enough glucose and fructose by fermentation to generate an acidic plaque pH of 5.5 or less causing demineralization of dental surfaces.
• chlorhexidine Certain substances have been identified as inhibiting the formation of dental plaque, such as chlorhexidine, when it is used twice a day in oral rinse at a concentration of 0.2%. Its prolonged persistence in the oral cavity makes it more effective. Chlorhexidine also has an affinity for hydroxyapatite (mineral component of enamel), but due to its side effects (staining of teeth, mucosa and composites), chlorhexidine is not suitable for long-term treatment .
• Chlorhexidine in oral rinse remains one of the most recommended antiseptics in the prevention of dental plaque, being indicated when the mechanical methods must be suspended or temporarily reinforced.
• Another non-ionic anti-bacterial agent, triclosan, mentioned for example in US Pat. No. 6,136,298, combined with a copolymer of polyvinyl methyl ether and maleic acid has the advantage of reducing plaque, gingivites, tartar and cavities, without side effects and without modifying the ecology of the oral flora.
• Another approach is to act on the specific interactions that exist between microorganisms in the oral cavity and dental surfaces. Specific compounds can interfere with these interactions and constitute a means of preventing or controlling the formation of dental plaque.
• Surfactants or polymers have thus been used intended to reduce or prevent salivary proteins from being adsorbed on the surface of the enamel. Surfactants naturally tend to adsorb on all surfaces, greatly reducing interfacial energy. The affinity of the molecule for an interface is generally affected by the properties of the hydrophobic and hydrophilic parts. Most surfactants adsorb on the surface in well-defined directions, and the action on protein adsorption and desorption can be closely associated with the orientation of the surfactants on the surface.
• a dental composition comprises between 0.01 and 20% by weight of a surfactant, or of a mixture of surfactants, anionic, cationic, nonionic, and zwitterionic.
• surfactants having an oral tolerance such as monoglycerides, glycerides, monoglycerides sulfonates, other fatty acid esters, alkyl sulfates, polysorbates, alkyl quaternary ammonium compounds, carboxylates, polyoxyethylenes, phosphonates, sodium alkyl sulfates, sodium lauryl sulfates.
• the invention aims to overcome the drawbacks of the prior art by proposing a compound and a composition which is particularly effective and suitable for oral hygiene, according to different possible applications, in particular toothpaste pastes and gels, mouthwashes, chewing gums, gels. non-abrasive.
• the invention also aims to provide oral hygiene compositions using an effective amount of active compound, capable of combating the bacterial agents causing alterations in the oral cavity which can be treated topically.
• the invention aims in particular to obtain a composition
• a composition comprising a compound capable of both being a good competitive inhibitor of the fixation of the proteins described above, of fixing effectively and sufficiently durably on the dental surface to be protected.
• a polyphosphonate compound used as a medicament said compound being of general formula I:
• R1, R2, R3, R5, R6, R7, R8 independently of one another represent a hydrogen atom or a C1-C6 alkyl or aryl group
• X is a carbon atom C or a nitrogen atom N;
• A, B and C represent a chemical bond, a C1-C6 alkyl or aryl group, a carbonyl group, or a hydrophilic group;
• R4 represents: a) either a hydrogen atom, an OH group, a C1-C6 alkyl or aryl group, or a C1-C6 carboxylic acid, a free doublet (if X is nitrogen N); b) or a phosphonate of formula;
• R9, R10 independently of one another represent a hydrogen atom, or a C1-C6 alkyl or aryl group; c) or a quaternary ammonium group of formula
• R11, R12, R13 represent independently of each other a hydrogen atom, or a C1-C6 alkyl or aryl group
• B represents a chemical bond, a C1-C6 alkyl group, a group carbonyl, or a hydrophilic group
• R'1, R'2, R'3, R'5, R'6, R'7, R'8 independently of one another represent a hydrogen atom, or an alkyl or aryl group in C1-C6;
• - A ', B' and C represent a chemical bond, a C1-C6 alkyl or aryl group, a carbonyl group, or a hydrophilic group;
• R'4 represents a C1-C6 alkyl or aryl group, or a C1-C6 carboxylic acid; or a pharmaceutically acceptable salt of these polyphosphonate compounds of formula I or II.
• This compound I is more especially intended to inhibit the appearance and the development of dental plaque.
• this compound I is a bisphosphonate compound.
• R1.R2.R3 are advantageously identical to each other and represent methyl or ethyl groups.
• R5, R6, R7, R8 are advantageously identical to each other and represent hydrogen atoms or methyl groups.
• hydrophilic group of 1 to 6 carbon atoms.
• the hydrophilic group or groups are typically chosen from the groups of formula -LQ, in which L is a chemical bond or a linear or branched C1-C6 alkyl group, and Q is chosen from: a) a hydroxyl, amino or carboxyl group , sulfate, phosphate; b) a linear or branched C1-C6 alkyl group containing one or more hydroxyl, amino, carboxyl, sulfate, phosphate groups; c) a group M, OM, CONHM, NHCOM in which M is a hydrophilic group; d) a hydrophilic group according to points a), b) or c), protected by a group which again becomes a hydrophilic group after biological hydrolysis.
• the invention relates to an oral composition, advantageously topical and intended for mouth hygiene, comprising a polyphosphonate compound I as described above, or a mixture of such polyphophonate compounds.
• the composition comprises between 0.01 and 20%, advantageously between 0.05 and 5%, and even more advantageously between approximately 0.1 and 2% by weight of compound I.
• the composition may also further comprise at least one of the elements chosen from an antibacterial agent, polishing agent, thickening agent, humectant, flavoring, sweetening agent, bleaching agent.
• the composition is typically in the form of a mouthwash, a liquid to be sprayed, a toothpaste, a toothpaste gel or the like.
• the subject of the invention is a polyphosphonate compound I as described above for the manufacture of an oral hygiene composition intended to inhibit the appearance and development of dental plaque.
• alkyl group is meant in the sense of the present invention any alkyl group of 1 to 10 carbon atoms, linear or branched substituted or not, in particular the group CH 3 .
• carboxylic acid is meant in the sense of the present invention any alkyl group as defined above to which is linked a carboxylic group (-COOH).
• salts of the polyphosphonate compound I have the same general pharmacological properties as the free acid form and are acceptable from the point of view of toxicity.
• the following salts are in particular included: acetate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, carbonate, chloride, citrate, lactate, isothionate, malate, methylbromide, methylnitrate, nitrate, ammonium salt , oleate, oxalate, palmitate, phosphate, diphosphate, stearate, sulfate, succinate, tartrate.
• the bisphosphonate compound comprises a part comprising an acid group
• pharmaceutically acceptable salt of alkali metal salts, such as the sodium or potassium salts, the calcium or magnesium salts, or the salts formed. with suitable organic ligands such as quaternary ammonium salts.
• the present invention relates to a method for treating or preventing the development of dental plaque, comprising the administration of such a dentifrice composition, of polyphosphonate compounds in therapeutically effective amount, or of a salt pharmaceutically acceptable polyphosphonate.
• therapeutically effective amount is meant that the amount of polyphosphonate administered makes it possible to limit and reduce the appearance and development of dental plaque. The invention will be particularly well understood on reading the detailed description which follows.
• Bisphosphonate compounds characterized by phosphorus-carbon bonds (P-C-P), are stable compounds resistant to chemical or biological hydrolysis, as mentioned in document WO9836064.
• the polyphosphonate compounds used have a behavior complementary to that of surfactants.
• a surfactant is a material which comprises both a non-polar hydrophobic part and a polar hydrophilic part, and which is capable of forming an interface between two surfaces of different polarities.
• the term surface is commonly used for surfactants and can be both a solid surface or a liquid surface, or a non-solid surface and a liquid surface.
• the non-polar part must be large enough to be sufficiently attached to a non-polar solid surface.
• the polarity ratio between the hydrophilic part and the hydrophobic part must also be appropriate and optimized for each application.
• Nonionic surfactants are generally defined as the product of the condensation of alkylene oxide groups (hydrophilic) with a hydrophobic compound which may be aliphatic or aromatic alkyl.
• hydrophobic compound which may be aliphatic or aromatic alkyl.
• polyoxyethylene sorbitan esters polyoxyethylene sorbitan esters, fatty alcohol ethoxylates, products resulting from the condensation of ethylene oxide and from the reaction product of propylene oxide and ethylene diamine.
• Amphoteric surfactants are generally defined as derivatives of secondary and tertiary aliphatic amines in which the aliphatic radical can be linear or branched, in which one of the aliphatic substituents has 8 to about 18 carbon atoms, and in which one of the substituents aliphatics comprises an anionic group soluble in water such as a carboxylate, sulfonate, sulfate, phosphate, or phosphonate group. Mention may also be made of betaines.
• Anionic surfactants typically include the water-soluble salts of alkyl sulfates having 8 to 20 carbon atoms in the alkyl radical (example: sodium alkyl sulfate) and the water-soluble salts of sulfonated monoglycerides fatty acids with 8 to 20 carbon atoms (example: sodium lauryl sulfate, coconut monoglyceride sulfonates, sarcosinates such as lauroyl sarcosinates, taurates, lauryl sulfoacetates, lauroyl isothionates, laureth carboxylates , dodecyl benzenesulfonates.
• the compound I demonstrated a high efficiency, this compound comprising at least two phosphonic groups in order to ensure the fixing on the surface to be protected, and at least one quaternary ammonium group advantageously trimethyl.
• the results are much better with two phosphonic groups than with one. It would seem that the presence of at least two phosphonic groups makes it possible to have at least two anchoring points for compound I on the surface to be protected.
• the increase in stability seems to be linked to a steric parameter: the synergy of two close phosphonate functions brings better stability to the polyphosphonate compound and in particular to the bisphosphonate due to the single X atom which separates the two phosphorus atoms.
• Compound I can also advantageously include: - two phosphonic groups (for good fixation) and two side chains of quaternary ammonium (for less repulsion during fixation) - or else two phosphonic groups (for good fixation), one quaternary ammonium chain (for less repulsion during fixing), and a bond with another polyphosphonic compound I, the adjacent compounds I then having a tendency to form a layer distributed over the surface to be protected.
• the radical A and / or B of compound I can be an aryl group.
• Aryl group means within the meaning of the present invention one or more aromatic rings having 5 to 8 carbon atoms, which can be joined or fused, substituted or not.
• the aryl groups can be phenyl groups. But typically there will be no particular interest in having more than three carbon atoms or a phenyl radical on the substituents of compound I so as not to generate unwanted hydrophobic interactions.
• the carbon chain of compound I can nevertheless typically contain up to six carbon atoms or hetero atoms.
• the compound I advantageously comprises hydrophilic groups between the phosphonic group functionalities and the quaternary ammonium functionality or functionalities of the molecule.
• the invention relates to the optical isomers of the polyphosphonate compound I.
• TMADP 2,2-diphosphono-5-hydroxy-3-oxa-6-hexyltrimethylammonium chloride
• HEDP hydroxyethylidene bisphosphonic acid
• glycidyltrimethylammonium chloride 6-trimethyiammoniohexyl ⁇ 1, 1-bisphosphonic acid.
• Compound I is incorporated into a composition for oral hygiene by topical route designated dentifrice composition typically comprising between 0.01 and 20%, advantageously between 0.05 and 5%, and even more advantageously between approximately 0.1 and 2% by weight of compound I.
• dentifrice composition typically comprising between 0.01 and 20%, advantageously between 0.05 and 5%, and even more advantageously between approximately 0.1 and 2% by weight of compound I.
• toothpaste means a composition for topical application to the teeth such as a liquid composition (for example mouthwash and rinsing) or a toothpaste (in the form of gel, powder or paste).
• composition can be applied to the teeth by various suitable techniques including brushing, dyeing, spraying, mouthwash. Other possible means of application are known to those skilled in the art.
• Various other ingredients can be incorporated into the composition, such as prophylactics, polishing agents, other surfactants, flavorings, suitable thickening or wetting agents. It must also be ensured that these agents do not prevent the desired fixation of the polyphosphonates on the dental surfaces.
• prophylactic agents mention may be made of caries-limiting compounds such as sodium fluoride, potassium fluoride, hexylamine hydrofluoride.
• these prophylactic agents are present in sufficient quantities to provide a concentration of fluoride ion of the order of 0.5 to 2% by weight of the dentifrice composition.
• polishing agents there may be mentioned resins (product of condensation of urea and formaldehyde), particles of resins polymerized by heating (see US 3,070,510), silica xerogels (US 3,538,230), precipitated silica particles, calcium pyrophosphate, insoluble sodium metaphosphate, hydrated alumina, dicalcium orthophosphate, these agents being sufficiently non-abrasive not to undesirably alter the surface of the tooth or dentin. These agents can represent for example 5 to 95% by weight of the toothpaste composition.
• the dentifrice composition is in the form of an oral liquid it typically contains an alcohol, a solubilizer, a non-abrasive cleaning agent, and when it is in the form of a gel it typically comprises a thickening agent.
• the humectants glycerin, sorbitol, polyethylene glycol and other polyhydric alcohols, these humectants possibly representing up to approximately 35% of the weight of the toothpaste composition.
• the toothpaste composition may comprise a liquid phase representing 10 to 99% by weight and comprising water and a humectant in variable proportion.
• the flavors it is possible to use optionally associated mint oils, menthol, eugenol, orange, lemon, anise, vanillin, thymol, these agents generally representing less than 5% by weight of the toothpaste composition.
• the composition can also comprise, for example, sweetening agents (sodium saccharinate), bleaching agents (titanium dioxide or zinc oxide), vitamins, other anti-plaque agents (zinc salts, including zinc citrate , copper salts, tin salts, strontinum salts, allantoin, chlorhexidine), antibacterial agents (triclosan: 2 ', 4,4'- trichloro-2-hydroxy-diphenyl ether), anti-calculus agents (pyrophosphates metal di and / or tetra alkali), pH adjusting agents, coloring agents, anti-caries agents (casein, urea, calcium glycerophosphates, sodium fluoride, monosodium fluorophosphate), stain-resistant compounds (silicone polymers ), anti-inflammatory agents (substituted salicylanilides), desensitizing agents (potassium nitrate, potassium citrate). Other agents are cited in US Pat. No. 5,258,173. The pH of the toothpaste
• composition for a toothpaste or gel - polyphosphonate compound 1: 0.2 to 5%
• Example of a non-abrasive gel composition such as a subgingival gel: - polyphosphonate compound 1: 0.2 to 5%
• a dental solution will typically include 90 to 99% water.
• a chewing gum type composition will typically include a base gum (about 50% to 99%), a flavoring agent (about 0.4% to 2%), a sweetening agent (about 0.01% to 20%).
• humectants such as glycerin, propylene glycol
• a mixer a mixer
• humectants such as glycerin, propylene glycol
• a pigment, a pH adjuster if necessary, an anti-caries agent is then added.
• These ingredients are mixed until a homogeneous phase is obtained, to which a polishing agent is then mixed.
• the mixture is then transferred to a high speed mixer, in which a thickening agent, an aroma, and the compound I are mixed, under reduced pressure from 20 to 100 mm of Hg.
• the product obtained is a semi-solid and extrudable paste .
• the toothpaste composition is typically applied regularly, every day or every two or three days, from one to three times a day, at a pH of about 5 to 9 or 10, generally between 5.5 and 8.
• the compound obtained can be used in compositions according to the present invention.

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• 2002
  • 2002-04-12 FR FR0204596A patent/FR2838339B1/fr not_active Expired - Fee Related
• 2003
  • 2003-04-14 CA CA002482230A patent/CA2482230A1/fr not_active Abandoned
  • 2003-04-14 EP EP03740602A patent/EP1494682A2/de not_active Withdrawn
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  • 2003-04-14 AU AU2003262154A patent/AU2003262154A1/en not_active Abandoned
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