EP1824867A1 - Composes bisphosphoniques pour empecher ou limiter la fixation de macromolecules, de microorganismes et d'un biofilm sur des surfaces solides, notamment metalliques ou minerales - Google Patents

Composes bisphosphoniques pour empecher ou limiter la fixation de macromolecules, de microorganismes et d'un biofilm sur des surfaces solides, notamment metalliques ou minerales

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Publication number
EP1824867A1
EP1824867A1 EP05813667A EP05813667A EP1824867A1 EP 1824867 A1 EP1824867 A1 EP 1824867A1 EP 05813667 A EP05813667 A EP 05813667A EP 05813667 A EP05813667 A EP 05813667A EP 1824867 A1 EP1824867 A1 EP 1824867A1
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EP
European Patent Office
Prior art keywords
group
formula
composition
compounds
branched
Prior art date
Legal status (The legal status 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 status listed.)
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EP05813667A
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German (de)
English (en)
French (fr)
Inventor
Benoît DENIZOT
François HINDRE
David Portet
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Universite dAngers
Institut National de la Sante et de la Recherche Medicale INSERM
Surfactis Technologies SAS
Original Assignee
Universite dAngers
Institut National de la Sante et de la Recherche Medicale INSERM
Surfactis Technologies SAS
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Publication of EP1824867A1 publication Critical patent/EP1824867A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)

Definitions

  • the invention relates to the field of the protection of solid surfaces, such as metal or mineral surfaces, against macromolecular and microbiological contamination, in particular bacterial contamination.
  • Microbiological contamination means contamination by microorganisms.
  • the invention particularly relates to novel bisphosphonic compounds, the anti-contamination compositions containing them, and their use for limiting the attachment of macromolecules and microorganisms, in particular bacteria, to surfaces, such as metal or mineral surfaces.
  • the polymeric layer formed may itself be potentially pathogenic, as in the case of adsorbed and partially denatured prions whose complete removal of the surface is difficult to obtain.
  • Microorganisms, and especially bacteria, are able to colonize various surfaces and form true communities. These surface colonization phenomena are at the origin of the formation of the biofilm which constitutes an important source of microbiological contamination.
  • the precursor phenomenon is the fixation or the adsorption of macromolecules by their denaturation and their spreading in contact with the surface.
  • macromolecules Polymers are of the protein or polysaccharide or even polyphenolic type. In general, they are of biological origin, in particular of bacterial origin. By binding to the surface, macromolecules form a potentially pathogenic polymeric layer, as in the case of adsorbed prions. Many microorganisms such as protozoa, bacteria, fungi or even algae, will then be able to develop in this polymeric layer by the presence of hydrophobic zones, amino groups or sulfides or mono or polysidic sites.
  • biofilm a film-like matrix
  • This film is known, for example, to be an essential factor in the contamination of air-conditioning installations by Legionella, allowing these germs to spread in high concentration.
  • this microbiological film will serve as a support for multicellular plant or animal organisms leading to thick films.
  • An example is the contamination of boat hulls, leading to a significant increase in their resistance to progress.
  • fouling or biofouling
  • biofouling all the successive processes leading to the colonization of surfaces by microorganisms or even multicellular organisms .
  • a close phenomenon is that of implanted prostheses, which quickly overlap macromolecules present in the media in contact, subsequently serving as a support for the invasion of migrating cells.
  • the structure of the biofilm is generally porous and allows the circulation of water and nutrients that allow the renewal and development of colonies of microorganisms.
  • This macromolecular layer also protects the microorganisms against external aggressions (biocides, antibiotics, antiseptics) by slowing the access of biologically active products to the cells.
  • different forces of attraction come into play depending on the type of surface. Those which generally intervene in this process are of electrostatic, ionic, Van Der Waals, hydrogen bonds or hydrophobic interactions.
  • the adsorption thus depends on the attraction or repulsion forces existing between the macromolecules and the surface.
  • the actual fixation of the microorganism depends on its type, the size of its population in the medium, the duration of its growth phase, and cell deformation. The latter also depends on the dispersion medium: solution temperature, pH, electrolyte concentration and nutrient availability.
  • the attachment force also depends on the load of the surface and the duration of the contact.
  • the best-known biofilm is probably the dental biofilm, commonly known as dental plaque, the complex ecosystem of the human oral cavity that causes dental caries, caries recurrence, periodontal disease and peri-implantitis. which jeopardize the longevity of the biomaterial.
  • Biocidal chemicals such as chlorine or anti-biotics
  • the use of chlorine to remove biofilm is only effective if it is removed manually from the surface.
  • Antibiotics are not satisfactory either because they are likely to cause the spread of resistance genes in microorganisms, including bacteria, thus making them gradually inactive. It is common to see active biocidal products in vitro against isolated bacteria becoming completely inactive against sessile bacteria.
  • repellent molecules are only effective for advanced multicellular organisms.
  • the approach chosen consists in rendering the physico-chemical properties of the solid surfaces, in particular the attraction forces of these surfaces, detrimental to adhesion or macromolecular adsorption, and thus to limiting or even preventing fixation. microorganisms, in particular bacteria, on these surfaces.
  • the difficulty of this approach lies in the identification of a compound which is capable of both binding or adsorbing rapidly, effectively and durably on the surface to be protected, and which prevents or limits the attachment of microorganisms on this surface. surface, through the creation of an interface between the surface and the external environment, unfavorable to the adhesion and development of microorganisms.
  • the aim of the invention is to overcome the drawbacks of the prior art by proposing particularly effective compounds and compositions adapted to the reduction of biofouling (in the broad sense of the term), according to various possible applications, in particular pastes and gels, aqueous solutions, alcoholic or organic, suspensions, foams, powders, aerosols ....
  • the aim of the invention is to define the most suitable manufacturing protocol for molecules that are effective in these applications.
  • the invention also aims to provide compositions using an effective amount of active compound, capable of combating microbiological contaminations of metal or mineral surfaces.
  • the invention aims in particular to obtain a composition comprising a compound capable of both being a good competitive inhibitor of protein binding and to attach effectively and sustainably to the metal or mineral surfaces to be protected.
  • the invention thus provides novel compounds capable of binding to metal or mineral surfaces and limiting the attachment of microorganisms, in particular bacteria, and the development thereof on these surfaces.
  • the invention is particularly directed to compositions containing these novel compounds and their use against microbiological contamination of metal or mineral surfaces, in the odontological field (limitation of the formation of dental plaque, fight against the formation of caries and periodontal diseases) and the fields of hospital hygiene and agri-food.
  • the invention firstly relates to the compounds of formula (I):
  • R 6 represents a hydrogen atom, a halogen atom, a linear or branched C 1 -C 12 alkyl group, an -OH group or an amine optionally substituted with one or two C 1 -C alkyl groups; 4, linear or branched, or a -A'- group N + R 5 R 2 R 5 3 ', X 1 -,
  • R 1 , R 1 ', R 2 , R 2 ', R 3 and R 3 ' represent independently of one another:
  • m is an integer between 0 and 12,
  • * p is an integer between 0 and 12,
  • Z represents an oxygen atom, a sulfur atom, a group - CR 7 R 8 R 8 -, a group -COO-, a group -CONR 7 - or a group -NR 7 R 8 - in which R 7 , R 8 and R 9 have the same meanings as R 6 , or a group - N + R 4 R 5 -, X 3 " in which R 4 and R 5 represent, independently of one another, an alkyl group in C 1 -C 12 , linear or branched,
  • pharmaceutically acceptable means acceptable from a toxicity point of view.
  • halogen atom means a fluorine, chlorine, bromine or iodine atom.
  • C 1 to C 4 alkyl and “C 1 to C 12 alkyl” respectively mean an alkyl of 1 to 4 carbon atoms and an alkyl of 1 to 12 carbon atoms.
  • a linear or branched C 1 to C 4 alkyl group especially includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl groups.
  • R 7 , R 8 and R 9 have the same meanings as R 6 " means that R 6 ,
  • R 7 , R 8 and R 9 represent, independently of one another, a hydrogen atom, a halogen atom, a linear or branched C 1 -C 12 alkyl group, an -OH group or an amine group; optionally substituted by one or two linear or branched C 1 -C 4 alkyl groups, or a group -A 1 N + R 1 5 R 2 5 R 3 ', X 1 " as defined above.
  • metal surfaces such as stainless or Tacier I 5 aluminum
  • inorganic such as the tooth surface
  • the compounds of formula (I) comprise two phosphonic groups bonded to the same carbon atom (bisphosphonic or gem-diphosphonic groups) which make it possible to bind to the solid surfaces to be protected, and one or two optionally branched chains, also linked to this same atom. of carbon and comprising at least two quaternary ammonium functions, located one after the other on the chain or on branched chains.
  • the quaternary ammonium functions have two important roles in combating the phenomenon of microbiological contamination:
  • R 6 represents a hydrogen atom, a halogen atom, an -OH group or an amine -NH 2 .
  • Z represents an oxygen atom, a sulfur atom, a group -
  • R 8 and R 9 are as defined above. Even more preferably, Z represents a group -N + R 4 R 5 -, X 3 " in which R 4 and R 5 represent, independently of one another, a C 1 -C 12 alkyl group, linear or branched.
  • R 1 , R 2 , R 31, R 4 and R 5 represent, independently of one another, a C 1 to C 4 alkyl group, which is preferably linear, such as ethyl or methyl.
  • R 1 , R 2 , and R 3 are identical and each represents a methyl or ethyl group and R 4 and R 5 are identical and each represents a methyl or ethyl group.
  • X, X 1 , X 2 and X 3 are chosen from iodide, chloride, bromide, fluoride, sulphonate, phosphate, phosphonate or any pharmacologically active ion.
  • the compounds according to the present invention are chosen from those corresponding to the following formula (Ia):
  • R 6 represents -OH or -NH 2 , m is an integer from 1 to 12, p is an integer from 1 to 12,
  • n + p is an integer between 2 and 12,
  • R 1 , R 2 , R 3 , R 4 and R 5 represent, independently of one another, a linear or branched C 1 -C 4 alkyl group, and
  • X " represents a pharmaceutically acceptable counterion.
  • m is preferably between 3 and 7 and p is preferably between 1 and 4.
  • R 1 , R 2 , R 31, R 4 and R 5 represent, independently of one another, a C 1 to C 4 alkyl group, which is preferably linear, such as ethyl or methyl.
  • R 1 , R 2 and R 3 are preferably identical and each represents a methyl or ethyl group
  • R 4 and R 5 are preferably identical and each represents a methyl or ethyl group.
  • X is chosen from iodide, chloride, bromide, fluoride, sulphonate, phosphate, phosphonate or any pharmacologically active ion.
  • the subject of the invention is a composition for topical oral hygiene, comprising at least one compound of formula (I) as described above, preferably a compound of formula (Ia), preferably in combination with one or more pharmaceutically acceptable excipients.
  • the composition advantageously comprises between 0.001% and 10% by weight of the compound of formula (I), preferably between 0.005% and 5% by weight, and even more preferably between 0.01% and 1% by weight.
  • the composition is typically in the form of a mouthwash, a spraying liquid, a toothpaste, a toothpaste gel, a paste to be applied, a powder, a chewing gum or to apply or foam.
  • composition may be applied to the teeth by various suitable techniques including brushing, dyeing, spraying, mouthwashing, chewing gum, or by means of a dental accessory such as a dental floss impregnated with said composition, a optionally disposable wipe impregnated with said composition or a sponge impregnated with said composition.
  • a dental accessory such as a dental floss impregnated with said composition, a optionally disposable wipe impregnated with said composition or a sponge impregnated with said composition.
  • Other possible means of application are known to those skilled in the art.
  • compositions such as prophylactic agents, polishing agents, other surfactants, flavorings, thickening agents, or suitable moistening agents. It must however be ensured that these agents do not prevent the desired fixation of the polyphosphonates on the dental surfaces.
  • prophylactic agents include caries limiting compounds such as sodium fluoride, potassium fluoride, hexylamine hydrofluoride, but also all antiseptics and antibiotics known for their activity in the mouth.
  • these prophylactic agents are caries limiting compounds such as sodium fluoride, potassium fluoride, hexylamine hydrofluoride, but also all antiseptics and antibiotics known for their activity in the mouth.
  • these prophylactic agents are caries limiting compounds such as sodium fluoride, potassium fluoride, hexylamine hydrofluoride, but also all antiseptics and antibiotics known for their activity in the mouth.
  • these prophylactic agents are caries limiting compounds such as sodium fluoride, potassium fluoride, hexylamine hydrofluoride, but also all antiseptics and antibiotics known for their activity in the mouth.
  • these prophylactic agents are caries limiting compounds such as sodium fluoride, potassium fluoride, hexylamine hydrofluoride, but also all antis
  • polishing agents there may be mentioned resins (condensation product of urea and formaldehyde), particles of resins polymerized by heating
  • silica xerogels US 3,538,230
  • precipitated silica particles calcium pyrophosphate, insoluble sodium metaphosphate, hydrated alumina, dicalcium orthophosphate, these agents being sufficiently not abrasive so as not to undesirably affect the surface of the tooth or dentine.
  • These agents may represent for example 5 to 95% by weight of the composition.
  • gelling or thickening agents examples include natural gums, such as gum arabic, sodium carboxyl cellulose and hydroxyethyl cellulose, generally representing 0.5 to 10% of the composition by weight.
  • composition When the composition is in the form of an oral liquid, it typically contains an alcohol, a solubilizer, a non-abrasive cleaning agent, and when in the form of a gel it typically comprises a thickening agent.
  • humectants include glycerin, sorbitol, polyethylene glycol and other polyhydric alcohols, these humectants can represent up to about 35% of the weight of the composition.
  • the composition may comprise a liquid phase representing 10 to 99% by weight and comprising water and a humectant in variable proportion.
  • mint oils menthol, eugenol, orange, lemon, anise, vanillin and thymol, these agents generally representing less than 5% by weight of the composition.
  • composition may furthermore comprise, for example, sweeteners
  • the pH of the composition is typically between 5 and 10.
  • the pH will preferably be between 5 and 7.
  • composition for a dough or toothpaste gel (% by weight):
  • thickening agent 0.1% to 5%
  • non-abrasive gel composition such as a subgingival gel (% by weight):
  • thickening agent 0.1% to 20%
  • Example of mouthwash composition (% by weight):
  • - humectant agent 0 to 50% - flavoring agent: 0.04% to 2%
  • a dental solution will typically comprise 90 to 99% water.
  • a chewing gum composition will typically comprise a base gum (about 80% to 99%), an aroma agent (about 0.4% to 2%), a sweetening agent (about 0.01% to about
  • humectants such as glycerol, propylene glycol
  • glycerol glycerol
  • propylene glycol a humectant
  • a pigment, a pH adjuster, if necessary, an anti-caries agent is then added.
  • These ingredients are mixed until a homogeneous phase, which is then mixed with a polishing agent.
  • the mixture is then transferred to a high speed mixer, in which a thickening agent, a flavor, and the compound of formula (I) are mixed under a reduced pressure of 20 to 100 mmHg.
  • the product obtained is a semi-pulp. -Solid and extrudable.
  • the dentifrice composition is typically applied regularly, every day or every two or three days, one to three times daily, at a pH of about 5 to 9 or 10, usually between 5.5 and 8.
  • the present invention also relates to a cosmetic method for preventing the appearance of dental plaque or limiting the development of dental plaque on the teeth, comprising the application of an effective amount of the oral hygiene composition as described above. , on the teeth.
  • An "effective amount” means an amount to limit or prevent the onset or development of plaque.
  • the present invention also relates to a medicament comprising at least one compound of formula (I), preferably (Ia), or the oral composition described above, in particular to prevent the formation of caries or to prevent parondotal diseases.
  • the present invention relates to an anti-contamination composition intended to prevent or limit the attachment of macromolecules to solid surfaces, such as metal or mineral surfaces, comprising at least one compound of formula (I) such that described above, preferably at least one compound of formula (Ia).
  • macromolecule an organic molecule having a relatively high molecular weight (molecular weight greater than 1000 Da) and can be used as a substrate for the fixation and development of microorganisms on solid surfaces.
  • macromolecules are in particular of the peptide, protein, polysaccharide, polyphenolic, lipid or nucleic acid type.
  • the anti-contamination composition according to the invention limits or prevents the attachment of microorganisms, in particular bacteria, and thus limits or prevents the formation and development of a biofilm on solid surfaces, especially metallic or mineral surfaces.
  • microorganism refers in particular to bacteria, viruses and prions.
  • the anti-contamination composition advantageously comprises between 0.001% and 10% by weight of the compound of formula (I), preferably the compound of formula (Ia), preferably between 0.005% and 5% by weight, even more preferably between 0, 01% and 1% by weight.
  • the pH of the composition is typically between 5 and 10. The pH will preferably be between 5 and 7. This product may be used as a mixture as an additive in detergent or disinfectant formulations used in industry.
  • surfactants ionic, nonionic or amphoteric
  • chelating agents alkalis and solvents.
  • alkalis alkalis and solvents.
  • active ingredients of the antiseptic, biocidal, antibiotic type.
  • the compound of formula (I) may be incorporated in a formulation of the following composition:
  • Disinfectants such as glutaraldehyde, peracetic acid, sodium hypochlorite, etc. representing, for example, 0.01% to 30% by weight of the composition
  • Surfactants such as ethanol, propoxylated fatty alcohols, amine oxides, condensates of ethylene oxide and propylene oxide, quaternary ammonium salts, sulphates, sulphonates and sulphosuccinates by 0.01% to 30% by weight of the composition,
  • Chelating agents for example EDTA, sodium iminodisuccianate, sodium carbonates, ortho phosphates and silicates, condensed phosphates representing for example 0.1% to 5% by weight of the composition,
  • Alkalis carbonates, phosphates and silicates representing for example 0.1% to 40% by weight of the composition
  • solvents miscible with water (alcohols, glycol) or immiscible with water (terebentine derivatives, petroleum derivatives), optionally ionic, representing for example 0.1% to 80% by weight of the composition.
  • the surfaces that can be protected by the anti-contamination composition according to the invention are, for example, metal surfaces such as iron, stainless steel, chromium, aluminum, zinc, titanium, tungsten, lead or copper, as well as alloys or composites containing at least one of these metals, or mineral surfaces, such as silicon and its derivatives, siliceous materials, calcium, ceramic or dental surfaces.
  • metal surfaces such as iron, stainless steel, chromium, aluminum, zinc, titanium, tungsten, lead or copper, as well as alloys or composites containing at least one of these metals, or mineral surfaces, such as silicon and its derivatives, siliceous materials, calcium, ceramic or dental surfaces.
  • the application of the anti-contamination composition to the surfaces to be treated can be done by dipping or immersing this surface in the composition, or by spraying the composition on the surface to be treated. It can also be done by means of accessories, such as by the use of possibly disposable wipes impregnated with the composition.
  • the subject of the present invention is therefore the use of the compounds of formula (I) as previously described or microbiological anti-contamination compositions as previously described, for limiting or preventing the fixation of macromolecules, microorganisms and biofilm on surfaces. solid, especially metallic or mineral.
  • These surfaces are for example the surface of industrial, agri-food or hospital equipment, buildings, constructions or land, air or sea vehicles, air conditioning or refrigeration equipment, or on the surface of surgical instruments, prostheses, dentistry or biological and medical sensors.
  • Example of a liquid microbiological anti-contamination composition applied by dipping, rinsing, deposition by wet cloth or by spraying (% by weight):
  • the presence of alcohol facilitates the wetting of the surface and the homogeneity of the coating.
  • the evaporation of the alcohol makes it possible to obtain very high concentrations on the surface, facilitating rapid adsorption.
  • Ethanol may advantageously be replaced by volatile compounds which are miscible with water (C1 to C6 alcohols, in particular isopropyl alcohol, aldehydes, ketones including acetone, ethers, etc.) or which are not very miscible with water (C4 alkanes). at C8 in particular).
  • Such a composition leaves little solid residue after evaporation of the liquids and is therefore particularly suitable when the surface is to be used directly after application, in particular for the apparatus and instruments to be in contact with the food or the human organism.
  • the presence of humectants, odoriferous or even coloring agents is provided to make the application easier but also to improve the aesthetic pleasure (for example, brightener color).
  • composition for a paste or gel (% by weight):
  • thickening agent 0.1% to 5%
  • This composition is especially intended for scrubbing heavily fouled surfaces, in particular on vertical or even inverted surfaces.
  • Example of composition of foam type (% by weight):
  • the propellant may be a liquefied gas such as alkanes (propane or butane), fluorocarbons (F14, F26, etc.), gases under pressure (CO2, N2,. volatile liquids.
  • alkanes propane or butane
  • fluorocarbons F14, F26, etc.
  • CO2, N2 gases under pressure
  • This formulation is particularly advantageous when the parts are difficult to reach (interior of fine pipes, heat exchangers, air conditioners, ...) • It is also interesting for the uses with large surfaces (fermenters in biotechnology, rooms of preparation or of cutting in agribusiness, ).
  • Example of composition of powder type (% by weight):
  • - humectant agent 1% to 5%
  • the overall composition may be that of a washing powder already known to those skilled in the art, to which is added the bisphosphonic compound of formula (I).
  • This formulation is particularly advantageous as a washing agent for dishwashing machines, washing machines.
  • the bisphosphonic compounds of formula (I) may be used either alone or in combination.
  • composition for covering prostheses (% by weight): bisphosphonic compound of formula (I): 0.02 to 5%
  • the addition of complexing agents and pH control is intended to ensure optimum fixation of the bisphosphonic compound of formula (I).
  • the use of a bisphosphonic compound of formula (I) linked to one or more biologically active molecules, of the peptide, protein, lipid, carbohydrate or nucleic acid type may allow a better biocompatibility, or an orientation of the reaction of the organization.
  • the prostheses concerned are in particular the metal systems (stainless steel, nitinol, titanium, nickel-chromium, etc.) or to be in contact with the tissues while remaining external to the body (such as dental or auditory prostheses) or implantable, at vascular, bone, dental implant levels ...
  • Example of composition for sensor coverage (% by weight):
  • a bisphosphonic compound of formula (I) linked to one or more biologically active molecules of the peptide, protein, lipid, carbohydrate, nucleic acid or other type makes it possible to detect a molecular, particulate, cellular, viral ... whose concentration can be measured.
  • the microbiological anti-contamination compositions according to the invention are typically applied after each use (as for example with the surgical equipment), after each cycle of use (as for example with industrial meat cutting equipment ), regularly during the general maintenance (aesthetic surfaces) or even in a unique way.
  • FIG. 1 represents the activity (in Becquerel) of the model bisphosphonic molecules fixed on the support as a function of the contact time.
  • m pH 5
  • Step 1 one can also use a diaminetétraméthylée of formula (CH 3) 2 N-CH2- (CH2) a - N (CH 3) 2 in place of the 2 ⁇ diaminediméthylée In this case, use less alkyl halide equivalents in Example 3.
  • A-2) Step 2
  • the starting material 2 is dispersed in chlorobenzene.
  • the mixture is refluxed for two hours.
  • the reaction is stopped by adding an excess of water.
  • the product 4 thus formed is refluxed (100 ° C.) for two hours.
  • the molecule 4 is purified by crystallization in ethanol.
  • the molecule 4 is taken up in an excess of CH 3 I to which three equivalents of anhydrous sodium hydroxide are added. The mixture is stirred in the absence of air and light at reflux for 24 to 72 hours. The product formed is condensed under vacuum.
  • Step 3 can also be carried out by reacting another alkyl halide in place of methyl iodide, such as for example methyl bromide.
  • the molecules whose number of quaternary ammonium functions is greater than two can easily be obtained by adding stoichiometric amounts of bromoalkyl-trialkylammonium bromide on a aminoalkyldiphosphonate. This step is followed or not by an iodomethane methylation according to the degree of saturation of the substituted amine.
  • molecules having three or four ammonium functions can be synthesized as follows:
  • Aqueous solutions of 125 I-radiolabeled bisphosphonic acids were prepared at concentrations of 0.1 mMIL -1 and 0.01 mM l -1 .
  • the pH of these solutions was adjusted to 5, 7, 9 and 11 by means of molar solutions of HCl and NaOH.
  • Each solution received a quantity of radiolabeled molecules corresponding to 5. 10 8 Bq / ml.
  • CHT hydroxyapatite powder
  • Ca 5 (PO 4) 3 OH calcium phosphate
  • the molecules used to cover the surfaces are synthetic bisphosphonic compounds whose structure is as follows:
  • a volume of 200 ⁇ L of coating solution is added to each tube containing the surfaces.
  • a control is carried out using 200 ⁇ l of sterile distilled water (pH 6.8 ⁇ 0.2).
  • the incubation times used for fixing the bisphosphonic compound molecules are 30 seconds, 5 minutes or 1 hour.
  • the supernatant is then removed taking care not to suck up the surface particles, and then two cycles of rinsing / decantation / removal of the supernatant are carried out using 3 ml of distilled water.
  • the gamma radioactivity emitted upon disintegration of the 125 I present on the bisphosphonic compounds attached to the surfaces of the hydroxyapatite beads is counted by means of a Cobra 2 autogamma counting System (Packard Bioscience Company, France).
  • the results are expressed as a function of pH.
  • the activity in Becquerel is measured as a function of the time of contacting, and this for a concentration of bisphosphonic compound of 0.1 mol / L.
  • the results are shown in Figure 1.
  • hydroxyapatite powder CHT ® Ceramic hydroxyapatite, calcium phosphate (Ca 5 (PO 4) 3 OH) 2, Biorad, France.
  • the particle size of the hydroxyapatite powder (PAH) is 80 ⁇ 8 ⁇ m and the developed surface is 72 cmlg -1 . This surface is packed in tubes with hemolysis at a rate of 14 mg per tube. per tube is 5000. Before use, they are sterilized by dry heat (oven Tau, Italy) at 180 ° C for 2 hours.
  • the molecules used to cover the surfaces are synthetic bisphosphonic acids.
  • the molecule used is molecule A, synthesized in Example A and of the following formula:
  • the artificial saliva is adjusted to isotonic pH (pH 7) and sterilized by filtration on a 0.2 ⁇ m filter (Minisart, Sartorius, France).
  • Streptococcus mutons ATCC 25175D LGC Promochem, Molscheim, France.
  • Streptococcus mutans is a constituent of dental plaque and a major etiological agent of tooth decay.
  • the strain is stored in aliquots at -80 ° C. It is cultured by transfer from a 2 mL pipette tip to a 10 mL tube of Schaedler broth (Bio Mérieux, France) and incubated at 37 ° C for 24 hours. The absorbance of a dilution of l / 20th of the mother solution obtained was measured at 600 nm and is then diluted in artificial saliva (prepared as in Cl-3.) To obtain 3 ml of suspension adjusted (SA ) at approximately 5.10 6 colony-forming units (cfu) in 100 ⁇ L.
  • SA suspension adjusted
  • a volume of 200 ⁇ L of overlay solution (C-1-2) is added to each tube containing the surfaces (CII).
  • a control is carried out using 200 ⁇ l of sterile distilled water (pH 6.8 ⁇ 0.2).
  • the incubation time used for the fixation of the bisphosphonic molecules is 3 minutes at 37 ° C.
  • the supernatant is then removed, taking care not to suck up the surface particles, and then two cycles of rinsing / decantation / removal of the supernatant are carried out using 3 ml of sterile distilled water.
  • a volume of 3 mL of artificial saliva (C-1-3) is added to the tubes containing the coated surfaces (controls and tests). Immediately thereafter, a volume of 100 ⁇ l of the adjusted bacterial suspension (C-1-4) is inoculated into the tubes. The tubes are incubated for 4 to 24 hours at 37 ° C.
  • the colonized particles are washed to remove non-adherent bacteria by performing three cycles of rinsing / decantation / removal of the supernatant (taking care not to suck the surface particles) with 3 mL of physiological saline.
  • the surface particles are resuspended in 1 mL of physiological saline and sonicated to remove adhering bacteria (Branson 1200, 47 KHz, 95 W, 5 minutes, Bransonic, USA).
  • the bacterial suspension obtained is counted by decimal dilutions in physiological saline and spread of 100 ⁇ l of dilutions -1 and -2 on blood agar. The count is performed after 48 to 72 hours of incubation at 37 ° C.
  • the number of bacteria is expressed in cfu for 14 mg of hydroxyapatite.
  • the recovery of PAH surfaces is carried out for 3 minutes with the test solution.
  • the PAH surfaces are then incubated for 4 to 24 hours with a bacterial solution.
  • Table 1 summarizes the results obtained showing bacterial colonization as a function of time for hydroxyapatite surfaces covered or not by bisphosphonic compounds (respectively test and control). For statistical analysis the numbers of cfu were transformed into 10 log to obtain a normal distribution of the results. The Student's test was used to evaluate the significance of the values in both experiments (Table I). Table I. Mean counts of Streptococcus mutans adhering to hydroxyapatite
  • the bactericidal activity of the molecule A is evaluated according to the protocol of the standard NF EN 1040 modified so as to take into account the practical conditions of use.
  • the conditions selected are the following: target strain Streptococcus mutans, physiological saline medium, temperature 37 ° C., contact time 5 minutes.
  • a stock solution at 2.10 "1 mol.L-1 (pH adjusted to 6.0 ⁇ 0.1) is prepared and sterilized by filtration on a 0.2 ⁇ m filter (Minisart, Sartorius, France). carried out by dilutions in sterile distilled water, that is, 10 -1 , 2 ⁇ 10 -2 and 10 -2 mol / l . D-2-2) Bacterial strain
  • the strain is stored in aliquots at -80 ° C. It is replanted by transferring a 2 mL pipette tip to a 13 mL tube of Schaedler Broth (Bio
  • SA adjusted suspension
  • the number of bacteria present in the tubes is determined by decimal dilutions in physiological saline (Bio Mérieux, France) and spreading of 100 ⁇ l of dilutions -2, -3 and -4 on blood agar (Columbia + 5% of blood). mutton, Bio Mérieux, France). The count is performed after 48 hours of incubation at 37 ° C. The number of bacteria is expressed in cfu per ml.
  • Table II summarizes the results obtained for the physiological saline medium. Table II. Results of measurement tests for the bactericidal activity of the molecule A on S. mutans ATCC 25175D in physiological saline

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EP05813667A 2004-11-22 2005-11-21 Composes bisphosphoniques pour empecher ou limiter la fixation de macromolecules, de microorganismes et d'un biofilm sur des surfaces solides, notamment metalliques ou minerales Withdrawn EP1824867A1 (fr)

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FR0412358A FR2878248B1 (fr) 2004-11-22 2004-11-22 Composes bisphosphoniques pour empecher ou limiter la fixation de macromolecules, de microorganismes et d'un biofilm sur des surfaces solides, notamment metallique ou minerales
PCT/EP2005/056120 WO2006053910A1 (fr) 2004-11-22 2005-11-21 Composes bisphosphoniques pour empecher ou limiter la fixation de macromolecules, de microorganismes et d'un biofilm sur des surfaces solides, notamment metalliques ou minerales

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JP5166808B2 (ja) * 2007-09-25 2013-03-21 花王株式会社 洗浄機内のバイオフィルム生成抑制方法
FR2969663B1 (fr) * 2010-12-23 2013-01-18 Surfactis Technologies Composition hydrophobe et lipophobe de molecules bisphosphoniques et thiols
WO2014089680A1 (en) 2012-12-11 2014-06-19 Nano Safe Coatings Incorporated (A Florida Corporation 3 P14000024914) Uv cured benzophenone terminated quaternary ammonium antimicrobials for surfaces
HU230718B1 (hu) * 2011-02-08 2017-11-28 Richter Gedeon Nyrt. Új eljárás dronsavak gyógyszeripari előállítására
FR2990433A1 (fr) * 2012-05-10 2013-11-15 Surfactis Technologies Compositions catanioniques de recouvrement de surface par des molecules phosphoniques et amines
US9642369B2 (en) * 2013-02-19 2017-05-09 Nano Safe Coatings Incorporated Phosphorus functional antimicrobial coatings for metal surfaces
US11039621B2 (en) 2014-02-19 2021-06-22 Corning Incorporated Antimicrobial glass compositions, glasses and polymeric articles incorporating the same
US11039620B2 (en) 2014-02-19 2021-06-22 Corning Incorporated Antimicrobial glass compositions, glasses and polymeric articles incorporating the same
US9622483B2 (en) 2014-02-19 2017-04-18 Corning Incorporated Antimicrobial glass compositions, glasses and polymeric articles incorporating the same
US10072032B2 (en) * 2016-09-19 2018-09-11 Afton Chemical Corporation AminoBisPhosphonate antiwear additives
US10563069B2 (en) 2017-03-30 2020-02-18 International Business Machines Corporation Prevention of biofilm formation
US10507267B2 (en) 2017-04-25 2019-12-17 International Business Machines Corporation Highly hydrophobic antifouling coatings for implantable medical devices
US10745586B2 (en) 2017-08-08 2020-08-18 International Business Machines Corporation Fluorinated networks for anti-fouling surfaces
US10696849B2 (en) 2017-08-08 2020-06-30 International Business Machines Corporation Tailorable surface topology for antifouling coatings

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US3538230A (en) * 1966-12-05 1970-11-03 Lever Brothers Ltd Oral compositions containing silica xerogels as cleaning and polishing agents
US4208401A (en) * 1977-08-19 1980-06-17 Colgate-Palmolive Company Quaternary ammonium alkylene diphosphonate anti-calculus agents
GB9110721D0 (en) * 1991-05-17 1991-07-10 Unilever Plc Dentifrice compositions
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US6132702A (en) * 1998-02-27 2000-10-17 The Procter & Gamble Company Oral care compositions comprising chlorite and methods
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