WO2016187236A1 - Preparation and use of silver sulfadiazine-immobilized fillers - Google Patents

Preparation and use of silver sulfadiazine-immobilized fillers Download PDF

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Publication number
WO2016187236A1
WO2016187236A1 PCT/US2016/032938 US2016032938W WO2016187236A1 WO 2016187236 A1 WO2016187236 A1 WO 2016187236A1 US 2016032938 W US2016032938 W US 2016032938W WO 2016187236 A1 WO2016187236 A1 WO 2016187236A1
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composition
matter
amine
sulfadiazine
molecule moiety
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French (fr)
Inventor
Rohit Srivastava
Yuyu Sun
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University of Massachusetts Amherst
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University of Massachusetts Amherst
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Priority to US15/571,491 priority Critical patent/US10736821B2/en
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Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C03—GLASS; MINERAL OR SLAG WOOL
    • C03C—CHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
    • C03C17/00—Surface treatment of glass, not in the form of fibres or filaments, by coating
    • C03C17/28—Surface treatment of glass, not in the form of fibres or filaments, by coating with organic material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/50—Preparations specially adapted for dental root treatment
    • A61K6/54—Filling; Sealing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/60—Preparations for dentistry comprising organic or organo-metallic additives
    • A61K6/69—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/70—Preparations for dentistry comprising inorganic additives
    • A61K6/71—Fillers
    • 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
    • A61K6/84—Preparations for artificial teeth, for filling teeth or for capping teeth comprising metals or alloys
    • A61K6/844—Noble metals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/44—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/12—Nitrogen atoms not forming part of a nitro radical
    • C07D239/18—Nitrogen atoms not forming part of a nitro radical with hetero atoms attached to said nitrogen atoms, except nitro radicals, e.g. hydrazine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/28—Only halogen atoms, e.g. cyanuric chloride
    • 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
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C07F1/10—Silver compounds
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01D—COMPOUNDS OF ALKALI METALS, i.e. LITHIUM, SODIUM, POTASSIUM, RUBIDIUM, CAESIUM, OR FRANCIUM
    • C01D7/00—Carbonates of sodium, potassium or alkali metals in general
    • C—CHEMISTRY; METALLURGY
    • C03—GLASS; MINERAL OR SLAG WOOL
    • C03C—CHEMICAL COMPOSITION OF GLASSES, GLAZES OR VITREOUS ENAMELS; SURFACE TREATMENT OF GLASS; SURFACE TREATMENT OF FIBRES OR FILAMENTS MADE FROM GLASS, MINERALS OR SLAGS; JOINING GLASS TO GLASS OR OTHER MATERIALS
    • C03C2201/00—Glass compositions
    • C03C2201/06—Doped silica-based glasses
    • C03C2201/30—Doped silica-based glasses containing metals
    • C03C2201/54—Doped silica-based glasses containing metals containing beryllium, magnesium or alkaline earth metals
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
    • G01N2021/3595—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using FTIR
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2223/00—Investigating materials by wave or particle radiation
    • G01N2223/40—Imaging
    • G01N2223/418—Imaging electron microscope

Definitions

  • the invention relates to antimicrobial compositions of matter in general and particularly to a composition of matter that employs silver metal ions.
  • the first method is to add monomeric organic antimicrobial agents directly into the composites. However, release of the antimicrobial agents will shorten the antimicrobial duration and deteriorate physical properties of the resulting materials.
  • the second method is to add inorganic nano particles (e.g., silver, titanium dioxide, zinc oxide, etc.) into dental composites.
  • inorganic nano particles e.g., silver, titanium dioxide, zinc oxide, etc.
  • the cost to prepare and use the nano particles is high, the complete mixing of the nano particles with the current dental composite formulation is difficult to achieve (e.g., nano particle aggregation occurs), and the potential health risk associated with the processing and use of nano particles is a concern.
  • the third method is to add quaternary ammonium-containing monomers into the formulation to copolymerize with resin monomers.
  • the new monomers have misciblity/compatiblity issues with the current resin monomers.
  • quaternary ammonium salts have weak antimicrobial effects, and the effects can be quenched (stopped) by ionic compounds such as surface- active agents found in normal toothpastes.
  • the invention features a composition of matter, comprising: a particulate substrate comprising an inorganic filler; an amine-terminated hydrocarbon molecule moiety covalently bonded by way of a carbon atom of the hydrocarbon molecule moiety to the inorganic filler; a cyanuric chloride molecule moiety bonded to an amine group of the amine-terminated hydrocarbon molecule moiety; a sulfadiazine molecule moiety bonded to the cyanuric chloride molecule moiety; and a silver metal ion incorporated in the sulfadiazine moiety.
  • a second sulfadiazine molecule moiety is bonded to the cyanuric chloride molecule moiety.
  • the second sulfadiazine molecule moiety has a second silver metal ion incorporated therein.
  • the particulate substrate comprising an inorganic filler is a particulate glass substrate.
  • the particulate glass substrate comprises a glass containing BaO.
  • the amine-terminated hydrocarbon molecule moiety is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the invention relates to a method of producing a composition of matter, comprising the steps of: providing a particulate substrate comprising an inorganic filler; reacting the inorganic filler with an amine-terminated hydrocarbon molecule moiety to covalently bond the hydrocarbon molecule moiety by way of a carbon atom thereof to the inorganic filler to produce an amine modified substrate; reacting the amine modified substrate with a cyanuric chloride molecule moiety to bond the cyanuric chloride molecule moiety to an amine group of the amine-terminated hydrocarbon molecule moiety to produce an amine modified substrate-CyCl composition; reacting the amine modified substrate-CyCl composition with a sulfadiazine molecule moiety to bond an amine moiety of the sulfadiazine molecule moiety to the cyanuric chloride molecule moiety by displacing a chlorine atom thereof to produce an amine modified substrate-CyCl-SD composition;
  • the particulate substrate is a particulate glass substrate.
  • the step of reacting the inorganic filler with an amine- terminated hydrocarbon molecule moiety is performed using a reaction medium comprising cyclohexane and n-propyl amine.
  • the step of reacting the amine modified substrate with a cyanuric chloride molecule moiety is performed in a reaction medium comprising Na2CC>3, acetone and water.
  • CyCl composition with a sulfadiazine molecule moiety is performed using DMSO, Na2CC>3 and water.
  • CyCl-SD composition with a silver metal ion is performed in a reaction medium of DI water.
  • the invention relates to a method of using a composition of matter, comprising the steps of: providing a composition of matter comprising a silver sulfadiazine-immobilized inorganic filler; mixing the composition of matter comprising a silver sulfadiazine-immobilized inorganic filler with a dental composite or dental adhesive formulation to produce a mixture; and applying the mixture as a replacement material for at least a part of a tooth in a mouth of a patient.
  • the silver sulfadiazine-immobilized inorganic filler comprises a particulate glass substrate.
  • the particulate glass substrate comprises BaO.
  • the silver sulfadiazine-immobilized inorganic filler comprises an amine-terminated hydrocarbon molecule moiety.
  • the silver sulfadiazine-immobilized inorganic filler comprises a cyanuric chloride molecule moiety bonded to an amine group of the amine- terminated hydrocarbon molecule moiety.
  • the silver sulfadiazine-immobilized inorganic filler comprises an amine moiety of a sulfadiazine molecule moiety to the cyanuric chloride molecule moiety.
  • the silver sulfadiazine-immobilized inorganic filler comprises a silver metal ion incorporated in the sulfadiazine moiety.
  • FIG. 1 is a reaction scheme for preparing a glass substrate with (3- aminopropyl)trimethoxysilane (APTMS).
  • APITMS (3- aminopropyl)trimethoxysilane
  • FIG. 2 is an FTIR spectrum of A-Glass, or amine-functionalized glass as produced by the reaction scheme of FIG. 1.
  • FIG. 3 is a schematic reaction of A-Glass-CyCl with sulfadiazine to produce reaction product A-Glass-CyCl-SD.
  • FIG. 4 is an FTIR spectrum of A-Glass-Cy Cl-SD.
  • FIG. 5 A is an image of A-Glass-Cy Cl-SD treated with chlorine bleach.
  • FIG. 5B is an image of A-Glass-CyCl-SD treated with chlorine bleach and then with KI.
  • FIG. 6 is a reaction scheme for preparing a silver sulfadiazine- inorganic filler conjugate A-Glass-CyCl-SD-Ag according to principles of the invention.
  • FIG. 7 is an SEM-EDS spectrum of A-Glass-CyCl-SD-Ag. DETAILED DESCRIPTION
  • the invention creates silver sulfadiazine-immobilized inorganic fillers, and uses the resulting fillers in dental composites and dental adhesives to achieve potent, long-term, and none-leaching antimicrobial effects.
  • glass is recited as a substrate material. It is believed that other biologically-inert inorganic materials may also be used as suitable particulate substrates in place of glass.
  • the methods of the invention include the following steps:
  • Sulfadiazine is covalently attached onto conventional inorganic fillers (such as glass powders) used in dental composites. This can be achieved by chemically modifying the filler surfaces to introduce reactive groups onto the filler surfaces, and then reacting the new functional groups with the amino groups on sulfadiazine to form covalent linkage.
  • the resulting sulfadiazine-filler conjugates are believed to be novel. The following examples show how this can be done.
  • FIG. 1 is a reaction scheme for preparing a glass substrate with (3- aminopropyl)trimethoxysilane (APTMS).
  • APTMS (3- aminopropyl)trimethoxysilane
  • 8.0 g glass powder was reacted with 12.0 ml (3-aminopropyl)trimethoxysilane in a reaction medium comprising mixed with 100 ml cyclohexane and 3.2 ml n-propyl amine.
  • the reaction was allowed to proceed at room temperature for 2 h.
  • the solvent was then removed under vacuum and keep the sample in oven at 100 °C for 2 h.
  • the samples were washed with cyclohexane 3 times under ultracentrifugation to remove unattached APTMS and other side products.
  • the glass is illustrated in the lower right corner of FIG. 1 as silicate glass having approximately 33 % BaO content. It is believed that the reaction of the (3-aminopropyl)trimethoxysilane with the glass occurs at hydroxyl moieties in the glass surface.
  • FIG. 2 is an FTIR spectrum of A-Glass, or amine-functionalized glass as produced by the reaction scheme of FIG. 1.
  • Cyanune chloride is an organic compound with the formula (NCCl):, and the chemical structure
  • Sulfadiazine is a sulfonamide antibiotic having the chemical structure
  • FIG. 3 is a schematic reaction of A-Glass-CyCl with sulfadiazine to produce reaction product A-Glass-CyCl-SD.
  • reaction product A-Glass-CyCl-SD is confirmed by FTIR analysis and KI test.
  • FIG. 4 is an FTIR spectrum of A-Glass-CyCl-SD.
  • the KI Test Treat a small amount of modified glass powder A-Glass-CyCl-SD with 1 :30 dilute chlorine bleach at room temperature (RT) for lh. After treatment, filter it and wash with DI water thoroughly to remove unreacted chlorine bleach. Dry the powder at RT and treat it with 5% aqueous solution of KI. There is a color change from white to yellow-brown spontaneously as shown in FIG. 5A and FIG. 5B.
  • FIG. 5 A is an image of A-Glass-Cy Cl-SD treated with chlorine bleach.
  • FIG. 5B is an image of A-Glass-CyCl-SD treated with chlorine bleach and then with KI.
  • Silver sulfadiazine- inorganic filler conjugates are prepared. This is accomplished by reacting sulfadiazine-filler conjugates as described above with a source that can provide silver, e.g., silver nitrate aqueous solution. The sulfadiazine will form a complex with the silver cations, leading to the formation of silver sulfadiazine- inorganic filler conjugates, which are believed never to have been reported before. The following example shows how this can be done.
  • FIG. 6 is a reaction scheme for preparing a silver sulfadiazine- inorganic filler conjugate A-Glass-CyCl-SD-Ag
  • FIG. 7 is an SEM-EDS spectrum of A-Glass-CyCl-SD-Ag.
  • Antimicrobial dental composites and/or dental adhesives are prepared. This is achieved by adding silver sulfadiazine- inorganic filler conjugates into the dental composites or dental adhesive formulations to replace the conventional inorganic fillers totally or partially, and follow the conventional preparation methods to produce antimicrobial dental composites and/or dental adhesives. These composites or adhesives that contain silver sulfadiazine- inorganic filler conjugates to produce antimicrobial functions have never been reported.
  • bisGMA bisGMA
  • TEGDMA triethylene glycidyldimethacrylate
  • CQ camphor quinone
  • 4-EDMAB 4-ethyl dimethylamino benzoate
  • the control discs contained 100% of the original commercial glass to make up the 70% filler weight.
  • 2%, 5%, 10%, of the original glass was replaced by the silver glass powder (A-Glass-CyCl-SD-Ag).
  • the prepared composite mixture was placed in a custom made mold of 6.0 mm in diameter and 1.0 mm in height.
  • a blue LED light at the wavelength 395-480 nm with 1000 mW/cm 2 of intensity was focused on the composite mixtures for 100 seconds to cure the resins.
  • the resin discs were used for the following antimicrobial tests.
  • the bacteria, S. mutans, were grown and harvested following ATCC's recommendations.
  • 2.5 ⁇ bacteria solution with 10 6 -10 7 CFU of the bacteria were placed on a disc, which was covered by another identical disc to make a "sandwich".
  • the discs were placed in 1 ml PBS solution and vortexed for 60 seconds to wash out all the bacteria attached to the disks.
  • the solution was serially diluted, and each dilution was placed on agar plates for incubation at 37 °C with 95% air and 5% CO2 for 24 h.
  • CFUs Colony forming units
  • anti-microbial agents are novel.
  • the antimicrobial agents are covalently bound onto fillers, and will not leach away.
  • compositions described are expected to provide potent antimicrobial activity, be safe to use, and suffer no discoloration: Silver has potent
  • the antimicrobial agents are covalently bound onto conventional fillers.
  • the appearance and handling characteristics of the resulting fillers will not be significantly altered. From the users' (dentists') point of view, no new monomers or new nano fillers are used, and they can still use the instruments and procedures they are most familiar with in their clinics. This ease of use (and use as a substitute material in presently available application/treatment methods) is believed to be a further help for the acceptance of the resulting products.
  • compositions of the invention are believed to be useful in dental composites, dental adhesives, and other related applications. It is believed that the present invention provides a novel solution for a long-standing problem in dental (and possibly other medical) technology.

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Abstract

Silver sulfadiazine-immobilized inorganic fillers are described, and their synthesis is presented. The fillers are believed to have utility in dental composites and dental adhesives to achieve potent, long-term, and none-leaching antimicrobial effects.

Description

PREPARATION AND USE OF SILVER SULFADIAZINE-IMMOBILIZED FILLERS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to and the benefit of co-pending U.S.
provisional patent application Serial No. 62/164,844, filed May 21, 2015, which application is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The invention relates to antimicrobial compositions of matter in general and particularly to a composition of matter that employs silver metal ions.
BACKGROUND OF THE INVENTION
[0003] Polymer resin/inorganic filler-based composites are widely used as dental restorative materials and dental adhesives. In the US alone billions of dollars are spent in dental filling procedures using such materials every year. However, bacterial adhesion and biofilm-formation on such materials can lead to secondary caries, one of the major causes of the short service life (around several years) of the current resin-based dental restorations.
[0004] Three general methods have been tried to introduce antimicrobial functions into dental composites to control microbial adhesion and biofilm formation. The first method is to add monomeric organic antimicrobial agents directly into the composites. However, release of the antimicrobial agents will shorten the antimicrobial duration and deteriorate physical properties of the resulting materials. The second method is to add inorganic nano particles (e.g., silver, titanium dioxide, zinc oxide, etc.) into dental composites. However, the cost to prepare and use the nano particles is high, the complete mixing of the nano particles with the current dental composite formulation is difficult to achieve (e.g., nano particle aggregation occurs), and the potential health risk associated with the processing and use of nano particles is a concern. The third method is to add quaternary ammonium-containing monomers into the formulation to copolymerize with resin monomers. However, the new monomers have misciblity/compatiblity issues with the current resin monomers. In addition, quaternary ammonium salts have weak antimicrobial effects, and the effects can be quenched (stopped) by ionic compounds such as surface- active agents found in normal toothpastes.
[0005] In summary, antimicrobial activity is needed in resin-based dental restorative and adhesive materials that can inhibit microbial adhesion and secondary caries so as to prolong the service life of the resins. However, none of the current materials and methods provide a solution to these problems.
SUMMARY OF THE INVENTION
[0006] According to one aspect, the invention features a composition of matter, comprising: a particulate substrate comprising an inorganic filler; an amine-terminated hydrocarbon molecule moiety covalently bonded by way of a carbon atom of the hydrocarbon molecule moiety to the inorganic filler; a cyanuric chloride molecule moiety bonded to an amine group of the amine-terminated hydrocarbon molecule moiety; a sulfadiazine molecule moiety bonded to the cyanuric chloride molecule moiety; and a silver metal ion incorporated in the sulfadiazine moiety.
[0007] In one embodiment, a second sulfadiazine molecule moiety is bonded to the cyanuric chloride molecule moiety.
[0008] In another embodiment, the second sulfadiazine molecule moiety has a second silver metal ion incorporated therein.
[0009] In yet another embodiment, the particulate substrate comprising an inorganic filler is a particulate glass substrate.
[0010] In still another embodiment, the particulate glass substrate comprises a glass containing BaO.
[0011] In a further embodiment, the amine-terminated hydrocarbon molecule moiety is
(3-aminopropyl)trimethoxysilane.
[0012] According to another aspect, the invention relates to a method of producing a composition of matter, comprising the steps of: providing a particulate substrate comprising an inorganic filler; reacting the inorganic filler with an amine-terminated hydrocarbon molecule moiety to covalently bond the hydrocarbon molecule moiety by way of a carbon atom thereof to the inorganic filler to produce an amine modified substrate; reacting the amine modified substrate with a cyanuric chloride molecule moiety to bond the cyanuric chloride molecule moiety to an amine group of the amine-terminated hydrocarbon molecule moiety to produce an amine modified substrate-CyCl composition; reacting the amine modified substrate-CyCl composition with a sulfadiazine molecule moiety to bond an amine moiety of the sulfadiazine molecule moiety to the cyanuric chloride molecule moiety by displacing a chlorine atom thereof to produce an amine modified substrate-CyCl-SD composition; and reacting the amine modified substrate-CyCl-SD composition with a silver metal ion to incorporate the silver metal ion in the sulfadiazine moiety to produce a silver sulfadiazine-immobilized inorganic filler material.
[0013] In one embodiment, the particulate substrate is a particulate glass substrate.
[0014] In another embodiment, the step of reacting the inorganic filler with an amine- terminated hydrocarbon molecule moiety is performed using a reaction medium comprising cyclohexane and n-propyl amine.
[0015] In yet another embodiment, the step of reacting the amine modified substrate with a cyanuric chloride molecule moiety is performed in a reaction medium comprising Na2CC>3, acetone and water.
[0016] In still another embodiment, the step of reacting the amine modified substrate-
CyCl composition with a sulfadiazine molecule moiety is performed using DMSO, Na2CC>3 and water.
[0017] In a further embodiment, the step of reacting the amine modified substrate-
CyCl-SD composition with a silver metal ion is performed in a reaction medium of DI water.
[0018] According to another aspect, the invention relates to a method of using a composition of matter, comprising the steps of: providing a composition of matter comprising a silver sulfadiazine-immobilized inorganic filler; mixing the composition of matter comprising a silver sulfadiazine-immobilized inorganic filler with a dental composite or dental adhesive formulation to produce a mixture; and applying the mixture as a replacement material for at least a part of a tooth in a mouth of a patient.
[0019] In one embodiment, the silver sulfadiazine-immobilized inorganic filler comprises a particulate glass substrate.
[0020] In another embodiment, the particulate glass substrate comprises BaO.
[0021] In yet another embodiment, the silver sulfadiazine-immobilized inorganic filler comprises an amine-terminated hydrocarbon molecule moiety. [0022] In still another embodiment, the silver sulfadiazine-immobilized inorganic filler comprises a cyanuric chloride molecule moiety bonded to an amine group of the amine- terminated hydrocarbon molecule moiety.
[0023] In a further embodiment, the silver sulfadiazine-immobilized inorganic filler comprises an amine moiety of a sulfadiazine molecule moiety to the cyanuric chloride molecule moiety.
[0024] In yet a further embodiment, the silver sulfadiazine-immobilized inorganic filler comprises a silver metal ion incorporated in the sulfadiazine moiety.
[0025] The foregoing and other objects, aspects, features, and advantages of the invention will become more apparent from the following description and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] The objects and features of the invention can be better understood with reference to the drawings described below, and the claims. The drawings are not necessarily to scale, emphasis instead generally being placed upon illustrating the principles of the invention. In the drawings, like numerals are used to indicate like parts throughout the various views.
[0027] FIG. 1 is a reaction scheme for preparing a glass substrate with (3- aminopropyl)trimethoxysilane (APTMS).
[0028] FIG. 2 is an FTIR spectrum of A-Glass, or amine-functionalized glass as produced by the reaction scheme of FIG. 1.
[0029] FIG. 3 is a schematic reaction of A-Glass-CyCl with sulfadiazine to produce reaction product A-Glass-CyCl-SD.
[0030] FIG. 4 is an FTIR spectrum of A-Glass-Cy Cl-SD.
[0031] FIG. 5 A is an image of A-Glass-Cy Cl-SD treated with chlorine bleach.
[0032] FIG. 5B is an image of A-Glass-CyCl-SD treated with chlorine bleach and then with KI.
[0033] FIG. 6 is a reaction scheme for preparing a silver sulfadiazine- inorganic filler conjugate A-Glass-CyCl-SD-Ag according to principles of the invention.
[0034] FIG. 7 is an SEM-EDS spectrum of A-Glass-CyCl-SD-Ag. DETAILED DESCRIPTION
[0035] The invention creates silver sulfadiazine-immobilized inorganic fillers, and uses the resulting fillers in dental composites and dental adhesives to achieve potent, long-term, and none-leaching antimicrobial effects. In the examples that follow, glass is recited as a substrate material. It is believed that other biologically-inert inorganic materials may also be used as suitable particulate substrates in place of glass. In various embodiments, the methods of the invention include the following steps:
[0036] Sulfadiazine is covalently attached onto conventional inorganic fillers (such as glass powders) used in dental composites. This can be achieved by chemically modifying the filler surfaces to introduce reactive groups onto the filler surfaces, and then reacting the new functional groups with the amino groups on sulfadiazine to form covalent linkage. The resulting sulfadiazine-filler conjugates are believed to be novel. The following examples show how this can be done.
Preparation of amine modified Glass (A-Glass):
[0037] FIG. 1 is a reaction scheme for preparing a glass substrate with (3- aminopropyl)trimethoxysilane (APTMS). As shown in FIG. 1, in one embodiment 8.0 g glass powder was reacted with 12.0 ml (3-aminopropyl)trimethoxysilane in a reaction medium comprising mixed with 100 ml cyclohexane and 3.2 ml n-propyl amine. The reaction was allowed to proceed at room temperature for 2 h. The solvent was then removed under vacuum and keep the sample in oven at 100 °C for 2 h. The samples were washed with cyclohexane 3 times under ultracentrifugation to remove unattached APTMS and other side products. Finally the sample was dried under vacuum. The glass is illustrated in the lower right corner of FIG. 1 as silicate glass having approximately 33 % BaO content. It is believed that the reaction of the (3-aminopropyl)trimethoxysilane with the glass occurs at hydroxyl moieties in the glass surface.
[0038] The amine functionalization at the glass surface was confirmed by FTIR as shown in FIG. 2. FIG. 2 is an FTIR spectrum of A-Glass, or amine-functionalized glass as produced by the reaction scheme of FIG. 1.
The Reaction of Cyanuric Chloride with the amine-modified glass to prepare A-Glass-CyCl [0039] Cyanune chloride is an organic compound with the formula (NCCl):, and the chemical structure
Figure imgf000007_0001
[0040] Place 4 g amine modified glass (A-Glass) into a 3-neck round bottom flask. Add
80 ml acetone and stir the solution for 15 min at 0-5 °C. After proper dispersion of A-Glass in acetone, add 1.970 g (10.3 m mol) cyanuric chloride. After mixing, add Na2CC>3 solution (1.280 g in 35 ml water), and continue the reaction at 0-5 °C for 1 h and then at 30 °C for 2 h. Wash the product (A-Glass-CyCl) with acetone 3 times and dry it under vacuum.
Reaction of Sulfadiazine with the Cyanuric Chloride treated amine modified glass (A-Glass- CyCl-SD)
[0041] Sulfadiazine is a sulfonamide antibiotic having the chemical structure
Figure imgf000007_0002
[0042] 3 g of A-Glass-CyCl were added to 80 ml DMSO, and 1.5732 g sulfadiazine
(SD) was added, followed by the addition of aqueous Na2C03 solution (0.7417 g in 50 ml DI water) dropwise over the period of 30 min. After reaction at 60 °C for 5 h, the temperature was increased to 100 °C for the next 3 h. The reaction was then continued at room temperature overnight. The products were washed with 2 times with DMSO and then 3 times with DI water, and dried under vacuum.
[0043] FIG. 3 is a schematic reaction of A-Glass-CyCl with sulfadiazine to produce reaction product A-Glass-CyCl-SD.
[0044] The reaction product A-Glass-CyCl-SD is confirmed by FTIR analysis and KI test.
[0045] FIG. 4 is an FTIR spectrum of A-Glass-CyCl-SD.
The KI Test [0046] Treat a small amount of modified glass powder A-Glass-CyCl-SD with 1 :30 dilute chlorine bleach at room temperature (RT) for lh. After treatment, filter it and wash with DI water thoroughly to remove unreacted chlorine bleach. Dry the powder at RT and treat it with 5% aqueous solution of KI. There is a color change from white to yellow-brown spontaneously as shown in FIG. 5A and FIG. 5B.
[0047] FIG. 5 A is an image of A-Glass-Cy Cl-SD treated with chlorine bleach.
[0048] FIG. 5B is an image of A-Glass-CyCl-SD treated with chlorine bleach and then with KI.
Preparation of Silver sulfadiazine- inorganic filler conjugates
[0049] Silver sulfadiazine- inorganic filler conjugates are prepared. This is accomplished by reacting sulfadiazine-filler conjugates as described above with a source that can provide silver, e.g., silver nitrate aqueous solution. The sulfadiazine will form a complex with the silver cations, leading to the formation of silver sulfadiazine- inorganic filler conjugates, which are believed never to have been reported before. The following example shows how this can be done.
Silver salt of modified glass (A-Glass-CyCl-SD-Ag)
[0050] Put 2.5 g of A-Glass-Cy Cl-SD in 60 ml DI water in a small beaker under magnetic stirring. Add 0.65 g AgN03, and stir the mixture at room temperature under dark overnight. After the reaction, wash the sample with DI water 6 times to remove un-attached silver.
[0051] FIG. 6 is a reaction scheme for preparing a silver sulfadiazine- inorganic filler conjugate A-Glass-CyCl-SD-Ag
[0052] The surface functionalization was confirmed by SEM-EDS and the results are shown in FIG. 7.
[0053] FIG. 7 is an SEM-EDS spectrum of A-Glass-CyCl-SD-Ag.
[0054] The silver content attached to modified glass powder was also confirmed by inductively coupled plasma atomic emission spectrometric analysis. This analysis was outsourced from an external laboratory. [0055] Antimicrobial dental composites and/or dental adhesives are prepared. This is achieved by adding silver sulfadiazine- inorganic filler conjugates into the dental composites or dental adhesive formulations to replace the conventional inorganic fillers totally or partially, and follow the conventional preparation methods to produce antimicrobial dental composites and/or dental adhesives. These composites or adhesives that contain silver sulfadiazine- inorganic filler conjugates to produce antimicrobial functions have never been reported.
[0056] In the preparation of resin composite, 49.5% bis-glycidylmethacrylate
(bisGMA), 49.5% triethylene glycidyldimethacrylate (TEGDMA), 0.2% camphor quinone (CQ) and 0.8% 4-ethyl dimethylamino benzoate (4-EDMAB) were used as the resin parts (30% by weight), and glass powders were used as fillers (70% by weight). The control discs contained 100% of the original commercial glass to make up the 70% filler weight. For the antimicrobial discs, 2%, 5%, 10%, of the original glass was replaced by the silver glass powder (A-Glass-CyCl-SD-Ag).
[0057] The prepared composite mixture was placed in a custom made mold of 6.0 mm in diameter and 1.0 mm in height. A blue LED light at the wavelength 395-480 nm with 1000 mW/cm2 of intensity was focused on the composite mixtures for 100 seconds to cure the resins.
[0058] After curing, the resin discs were used for the following antimicrobial tests. The bacteria, S. mutans, were grown and harvested following ATCC's recommendations. In a typical test, 2.5 μΐ bacteria solution with 106-107 CFU of the bacteria were placed on a disc, which was covered by another identical disc to make a "sandwich". After 30 min of contact, the discs were placed in 1 ml PBS solution and vortexed for 60 seconds to wash out all the bacteria attached to the disks. The solution was serially diluted, and each dilution was placed on agar plates for incubation at 37 °C with 95% air and 5% CO2 for 24 h. Colony forming units (CFUs) on the agar plates were counted. We found that from the control disc, as high as 106 CFU/cm2 of bacteria could be recovered. From the discs with 10% of the silver glass, no any bacteria could be recovered, demonstrating powerful antimicrobial effects.
[0059] It is believed that the non-leaching properties of the anti-microbial agents are novel. The antimicrobial agents are covalently bound onto fillers, and will not leach away.
[0060] In addition, the compositions described are expected to provide potent antimicrobial activity, be safe to use, and suffer no discoloration: Silver has potent
antimicrobial effects and is safe to use. Thus, prior studies have used silver nano particles for dental applications. However, in the earlier applications, silver was easily oxidized and changed its appearance to a black color, which limited the acceptance of such materials as dental composites and dental adhesives. In the present invention, silver is bound onto the filler and forms coordination complexes with sulfadiazine. The resulting silver-sulfadiazine has the same efficacy and safety, yet it is white, and does not change to black. It is believed that this property will significantly improve the acceptance.
[0061] In the present invention, the antimicrobial agents are covalently bound onto conventional fillers. The appearance and handling characteristics of the resulting fillers will not be significantly altered. From the users' (dentists') point of view, no new monomers or new nano fillers are used, and they can still use the instruments and procedures they are most familiar with in their clinics. This ease of use (and use as a substitute material in presently available application/treatment methods) is believed to be a further help for the acceptance of the resulting products.
[0062] The compositions of the invention are believed to be useful in dental composites, dental adhesives, and other related applications. It is believed that the present invention provides a novel solution for a long-standing problem in dental (and possibly other medical) technology.
THEORETICAL DISCUSSION
[0063] Although the theoretical description given herein is thought to be correct, the operation of the devices described and claimed herein does not depend upon the accuracy or validity of the theoretical description. That is, later theoretical developments that may explain the observed results on a basis different from the theory presented herein will not detract from the inventions described herein.
[0064] Any patent, patent application, patent application publication, journal article, book, published paper, or other publicly available material identified in the specification is hereby incorporated by reference herein in its entirety. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.
[0065] While the present invention has been particularly shown and described with reference to the preferred mode as illustrated in the drawing, it will be understood by one skilled in the art that various changes in detail may be affected therein without departing from the spirit and scope of the invention as defined by the claims.

Claims

What is claimed is:
1. A composition of matter, comprising:
a particulate substrate comprising an inorganic filler;
an amine-terminated hydrocarbon molecule moiety covalently bonded by way of a carbon atom of said hydrocarbon molecule moiety to said inorganic filler;
a cyanuric chloride molecule moiety bonded to an amine group of said amine-terminated hydrocarbon molecule moiety;
a sulfadiazine molecule moiety bonded to said cyanuric chloride molecule moiety; and
a silver metal ion incorporated in said sulfadiazine moiety.
2. The composition of matter of claim 1 , wherein a second sulfadiazine molecule moiety is bonded to said cyanuric chloride molecule moiety.
3. The composition of matter of claim 2, wherein said second sulfadiazine molecule moiety has a second silver metal ion incorporated therein.
4. The composition of matter of claim 1 , wherein said particulate substrate comprising an inorganic filler is a particulate glass substrate.
5. The composition of matter of claim 4, wherein said particulate glass substrate comprises a glass containing BaO.
6. The composition of matter of claim 1 , wherein said amine-terminated hydrocarbon molecule moiety is (3-aminopropyl)trimethoxysilane.
7. A method of producing a composition of matter, comprising the steps of: providing a particulate substrate comprising an inorganic filler;
reacting said inorganic filler with an amine-terminated hydrocarbon molecule moiety to covalently bond said hydrocarbon molecule moiety by way of a carbon atom thereof to said inorganic filler to produce an amine modified substrate;
reacting said amine modified substrate with a cyanuric chloride molecule moiety to bond said cyanuric chloride molecule moiety to an amine group of said amine-terminated hydrocarbon molecule moiety to produce an amine modified substrate-CyCl composition;
reacting said amine modified substrate-CyCl composition with a
sulfadiazine molecule moiety to bond an amine moiety of said sulfadiazine molecule moiety to said cyanuric chloride molecule moiety by displacing a chlorine atom thereof to produce an amine modified substrate-CyCl-SD composition; and
reacting said amine modified substrate-CyCl-SD composition with a silver metal ion to incorporate said silver metal ion in said sulfadiazine moiety to produce a silver sulfadiazine-immobilized inorganic filler material.
8. The method of producing a composition of matter of claim 7, wherein said particulate substrate is a particulate glass substrate.
9. The method of producing a composition of matter of claim 7, wherein said step of reacting said inorganic filler with an amine-terminated hydrocarbon molecule moiety is performed using a reaction medium comprising cyclohexane and n-propyl amine.
10. The method of producing a composition of matter of claim 7, wherein said step of reacting said amine modified substrate with a cyanuric chloride molecule moiety is performed in a reaction medium comprising Na2CC>3, acetone and water.
11. The method of producing a composition of matter of claim 7, wherein said step of reacting said amine modified substrate-CyCl composition with a sulfadiazine molecule moiety is performed using DMSO, Na2CC>3 and water.
12. The method of producing a composition of matter of claim 7, wherein said step of reacting said amine modified substrate-CyCl-SD composition with a silver metal ion is performed in a reaction medium of DI water.
13. A method of using a composition of matter, comprising the steps of:
providing a composition of matter comprising a silver sulfadiazine- immobilized inorganic filler;
mixing said composition of matter comprising a silver sulfadiazine- immobilized inorganic filler with a dental composite or dental adhesive formulation to produce a mixture; and
applying said mixture as a replacement material for at least a part of a tooth in a mouth of a patient.
14. The method of using a composition of matter of claim 13, wherein said silver sulfadiazine-immobilized inorganic filler comprises a particulate glass substrate.
15. The method of using a composition of matter of claim 14, wherein said particulate glass substrate comprises BaO.
16. The method of using a composition of matter of claim 13, wherein said silver sulfadiazine-immobilized inorganic filler comprises an amine-terminated hydrocarbon molecule moiety.
17. The method of using a composition of matter of claim 16, wherein said silver sulfadiazine-immobilized inorganic filler comprises a cyanuric chloride molecule moiety bonded to an amine group of said amine-terminated hydrocarbon molecule moiety.
18. The method of using a composition of matter of claim 17, wherein said silver sulfadiazine-immobilized inorganic filler comprises an amine moiety of a sulfadiazine molecule moiety to said cyanuric chloride molecule moiety.
19. The method of using a composition of matter of claim 18, wherein said silver sulfadiazine-immobilized inorganic filler comprises a silver metal ion incorporated in said sulfadiazine moiety.
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