SELF-ADHESIVE POLYMERIZABLE MONOMER AND DENTAL/MEDICAL COMPOSITIONS THEREFROM

Abstract: The synthesis of self-adhesive polymerizabe monomers and their application as a water containing and a water free self-adhesive dental/medical composite is described. The dental/medical composite comprises a self-adhesive polymerizable monomer, a polymerizable monomer, an acid-reactive and/or reactive and/or non-reactive filler, a diluent, a polymerization initiator and a stabilizer. As polymerization initiators are used the commonly known thermal initiators, redox initiators and/or photo initiators. The new adhesive dental composite develops adhesion to dentine of about 4 MPa. Fillers of high X-ray absorbance provide radio-opacity values graeter than that of the same thickness of aluminium.

Description: wheπn R4 denotes a substituted or unsubstituted alkylene having 3 to 20 carbon atoms, Z is an acidic moiety selected from the group O O II II -P— OH — S— OH -B— OH II I OH OO OH or an ionic moiety selected from the group wherein the R\, R2, R3 are the same or different substituted or unsubstituted residues of Hydrogen or an alkylene having 2 to 20 carbon atoms, a cycloalkylene having 5 to 20 carbon atoms, an aryl or a heteroaryl having 4 to 12 carbon atoms, X is a cation such as ammonium, sulfonium, sodium, potassium, strontium, calcium or magnesium salts and Y is an amon such as OH-, F-, C1-, Br-, Tosyl- Most preferably the self-adhesive polymeπzable monomer is characterized m the following formula: The self-adhesive polymerizable monomer is used in a dental/medical composition comprising a filler, a polymerizable monomer, a polymerization initiator and a stabilizer. The polymerizable monomer preferably is a mono- and polyfunctional (meth)- acrylate, such as a reaction product of a polyepoxide with (meth)acryhc acid), a polyalkylenoxide di- and poly(meth)acrylate, an urethane di- and poly(meth) acrylate, preferably were used Bis-GMA diethylenglycol dimethacrylate, triethylenglycol dimethacrylate, 3,(4),8,(9)-dιmethacryloyloxymethyltπcyclodecane, dioxolan bismethacrylate, glycerol tπmethacrylate, furfuryl methacrylate m a content of 5 to 80 wt-%. The polymerization initiator is a thermal initiator, a redox-mitiator or a photo initiator. As filler is an inorganic filler and/or an organic filler. The self-adhesive polymeπzable monomer is usable in a self-adhesive dental/medical composition characterized by the combination of A an adhesion to dentine of at least 5 MPa B a fluoride release of at least 1 μg F- per week and per cm^ of the exposed surface of the composition C an opacity of at least Co 7 = 40 % and D a compressive strength of at least 200 MPa. The self-adhesive polymerizable monomer is usable in a self-adhesive dental/medical cement comprising 25 to 50 wt-% of a self-adhesive polymerizable monomer, 0 to 25 wt-% of a polymeπzable monomer, 50 to 75 wt-% of a filler and polymerization initiator and stabilizers. The self-adhesive polymerizable monomer is usable in a self-adhesive dental/medical composite compπs g 15 to 50 wt-% of a self-adhesive polymerizable monomer of claims 1 to 3, 0 to 35 wt-% of a polymerizable monomer, 50 to 85 wt-% of a filler and polymerization initiator and stabilizers. The self-adhesive polymerizable monomer is usable in a self-adhesive dental/medical sealant compπsmg 45 to 90 wt-% of a self-adhesive polymeπzable monomer of claims 1 to 3, 0 to 45 wt-% of a polymerizable monomer, 10 to 55 wt-% of a filler and polymerization initiator and stabilizers. The self-adhesive polymerizable monomer is usable in a self-adhesive dental/medical primer comprising 15 to 80 wt-% of a self-adhesive polymeπzable monomer of claims 1 to 3, 0 to 65 wt-% of a polymerizable monomer, 0 to 65 wt-% of a filler and polymerization initiator and stabilizers 20 to 85 wt-% of a diluent and polymerization initiator and stabilizers. An adhesive dental composite containing radioopac fillers provides a radio-opacity of at least 2 mm/ mm Al, preferably at least 3 to 7 mm/mm Al, most preferably at least 7 mm/mm Al. The self-adhesive dental/medical composites have a fluoride release of at least 1 μg/cm^, preferably at least 1-3 μg/cm-2, most preferably at least 3-10 μg/cmJ Furthermore the self-adhesive dental/medical composites show a opacity of at least 40 %, preferably at least 20-40 %, most preferably at least 5-20 %. Example 1 Glycerine dimethacrylate- 11-bromoundecanoιc acid ester In a 1-1-three necked bottle equipped with a thermometer, condenser and stirrer 75.00 g (OJ83 mol) 11-bromoundecanoιc acid, 64.55 g (0J83 mol) glycerine dimethacrylate and 1 JO g dimethylammo pyridme were dissolved m 250 ml methylene chloride and cooled to 0 - 5 °C. Under stirring a solution of 64.23 g (0J11 mol) dicyclohexyl carbodπmid were added drop-wise. The resulting suspension was stirred for three hours at 20°C. Then the precipitated solid was removed by filtration and washed three times with 20 ml methylene chloπde. The filtrate was cooled to 0 °C over night. The precipitated solid was removed again. Thereafter the solution was washed with 75 ml In HC1, In NaHCθ3-solutιon and 2 times with 150 ml water. After drying the organic solution over NaSO 0J345 g BHT were added and the solvent was removed by vacuum destination (mm. 30 mbar, at 40 °C). Yield: 118.67 g (88.3 % of th.) Glycenne dimethacrylate- 11- tπethylammonium bromo undecanoic acid ester A mixture of 23.17 g (0.050 mol) glycenne dimethacrylate- 11-bromoundecanoιc acid ester, 6.07 g (0.060 mol) tπethylamme in 50 ml ethanol was reflued for 6 hours. Then ethanol and excessive tπethylamme was destilled off at 50 to 70 °C and 18 mbar. Yield: 26.58 g (92.2 % of th.) IR: 2600 - 2800 cm"l (absorption of the ammonium salt) Example 2 Glycenne dimethacrylate- 11- hydroxy undecanoic acid ester Preparation of Glycenne dimethacrylate- 11 -bromoundecanoic acid ester according example 1. To 15.00 g (0.032 mol) glycerine dimethacrylate- 11 -bromoundecanoic acid ester dissolved in 50 ml ethanol were added 25 ml of sodium hydoxide solution comprising 1J62 g (0.032 mol) NaOH. The mixture was shaked for one hour. Then the crude product was extracted with methylene chloride. The obtained solution was dried over NaS04 and the solvent was remouved. Yield: 12.50 g (96.0 % of th.) IR: 3430 cm" 1 (OH) Glycerine dimethacrylate- 11 -(phosphoric acid) undecanoic acid ester Esteπfication of the hydroxyl groups of the glycerine dimethacrylate- 11 -hydroxy undecanoic acid ester with POCI3. To 11.551 g (0.028 mmol) of glycerine dimethacrylate- 11 -hydroxy undecanoic acid ester dissolved in 50 ml THF were added 3.H7 g tnethylamme in 10 ml THF. After adding 4J23 g POCI3 (0.031 mmol) drops by drops while stirring at 0° to 5 °C the solution is stirred for further two hours at room temperature. Than the tnethylamme hydrochlonde is filtered off and the mixture is hydrolysed with 20 ml water. The organic solution is extracted three times with Na2Cθ3 solution and is separated from water. From the solution, dried over MgSO the solvent is evaporated and the macromonomer is dried. In the IR-spectrum the newly self-adhesive polymerizabe monomer containing phosphoric ester units shows no absorption of hydroxyl groups at J=3400 cm " * --. New absorptions were found at J= 1007 cm " * --, J= 2362 cm " --- and as shoulder at D= 3302 cm"l . In the 1H NMR spectrum signals of the olefϊmc double bonds at ^(CH2=) = 6.06/6J2 ppm and at J(CH2=) = 5.58/5.59 ppm were found. The signals of the methine protons (CH-OP) appears at ϋ(CH) = 5.22 and 5.88 ppm. Those of unreacted macromonomer ( CH-OH) appears at D(CH) = 4.34/4.35 ppm. Application Example 1 (Dental adhesive) 1,242 g of the obtained self-adhesive polymerizabe monomer example 2, 0,411 g triethylenglycol dimethacrylate, 0,008 g N,N-bιs(u-hydroxyethyl)-p-toluidine and 0,006 g camphor qumone were homogeneously mixed. This mixture was applied in a ring (2mm high, 5 mm i.d.) on the surface of teeth and exposed with visible light (irradiation lamp Pnsmetics Lite De Trey Dentsply) for 40 seconds. Immediately after fixation, the teeth were transfered for 24 hours to a chamber at 37 ± 2 °C and 100 % relative humidity. The adhesion measured with a Zwick-apparatus is 5.74 ± 1J9 MPa. Comparative Example 1 2,420 g of 2J-Bιs-[p-(2-hydroxy-3-methacryloyloxypropoxy)-phenyl]-propan (Bis-GMA) which is modified with succmic anhydride at the hydroxyl groups, 0,821 g tn-ethylenglycol dimethacrylate, 0,016 g N,N-bιs( j -hydroxyethyl)-p-toluidine and 0,012 g camphor qumone were homogeneously mixed. This mixture was applied in a ring (2mm high, 5 mm i.d.) on the surface of teeth and exposed with visible light (irradia-tion lamp Pnsmetics Lite De Trey Dentsply) for 40 seconds. Immediately after fixa-tion, the teeth were transferred for 24 hours to a chamber at 37 ± 2 °C and 100 % relative humidity. The adhesion measured with a Zwick-apparatus is 0.45 ± 0.20 MPa. International Bureau INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification (11) International Publication Number: WO 00/67701 A61K 6/083 Al (43) International Publication Date: 16 November 2000 (16.11.00) (21) International Application Number: PCT/USOO/11 198 (81) Designated States: JP, European patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE). (22) International Filing Date: 26 April 2000 (26.04.00) Published (30) Priority Data: With international search report. 60/133,824 12 May 1999 (12.05.99) US 09/541 ,831 3 April 2000 (03.04.00) US (71) Applicant: DENTSPLY INTERNATIONAL INC. [US/US]; 570 West College Avenue, P.O. Box 872, York, PA 17404-0872 (US). (72) Inventors: KLEE, Joachim, E.; Espelweg 3/4, D-78315 Radolfzell (DE). WALZ, Uwe; Zum Klausenhorn 9, d-78465 Konstanz (DE). (74) Agents: HURA, Douglas, J. et al.; Dentsply International Inc., 570 West College Avenue, P.O. Box 872, York, PA 17404-0872 (US). (54) Title: SELF-ADHESIVE POLYMERIZABLE MONOMER AND DENTAL/MEDICAL COMPOSITIONS THEREFROM (57) Abstract The synthesis of self-adhesive polymerizabe monomers and their application as a water containing and a water free self-adhesive dental/medical composite is described. The dental/medical composite comprises a self-adhesive polymerizable monomer, a polymerizable monomer, an acid-reactive and/or reactive and/or non-reactive filler, a diluent, a polymerization initiator and a stabilizer. As polymerization initiators are used the commonly known thermal initiators, redox initiators and/or photo initiators. The new adhesive dental composite develops adhesion to dentine of about 4 MPa. Fillers of high X-ray absorbance provide radio-opacity values graeter than that of the same thickness of aluminium. FOR THE PURPOSES OF INFORMATION ONLY Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT. AL Albania ES Spain LS Lesotho SI Slovenia AM Armenia FI Finland LT Lithuania SK Slovakia AT Austria FR France LU Luxembourg SN Senegal AU Australia GA Gabon LV Latvia SZ Swaziland AZ Azerbaijan GB United Kingdom MC Monaco TD Chad BA Bosnia and Herzegovina GE Georgia MD Republic of Moldova TG Togo BB Barbados GH Ghana MG Madagascar TJ Tajikistan BE Belgium GN Guinea MK The former Yugoslav TM Turkmenistan BF Burkina Faso GR Greece Republic of Macedonia TR Turkey BG Bulgaria HU Hungary ML Mali TT Tπnidad and Tobago BJ Benin IE Ireland MN Mongolia UA Ukraine BR Brazil IL Israel MR Mauritania UG Uganda BY Belarus IS Iceland MW Malawi US United States of America CA Canada IT Italy MX Mexico uz Uzbekistan CF Central African Republic JP Japan NE Niger VN Viet Nam CG Congo KE Kenya NL Netherlands YU Yugoslavia CH Switzerland KG Kyrgyzstan NO Norway ZW Zimbabwe CI Cόte d'lvoire KP Democratic People's NZ New Zealand CM Cameroon Republic of Korea PL Poland CN China KR Republic of Korea PT Portugal CU Cuba KZ Kazakstan RO Romania cz Czech Republic LC Saint Lucia RU Russian Federation DE Germany LI Liechtenstein SD Sudan DK Denmark LK Sπ Lanka SE Sweden EE Estonia LR Liberia SG Singapore We claim 1. A self-adhesive polymerizable monomer that comprises (1) at least two polymerizable moieties (n) at least one substituted or unsubstituted C3 to C20 alkylene, substituted or unsubstituted C5 to C20 cycloalkylene that is connected with (1) by a linking unit, (111) at least an acidic moiety selected from the group O O — P— OH — S— OH — B— OH OH O OH or at least an ionic moiety selected from the group Y Θ which is connected with (11) and wherein the R\, R.2, R3 are the same or different substituted or unsubstituted residues of Hydrogen or an alkylene having 2 to 20 carbon atoms, a cycloalkylene having 5 to 20 carbon atoms, an aryl or a heteroaryl having 4 to 12 carbon atoms, X is a catioms counteπon such as and Y is an amonic ion selected from the group consisting of OH", F", Cl", Br", and Tosyl". 2. A self-adhesive polymerizable monomer of claim 1, wherein the polymerizable groups are methacryhc or acrylic groups. 3. A self-adhesive polymerizable monomer of claim 1, wherein the linking unit is an ether or a thioether, an ester, a carbonate or a urethane moiety. 4. A self-adhesive polymerizable monomer of claim lhaving a formula selected from the group consisting of wherin R4 denotes a substituted or unsubstituted C3 to C20 alkylene, C5 to C20 substituted or unsubstituted cycloalkylene, Z is an acidic moiety selected from the group consisting of O II -P— OH -S— OH -B— OH I II I OH o OH or an ionic moiety selected from the group consisting of Y Θ wherein the R\, R2, R3 are the same or different substituted or unsubstituted residues of hydrogen or an alkylene having 2 to 20 carbon atoms, a cycloalkylene having 5 to 20 carbon atoms, an aryl or a heteroaryl having 4 to 12 carbon atoms, X is a cation, preferably ammonium, sulfonium, sodium, potassium, strontium, calcium or magnesium salts and Y is an amon, selected from the group consisting of OH", F", Cl", Br", and Tosyl". 5. A self-adhesive polymeπzable monomer of claims 1 having the formula: 6. A self-adhesive dental/medical composition comprising a self-adhesive polymeπzable monomer according to one of claim 1, a filler, a polymeπzable monomer, a polymerization initiator and a stabilizer. 7. The self-adhesive dental/medical composition according to claim 6 characterized in that the polymeπzable monomer is a mono- and polyfunctional (meth)-acrylate 8. The self-adhesive dental/medical composition according to claim 6 characterized in that the polymeπzation initiator is a thermal initiator, a redox-mitiator or a photo initiator. 9. The self-adhesive dental/medical composition according to claim 6 characterized in that the filler is an inorganic filler or an organic filler. 10. The self-adhesive dental/medical composition according to claim 9 comprising a fluoride releasing inorganic filler. 11. The self-adhesive dental/medical composition according to one of claim 6 compπsmg the combination of A an adhesion to dentine of at least 5 MPa B a fluoride release of at least 1 μg F" per week and per cm-2 of the exposed surface of the composition C an opacity of at least Co 7 = 40 % and D a compressive strength of at least 200 MPa. 12. A self-adhesive dental/medical cement comprising 25 to 50 wt-% of a self-adhesive polymerizable monomer of claim 1, 0 to 25 wt-% of a polymerizable monomer, 50 to 75 wt-% of a filler and polymerization initiator and stabilizers. 13. A self-adhesive dental/medical composite comprising 15 to 50 wt-% of a self-adhesive polymerizable monomer of claim 1, 0 to 35 wt-% of a polymerizable monomer, 50 to 85 wt-% of a filler and polymeπzation initiator and stabilizers. 14. A self-adhesive dental/medical sealant comprising 45 to 90 wt-% of a self-adhesive polymeπzable monomer of claim 1 , 0 to 45 wt-% of a polymerizable monomer, 10 to 55 wt-% of a filler and polymerization initiator and stabilizers. 15. A dental/medical primer comprising 15 to 80 wt-% of a self-adhesive polymerizable monomer of claim 1, 0 to 65 wt-% of a polymeπzable monomer, 0 to 65 wt-% of a filler and polymerization initiator and stabilizers 20 to 85 wt-% of a diluent and polymeπzation initiator and stabilizers.

Claims: EMI1.1 <tb> <SEP> INTERNATIONAL <SEP> APPLICATION <SEP> PUBLISHED <SEP> UNDER <SEP> THE <SEP> PATENT <SEP> COOPERATION <SEP> TREATY <SEP> (PCT) <tb> (51) <SEP> International <SEP> Patent <SEP> Classification <SEP> 7: <SEP> (11) <SEP> International <SEP> Publication <SEP> Number: <SEP> WO <SEP> 00/67701 <tb> <SEP> A61K <SEP> 6/083 <SEP> Al <tb> <SEP> (43) <SEP> International <SEP> Publication <SEP> Date: <SEP> 16 <SEP> November <SEP> 2000 <SEP> (16.11.00) <SEP> <tb> (21) <SEP> International <SEP> Application <SEP> Number: <SEP> PCT/USOO/11198 <SEP> (81) <SEP> Designated <SEP> States: <SEP> JP, <SEP> European <SEP> patent <SEP> (AT, <SEP> BE, <SEP> CH, <SEP> CY, <SEP> DE, <tb> <SEP> DK, <SEP> ES, <SEP> FI, <SEP> FR, <SEP> GB, <SEP> GR, <SEP> IE, <SEP> IT, <SEP> LU, <SEP> MC, <SEP> NL, <SEP> PT, <SEP> SE). <tb> (22) <SEP> International <SEP> Filing <SEP> Date: <SEP> 26 <SEP> April <SEP> 2000 <SEP> (26.04.00) <tb> <SEP> Published <tb> (30) <SEP> Priority <SEP> Data: <SEP> With <SEP> international <SEP> search <SEP> report. <tb> <SEP> 60/133,824 <SEP> 12 <SEP> May <SEP> 1999 <SEP> (12.05.99) <SEP> US <tb> <SEP> 09/541,831 <SEP> 3 <SEP> April <SEP> 2000 <SEP> (03.04.00) <SEP> US <tb> (71) <SEP> Applicant: <SEP> DENTSPLY <SEP> INTERNATIONAL <SEP> INC. <SEP> [US/US]; <tb> <SEP> 570 <SEP> West <SEP> College <SEP> Avenue, <SEP> P. <SEP> O. <SEP> Box <SEP> 872, <SEP> York, <SEP> PA <tb> <SEP> 17404-0872 <SEP> (US). <tb> (72) <SEP> Inventors: <SEP> KLEE, <SEP> Joachim, <SEP> E.; <SEP> Espelweg <SEP> 3/4, <SEP> D-78315 <tb> <SEP> Radolfzell <SEP> (DE). <SEP> WALZ, <SEP> Uwe; <SEP> Zum <SEP> Klausenhom <SEP> 9, <tb> <SEP> d-78465 <SEP> Konstanz <SEP> (DE). <tb> (74) <SEP> Agents: <SEP> HURA, <SEP> Douglas, <SEP> J. <SEP> et <SEP> al.; <SEP> Dentsply <SEP> International <tb> <SEP> Inc., <SEP> 570 <SEP> West <SEP> College <SEP> Avenue, <SEP> P. <SEP> O. <SEP> Box <SEP> 872, <SEP> York, <SEP> PA <tb> <SEP> 17404-0872 <SEP> (US). <tb> (54) <SEP> Title: <SEP> SELF-ADHESIVE <SEP> POLYMERIZABLE <SEP> MONOMER <SEP> AND <SEP> DENTAL/MEDICAL <SEP> COMPOSITIONS <SEP> THEREFROM <tb> (57) <SEP> Abstract <tb> <SEP> The <SEP> synthesis <SEP> of <SEP> self-adhesive <SEP> polymerizabe <SEP> monomers <SEP> and <SEP> their <SEP> application <SEP> as <SEP> a <SEP> water <SEP> containing <SEP> and <SEP> a <SEP> water <SEP> free <SEP> self-adhesive <tb> dental/medical <SEP> composite <SEP> is <SEP> described. <SEP> The <SEP> dental/medical <SEP> composite <SEP> comprises <SEP> a <SEP> self-adhesive <SEP> polymerizable <SEP> monomer, <SEP> a <SEP> polymerizable <tb> monomer, <SEP> an <SEP> acid-reactive <SEP> and/or <SEP> reactive <SEP> and/or <SEP> non-reactive <SEP> filler, <SEP> a <SEP> diluent, <SEP> a <SEP> polymerization <SEP> initiator <SEP> and <SEP> a <SEP> stabilizer. <SEP> As <SEP> polymerization <tb> initiators <SEP> are <SEP> used <SEP> the <SEP> commonly <SEP> known <SEP> thermal <SEP> initiators, <SEP> redox <SEP> initiators <SEP> and/or <SEP> photo <SEP> initiators. <SEP> The <SEP> new <SEP> adhesive <SEP> dental <SEP> composite <tb> develops <SEP> adhesion <SEP> to <SEP> dentine <SEP> of <SEP> about <SEP> 4 <SEP> MPa. <SEP> Fillers <SEP> of <SEP> high <SEP> X-ray <SEP> absorbance <SEP> provide <SEP> radio-opacity <SEP> values <SEP> graeter <SEP> than <SEP> that <SEP> of <SEP> the <SEP> same <tb> thickness <SEP> of <SEP> aluminium. <tb> FOR THE PURPOSES OF INFORMATION ONLY Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT. AL Albania ES Spain LS Lesotho Sl Slovenia AM Armenia Fl Finland LT Lithuania SK Slovakia AT Austria FR France LU Luxembourg SN Senegal AU Australia GA Gabon LV Latvia SZ Swaziland AZ Azerbaijan GB United Kingdom MC Monaco TD Chad BA Bosnia and Herzegovina GE Georgia MD Republic of Moldova TG Togo BB Barbados GH Ghana MG Madagascar TJ Tajikistan BE Belgium GN Guinea MK The former Yugoslav TM Turkmenistan BF Burkina Faso GR Greece Republic of Macedonia TR Turkey BG Bulgaria HU Hungary ML Mali TT Trinidad and Tobago BJ Benin IE Ireland MN Mongolia UA Ukraine BR Brazil IL Israel MR Mauritania UG Uganda BY Belarus IS Iceland MW Malawi US United States of America CA Canada IT Italy MX Mexico UZ Uzbekistan CF Central African Republic JP Japan NE Niger VN Viet Nam CG Congo KE Kenya NL Netherlands YU Yugoslavia CH Switzerland KG Kyrgyzstan NO Norway ZW Zimbabwe CI Cote d'lvoire KP Democratic People's NZ New Zealand CM Cameroon Republic of Korea PL Poland CN China KR Republic of Korea PT Portugal CU Cuba KZ Kazakstan RO Romania CZ Czech Republic LC Saint Lucia RU Russian Federation DE Germany Ll Liechtenstein SD Sudan DK Denmark LK Sri Lanka SE Sweden EE Estonia LR Liberia SG Singapore

Inventors: KLEE JOACHIM E, WALZ UWE, KLEE, JOACHIM, E., WALZ, UWE
Applicants: DENTSPLY INT INC, DENTSPLY INTERNATIONAL INC.
Application year: 2000
Main classification: A61K6
IPC codes: A61K6, C07C69, C07F9