US20240026049A1 - Dual-phase zwitterionic monomers - Google Patents
Dual-phase zwitterionic monomers Download PDFInfo
- Publication number
- US20240026049A1 US20240026049A1 US18/223,791 US202318223791A US2024026049A1 US 20240026049 A1 US20240026049 A1 US 20240026049A1 US 202318223791 A US202318223791 A US 202318223791A US 2024026049 A1 US2024026049 A1 US 2024026049A1
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- US
- United States
- Prior art keywords
- divalent radical
- nhz
- nhc
- vinyl
- composition
- Prior art date
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- 239000000178 monomer Substances 0.000 title claims abstract description 136
- 239000000017 hydrogel Substances 0.000 claims abstract description 79
- 239000000203 mixture Substances 0.000 claims abstract description 79
- 229920002554 vinyl polymer Polymers 0.000 claims abstract description 38
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 24
- 239000003431 cross linking reagent Substances 0.000 claims abstract description 10
- -1 3-methacryloxy-2-hydroxypropyloxy Chemical group 0.000 claims description 73
- 229920001296 polysiloxane Polymers 0.000 claims description 48
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 229920000642 polymer Polymers 0.000 claims description 23
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 9
- 239000007983 Tris buffer Substances 0.000 claims description 8
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims description 7
- JZUCDZZFJRODNS-UHFFFAOYSA-N (4-tert-butyl-2-hydroxycyclohexyl) 2-methylprop-2-enoate Chemical group CC(=C)C(=O)OC1CCC(C(C)(C)C)CC1O JZUCDZZFJRODNS-UHFFFAOYSA-N 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 229910000077 silane Inorganic materials 0.000 claims description 5
- 125000000129 anionic group Chemical group 0.000 claims description 3
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 3
- PBGPBHYPCGDFEZ-UHFFFAOYSA-N 1-ethenylpiperidin-2-one Chemical compound C=CN1CCCCC1=O PBGPBHYPCGDFEZ-UHFFFAOYSA-N 0.000 claims description 2
- VOCDJQSAMZARGX-UHFFFAOYSA-N 1-ethenylpyrrolidine-2,5-dione Chemical compound C=CN1C(=O)CCC1=O VOCDJQSAMZARGX-UHFFFAOYSA-N 0.000 claims description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 2
- JWYVGKFDLWWQJX-UHFFFAOYSA-N 1-ethenylazepan-2-one Chemical compound C=CN1CCCCCC1=O JWYVGKFDLWWQJX-UHFFFAOYSA-N 0.000 claims 1
- UNMSMHCTGCYBJM-UHFFFAOYSA-N 1-ethenylimidazolidin-2-one Chemical compound C=CN1CCNC1=O UNMSMHCTGCYBJM-UHFFFAOYSA-N 0.000 claims 1
- SQBOVWCFAVIYHU-UHFFFAOYSA-N C(C(=C)C)(=O)OC(CC(OC(C(=C)C)=O)(O[Si](C)(C)C)O[Si](C)(C)C)O[Si](C)(C)C Chemical compound C(C(=C)C)(=O)OC(CC(OC(C(=C)C)=O)(O[Si](C)(C)C)O[Si](C)(C)C)O[Si](C)(C)C SQBOVWCFAVIYHU-UHFFFAOYSA-N 0.000 claims 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 claims 1
- FXPHJTKVWZVEGA-UHFFFAOYSA-N ethenyl hydrogen carbonate Chemical compound OC(=O)OC=C FXPHJTKVWZVEGA-UHFFFAOYSA-N 0.000 claims 1
- PEOHLVWFSVQRLK-UHFFFAOYSA-N ethenylcarbamic acid Chemical compound OC(=O)NC=C PEOHLVWFSVQRLK-UHFFFAOYSA-N 0.000 claims 1
- FAFWKDXOUWXCDP-UHFFFAOYSA-N ethenylurea Chemical compound NC(=O)NC=C FAFWKDXOUWXCDP-UHFFFAOYSA-N 0.000 claims 1
- ZQXSMRAEXCEDJD-UHFFFAOYSA-N n-ethenylformamide Chemical compound C=CNC=O ZQXSMRAEXCEDJD-UHFFFAOYSA-N 0.000 claims 1
- 238000005728 strengthening Methods 0.000 claims 1
- PGRZLADNCDNGTC-UHFFFAOYSA-N trimethyl-(methyl-propyl-trimethylsilyloxysilyl)oxysilane Chemical compound CCC[Si](C)(O[Si](C)(C)C)O[Si](C)(C)C PGRZLADNCDNGTC-UHFFFAOYSA-N 0.000 claims 1
- 239000000463 material Substances 0.000 abstract description 47
- 238000006116 polymerization reaction Methods 0.000 abstract description 23
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 abstract description 16
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 abstract description 13
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 230000000704 physical effect Effects 0.000 abstract description 5
- 238000010526 radical polymerization reaction Methods 0.000 abstract description 4
- MUZDXNQOSGWMJJ-UHFFFAOYSA-N 2-methylprop-2-enoic acid;prop-2-enoic acid Chemical compound OC(=O)C=C.CC(=C)C(O)=O MUZDXNQOSGWMJJ-UHFFFAOYSA-N 0.000 abstract description 2
- 150000003254 radicals Chemical class 0.000 description 28
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 description 20
- 239000003999 initiator Substances 0.000 description 16
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical class N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 238000009472 formulation Methods 0.000 description 12
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 11
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 11
- 229960003237 betaine Drugs 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 239000003085 diluting agent Substances 0.000 description 10
- 230000009257 reactivity Effects 0.000 description 10
- 230000009977 dual effect Effects 0.000 description 9
- FBCQUCJYYPMKRO-UHFFFAOYSA-N prop-2-enyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCC=C FBCQUCJYYPMKRO-UHFFFAOYSA-N 0.000 description 9
- 238000009736 wetting Methods 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 239000004971 Cross linker Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 6
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 238000013459 approach Methods 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 229920001577 copolymer Polymers 0.000 description 6
- 238000004132 cross linking Methods 0.000 description 6
- 239000004205 dimethyl polysiloxane Substances 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 239000012632 extractable Substances 0.000 description 6
- 229920001477 hydrophilic polymer Polymers 0.000 description 6
- 230000002209 hydrophobic effect Effects 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 230000035699 permeability Effects 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 229920001519 homopolymer Polymers 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 150000002734 metacrylic acid derivatives Chemical class 0.000 description 4
- 125000006702 (C1-C18) alkyl group Chemical group 0.000 description 3
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 3
- QRIMLDXJAPZHJE-UHFFFAOYSA-N 2,3-dihydroxypropyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCC(O)CO QRIMLDXJAPZHJE-UHFFFAOYSA-N 0.000 description 3
- HWSSEYVMGDIFMH-UHFFFAOYSA-N 2-[2-[2-(2-methylprop-2-enoyloxy)ethoxy]ethoxy]ethyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCOCCOCCOC(=O)C(C)=C HWSSEYVMGDIFMH-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000004743 Polypropylene Substances 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000006096 absorbing agent Substances 0.000 description 3
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 3
- 125000005250 alkyl acrylate group Chemical group 0.000 description 3
- VEZXCJBBBCKRPI-UHFFFAOYSA-N beta-propiolactone Chemical compound O=C1CCO1 VEZXCJBBBCKRPI-UHFFFAOYSA-N 0.000 description 3
- 238000012790 confirmation Methods 0.000 description 3
- 238000007334 copolymerization reaction Methods 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 239000005447 environmental material Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- PYGSKMBEVAICCR-UHFFFAOYSA-N hexa-1,5-diene Chemical group C=CCCC=C PYGSKMBEVAICCR-UHFFFAOYSA-N 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 150000003951 lactams Chemical group 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229920000193 polymethacrylate Polymers 0.000 description 3
- 229920001155 polypropylene Polymers 0.000 description 3
- 229960000380 propiolactone Drugs 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- VAYTZRYEBVHVLE-UHFFFAOYSA-N 1,3-dioxol-2-one Chemical compound O=C1OC=CO1 VAYTZRYEBVHVLE-UHFFFAOYSA-N 0.000 description 2
- LTHJXDSHSVNJKG-UHFFFAOYSA-N 2-[2-[2-[2-(2-methylprop-2-enoyloxy)ethoxy]ethoxy]ethoxy]ethyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCOCCOCCOCCOC(=O)C(C)=C LTHJXDSHSVNJKG-UHFFFAOYSA-N 0.000 description 2
- XMLYCEVDHLAQEL-UHFFFAOYSA-N 2-hydroxy-2-methyl-1-phenylpropan-1-one Chemical compound CC(C)(O)C(=O)C1=CC=CC=C1 XMLYCEVDHLAQEL-UHFFFAOYSA-N 0.000 description 2
- WHNPOQXWAMXPTA-UHFFFAOYSA-N 3-methylbut-2-enamide Chemical compound CC(C)=CC(N)=O WHNPOQXWAMXPTA-UHFFFAOYSA-N 0.000 description 2
- LEBRCVXHIFZXEM-UHFFFAOYSA-N 4-(benzotriazol-2-yl)benzene-1,3-diol Chemical class OC1=CC(O)=CC=C1N1N=C2C=CC=CC2=N1 LEBRCVXHIFZXEM-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 2
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- ATSPJETUWGCTIK-UHFFFAOYSA-N [ethyl(methyl)amino]methanol Chemical compound CCN(C)CO ATSPJETUWGCTIK-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- MQDJYUACMFCOFT-UHFFFAOYSA-N bis[2-(1-hydroxycyclohexyl)phenyl]methanone Chemical compound C=1C=CC=C(C(=O)C=2C(=CC=CC=2)C2(O)CCCCC2)C=1C1(O)CCCCC1 MQDJYUACMFCOFT-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 125000005395 methacrylic acid group Chemical group 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
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- 239000012299 nitrogen atmosphere Substances 0.000 description 2
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- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 150000002978 peroxides Chemical class 0.000 description 2
- 125000000864 peroxy group Chemical class O(O*)* 0.000 description 2
- 238000005191 phase separation Methods 0.000 description 2
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
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- 239000002244 precipitate Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
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- 229940117986 sulfobetaine Drugs 0.000 description 2
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- GVYHLYQWXHOJGV-UHFFFAOYSA-N (1-propan-2-ylcyclopentyl) prop-2-enoate Chemical compound C=CC(=O)OC1(C(C)C)CCCC1 GVYHLYQWXHOJGV-UHFFFAOYSA-N 0.000 description 1
- XPEMPJFPRCHICU-UHFFFAOYSA-N (1-tert-butylcyclohexyl) prop-2-enoate Chemical compound C=CC(=O)OC1(C(C)(C)C)CCCCC1 XPEMPJFPRCHICU-UHFFFAOYSA-N 0.000 description 1
- HJIAMFHSAAEUKR-UHFFFAOYSA-N (2-hydroxyphenyl)-phenylmethanone Chemical class OC1=CC=CC=C1C(=O)C1=CC=CC=C1 HJIAMFHSAAEUKR-UHFFFAOYSA-N 0.000 description 1
- PILKNUBLAZTESB-UHFFFAOYSA-N (4-tert-butylcyclohexyl) 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OC1CCC(C(C)(C)C)CC1 PILKNUBLAZTESB-UHFFFAOYSA-N 0.000 description 1
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 description 1
- HSLFISVKRDQEBY-UHFFFAOYSA-N 1,1-bis(tert-butylperoxy)cyclohexane Chemical compound CC(C)(C)OOC1(OOC(C)(C)C)CCCCC1 HSLFISVKRDQEBY-UHFFFAOYSA-N 0.000 description 1
- ZXHDVRATSGZISC-UHFFFAOYSA-N 1,2-bis(ethenoxy)ethane Chemical compound C=COCCOC=C ZXHDVRATSGZISC-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- MMMZJMRWWRQXJM-UHFFFAOYSA-N 1-chlorophospholane Chemical compound ClP1CCCC1 MMMZJMRWWRQXJM-UHFFFAOYSA-N 0.000 description 1
- JHYYINIEKJKMDD-UHFFFAOYSA-N 1-ethenyl-3,3-dimethylpyrrolidin-2-one Chemical compound CC1(C)CCN(C=C)C1=O JHYYINIEKJKMDD-UHFFFAOYSA-N 0.000 description 1
- DJABNVJZYFGAJE-UHFFFAOYSA-N 1-ethenyl-5-ethylpyrrolidin-2-one Chemical compound CCC1CCC(=O)N1C=C DJABNVJZYFGAJE-UHFFFAOYSA-N 0.000 description 1
- HQGPZXPTJWUDQR-UHFFFAOYSA-N 1-ethenyl-5-methylpyrrolidin-2-one Chemical compound CC1CCC(=O)N1C=C HQGPZXPTJWUDQR-UHFFFAOYSA-N 0.000 description 1
- FFDNCQYZAAVSSF-UHFFFAOYSA-N 1-ethenyl-6-methylpiperidin-2-one Chemical compound CC1CCCC(=O)N1C=C FFDNCQYZAAVSSF-UHFFFAOYSA-N 0.000 description 1
- OSSNTDFYBPYIEC-UHFFFAOYSA-N 1-ethenylimidazole Chemical compound C=CN1C=CN=C1 OSSNTDFYBPYIEC-UHFFFAOYSA-N 0.000 description 1
- XXVUSJBWYAWVQV-UHFFFAOYSA-N 1-ethenylpiperidine-2,6-dione Chemical compound C=CN1C(=O)CCCC1=O XXVUSJBWYAWVQV-UHFFFAOYSA-N 0.000 description 1
- 239000012956 1-hydroxycyclohexylphenyl-ketone Substances 0.000 description 1
- HMPUKFGKTNAIRX-UHFFFAOYSA-N 1-prop-1-en-2-ylpyrrolidin-2-one Chemical compound CC(=C)N1CCCC1=O HMPUKFGKTNAIRX-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- KWVGIHKZDCUPEU-UHFFFAOYSA-N 2,2-dimethoxy-2-phenylacetophenone Chemical compound C=1C=CC=CC=1C(OC)(OC)C(=O)C1=CC=CC=C1 KWVGIHKZDCUPEU-UHFFFAOYSA-N 0.000 description 1
- BJELTSYBAHKXRW-UHFFFAOYSA-N 2,4,6-triallyloxy-1,3,5-triazine Chemical compound C=CCOC1=NC(OCC=C)=NC(OCC=C)=N1 BJELTSYBAHKXRW-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- XMNIXWIUMCBBBL-UHFFFAOYSA-N 2-(2-phenylpropan-2-ylperoxy)propan-2-ylbenzene Chemical compound C=1C=CC=CC=1C(C)(C)OOC(C)(C)C1=CC=CC=C1 XMNIXWIUMCBBBL-UHFFFAOYSA-N 0.000 description 1
- FJGQBLRYBUAASW-UHFFFAOYSA-N 2-(benzotriazol-2-yl)phenol Chemical class OC1=CC=CC=C1N1N=C2C=CC=CC2=N1 FJGQBLRYBUAASW-UHFFFAOYSA-N 0.000 description 1
- HTTGVORJOBRXRJ-UHFFFAOYSA-N 2-(triazin-4-yl)phenol Chemical class OC1=CC=CC=C1C1=CC=NN=N1 HTTGVORJOBRXRJ-UHFFFAOYSA-N 0.000 description 1
- XHZPRMZZQOIPDS-UHFFFAOYSA-N 2-Methyl-2-[(1-oxo-2-propenyl)amino]-1-propanesulfonic acid Chemical compound OS(=O)(=O)CC(C)(C)NC(=O)C=C XHZPRMZZQOIPDS-UHFFFAOYSA-N 0.000 description 1
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- VCYCUECVHJJFIQ-UHFFFAOYSA-N 2-[3-(benzotriazol-2-yl)-4-hydroxyphenyl]ethyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCC1=CC=C(O)C(N2N=C3C=CC=CC3=N2)=C1 VCYCUECVHJJFIQ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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 System
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F218/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an acyloxy radical of a saturated carboxylic acid, of carbonic acid or of a haloformic acid
- C08F218/22—Esters containing nitrogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
- C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/12—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
- C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
-
- 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 System
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/10—Phosphatides, e.g. lecithin
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/26—Esters containing oxygen in addition to the carboxy oxygen
- C08F220/28—Esters containing oxygen in addition to the carboxy oxygen containing no aromatic rings in the alcohol moiety
- C08F220/281—Esters containing oxygen in addition to the carboxy oxygen containing no aromatic rings in the alcohol moiety and containing only one oxygen, e.g. furfuryl (meth)acrylate or 2-methoxyethyl (meth)acrylate
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F226/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen
- C08F226/06—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen by a heterocyclic ring containing nitrogen
- C08F226/10—N-Vinyl-pyrrolidone
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F230/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal
- C08F230/04—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal containing a metal
- C08F230/08—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal containing a metal containing silicon
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- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B1/00—Optical elements characterised by the material of which they are made; Optical coatings for optical elements
- G02B1/04—Optical elements characterised by the material of which they are made; Optical coatings for optical elements made of organic materials, e.g. plastics
- G02B1/041—Lenses
- G02B1/043—Contact lenses
Definitions
- This invention is directed to zwitterionic hydrogel materials that are useful in the manufacture of biocompatible medical devices, for example, hydrogel materials having desirable physical properties for use as a contact lens.
- the contact lens incorporates novel zwitterionic monomers that provide unique functionality to enhance wettability, lubricity, and chemical attributes such as a low affinity for bacteria, viruses, lipids, proteins and other environmental materials.
- the zwitterionic materials are prepared through a dual-phase polymerization mechanism.
- Hydrogels are hydrophilic polymers that absorb water, and are essentially insoluble in water at physiologic temperature, pH, and ionic strength due to the presence of a three-dimensional polymeric network.
- the three-dimensional network includes crosslinks between polymer chains of the network, and these crosslinks can be formed by covalent bonds, electrostatic, hydrophobic, or dipole-dipole interactions.
- the hydrophilicity of the hydrogel materials is in large part due to the presence of hydrophilic groups, including, but not limited to, hydroxyl, carboxyl, acid, amide, sulfonic or phosphonic groups, in some instances, along the polymer backbone, and in other instances, as functional side groups that extend from the polymer backbone.
- a hydrogel is a crosslinked polymer that absorbs water to an equilibrium value of at least 10% water.
- the water-swollen equilibrated state of a hydrogel results from a balance between an osmotic force that drives the water to enter the hydrophilic polymer network, and a cohesive force exerted by the polymer chains in resisting expansion.
- both the osmotic force and the cohesive force correlates with the type of monomers used to prepare the hydrogel polymeric material and the crosslink density of the polymeric hydrogel material.
- Water content (%) is simply: ⁇ [wet lens (g) ⁇ dry lens (g)]/wet lens (g) ⁇ 100 at equilibrium.
- Hydrogels can be classified as synthetic or natural according to their origin; degradable or stable depending on their stability characteristics, and intelligent or conventional depending on their ability to exhibit significant dimensional changes with variations in pH, temperature, or electric field.
- One class of conventional synthetic hydrogels is prepared by free-radical polymerization of vinyl or (meth)acrylate monomers. Several important classes of monomers are recognized by persons of skill with an interest to prepare hydrogel polymeric materials.
- neutral monomers for example, but not limited to, methacrylates and acrylates, e.g., 2-hydroxyethyl methacrylate (HEMA), acrylamide/methacrylamides, e.g., dimethyl acrylamide (DMA), glycerol methacrylate (GMA) and cyclic lactams, e.g., N-vinyl-2-pyrrolidone (NVP).
- HEMA 2-hydroxyethyl methacrylate
- DMA dimethyl acrylamide
- GMA glycerol methacrylate
- NDP N-vinyl-2-pyrrolidone
- N-vinyl-2-pyrrolidone N-vinyl-2-pyrrolidone
- Another class of monomers is the ionic or charged (under physiological conditions) monomers, including, but not limited to, methacrylic acid, acrylic acid, methylpropylsulfonic acid and p-styrene sulfonate.
- the ionic class of monomer is present at low concentration relative to the neutral class of monomer, but the former can have a dramatic effect on water content of the material.
- the ionic functionality in a buffered saline environment can significantly increase the water content of a hydrogel. For example, copolymerization of 2% w/w methacrylic acid with HEMA results in a hydrogel possessing a water content of 58% (compared with 38% water content for HEMA alone).
- (meth) refers to an optional methyl substitution.
- a term such as “(meth)acrylate” denotes both methacrylic and acrylic radicals.
- NVP N-vinyl-2-pyrrolidone
- Hydrogel materials prepared with vinyl cyclic lactams. e.g., N-vinyl-2-pyrrolidone (NVP) can have relatively high-water content, and thus, an acceptable level of oxygen permeability.
- NVP is often copolymerized with an alkyl acrylate or methacrylate such as methyl methacrylate to provide lens materials that typically have a water content of 50% to 80% by weight.
- such copolymers are difficult to synthesize in a controlled manner because of the difference in their respective rates of polymerization between the N-vinyl groups of NVP and the acryloyl or methacryloyl groups of the alkyl acrylate or methacrylate.
- the methacryate monomers polymerize relatively quickly while the vinyl cyclic lactam monomer polymerize more slowly, and therefore, only small amounts of the two comonomers actually react with the other.
- the polymer network is essentially an interpenetrating network of poly(vinyl monomer) and poly((meth)acrylate)).
- An ideal level of dual crosslinker is vital in that the mobility of the NVP-phase can not be compromised.
- the resulting hydrogel material can exhibit loss of lubricity at the surface of the hydrogel due to a reduction in the mobility of the PVP phase.
- the loss of lubricity will result in reduced on-eye wearing comfort.
- Silicone hydrogels combine the high oxygen permeability of polydimethylsiloxane and the excellent water absorption characteristics of a hydrogel.
- silicone-based monomers are hydrophobic, and relatively, incompatible in regard to forming a homogeneous polymerization mixture with the hydrophilic monomers present in the mixture.
- the copolymerization of (meth)acrylate functionalized silicones with hydrophilic monomers generally results in opaque, phase separated materials.
- Technical approaches to minimize such mix incompatibility can include the use of a solubilizing co-solvent or incorporating hydrophilic groups to the silicone backbone.
- the design of a silicone hydrogel involves several important considerations. The development involves not only the design of a material possessing excellent physical properties such as modulus, tear strength, and oxygen permeability, but also the design of a material possessing excellent wetting and lubricity without the use of a secondary plasma treatment to impart wettability.
- the first silicone hydrogels that were commercially introduced in the mid 1990's utilized a plasma treatment to render the surface wettable. This technique is extremely costly and provides marginal clinical performance.
- Another approach makes use of hydrophilic molds for casting.
- a next generation silicone hydrogel material included the addition of a high molecular weight, hydrophilic polymer directly mixed in with the monomer mix formulation. See, McCabe et al. (U.S. Pat. Nos. 6,367,929 and 7,052,131). McCabe takes a somewhat different approach to incorporating poly(NVP). McCabe describe a process of making a polymeric, ophthalmic lens material from a high molecular weight hydrophilic polymer and a silicone monomer. The McCabe process polymerizes the silicon monomer in the presence of an already formed hydrophilic polymer, e.g., poly(NVP) having a molecular weight of no less than about 100,000 Daltons. The PVP is entrapped within the matrix and not covalently linked.
- an already formed hydrophilic polymer e.g., poly(NVP) having a molecular weight of no less than about 100,000 Daltons.
- the PVP is entrapped within the matrix and not covalently linked.
- Still another approach relies upon the use of a dual phase or a dual network polymerization.
- the wetting of a dual-phase silicone hydrogel material is achieved through the selective use of monomers with very different reactivity rates as described above. It is when two or more free-radically polymerizable monomers with two very different reactivity rates form a polymer system containing essentially two homopolymers, such as a polymethacrylate (fast) and poly(NVP) (slow).
- the reactivity of the monomers allows for the fast and complete polymerization of the methacrylate functionality followed by NVP.
- PVP poly vinyl pyrrolidone
- the PVP chains are essentially free to migrate within the silicone matrix and, and in an aqueous environment, are driven to the surface of the lens resulting in good wetting and lubricity. This has been an important discovery in the ophthalmic filed, and it has allowed for improved wetting of a contact lens without the need for plasma or other complicated surface-treatment processes.
- U.S. Pat. No. 9,039,174 describes the use of a dual phase polymerization in which a methacrylate-based silicone reacts with NVP resulting in a hydrogel material of reported good wetting and lubricity. It is also reported that a discrete network of PVP can be seen within a silicone network using SEM.
- This invention is directed to zwitterionic hydrogel materials that are useful in the manufacture of biocompatible medical devices, for example, hydrogel materials having desirable physical properties for use as a contact lens through the incorporation of novel zwitterionic monomers provide unique functionality to enhance wettability and other chemical attributes such as a low affinity for bacteria, viruses, lipids proteins and other environmental materials.
- novel zwitterionic monomers provide unique functionality to enhance wettability and other chemical attributes such as a low affinity for bacteria, viruses, lipids proteins and other environmental materials.
- the zwitterionic monomers are well-suited for materials polymerized through a dual-phase mechanism.
- the invention relates primarily to a monomer having the structure as shown in Formula 1:
- R 1 is selected from the group as shown below (II-VIII):
- Y 1 and Y 2 are independent of one other and each one is a linkage selected from the group consisting of a direct bond, H, C 1 -C 6 divalent radical, O, NR a , C(O), C(O)NR a , NR a C(O), OC(O)NH, NHC(O)O, NR a C(O)NH, NHC(O)NR a , C(O)O, OC(O), NHC(O)NHZ 0 —NH—C(O)NH, OC(O)NHZ 0 —NH—C(O)O, OC(O)NHZ 0 —NH—C(O)NH, and NHC(O)NHZ 0 —NH—C(O)O; where R a is H, C 1 -C 4 alkyl or C 1 -C 3 alkanol, and Z 0 is a linear or branched C 2 -C 12 alkylene divalent radical, or a C 5
- Z 2 is selected from the group consisting of a direct bond, a C 1 -C 12 unsubstituted or substituted, linear or branched alkylene divalent radical, where each alkylene divalent radical can optionally include one or more linkages of O, NR a , and C(O), an unsubstituted phenylene divalent radical, a C 5 -C 7 cycloaliphatic divalent radical, and a C 7 -C 12 arylalkylene divalent radical, with the proviso that at least two of the groups Y 1 , Y 2 , and Z 2 is not a direct bond.
- R 2 for structures II-VII is selected from the group of zwitterionic functionality as shown in the following formulas:
- R is a group consisting of a direct bond, C 1 -C 6 divalent radical, O, NR a , C(O), C(O)NR a , NR a C(O), OC(O)NH, NHC(O)O, NR a C(O)NH, NHC(O)NR a , C(O)O, OC(O), NHC(O)NHZ 0 —NH—C(O)NH, OC(O)NHZ 0 —NH—C(O)O, OC(O)NHZ 0 —NH—C(O)NH, and NHC(O)NHZ 0 —NH—C(O)O;
- R a is H, C 1 -C 4 alkyl or C 1 -C 3 alkanol, and Z 0 s a linear or branched C 2 -C 12 alkylene divalent radical, or a C 5 -C 7 cycloaliphatic divalent radical, each of which can optionally
- R 2 can be selected from the following anionic groups to provide a zwitterionic monomer capable of cyclo-copolymerizing:
- R is a group consisting of a direct bond, C 1 -C 6 divalent radical, O, NR a , C(O), C(O)NR a , NR a C(O), OC(O)NH, NHC(O)O, NR a C(O)NH, NHC(O)NR a , C(O)O, OC(O), NHC(O)NHZ 0 —NH—C(O)NH, OC(O)NHZ 0 —NH—C(O)O, OC(O)NHZ 0 —NH—C(O)NH, and NHC(O)NHZ 0 —NH—C(O)O;
- R a is H, C 1 -C 4 alkyl or C 1 -C 3 alkanol
- Z 0 is a linear or branched C 2 -C 12 alkylene divalent radical, or a C 5 -C 7 cycloaliphatic divalent radical, each of which can optionally include
- This invention is also directed to a biomedical device, such as a contact lens comprising a polymer prepared from a composition comprising the monomer of Formula 1 and at least one (meth)acrylic monomer, at least one vinyl containing monomer, and at least one crosslinking agent.
- a biomedical device such as a contact lens comprising a polymer prepared from a composition comprising the monomer of Formula 1 and at least one (meth)acrylic monomer, at least one vinyl containing monomer, and at least one crosslinking agent.
- This invention overcomes the above technical shortcomings of past attempts to prepare either a conventional hydrogel material or silicon hydrogel materials for contact lens application.
- This invention is directed to zwitterionic hydrogel materials that are useful in the manufacture of biocompatible medical devices, for example, hydrogel materials having desirable physical properties for use as a contact lens.
- the contact lens incorporates novel zwitterionic monomers that provide unique functionality to enhance wettability, lubricity, and chemical attributes such as a low affinity for bacteria, viruses, lipids, proteins and other environmental materials, all important features to enhance lens comfort.
- the zwitterionic materials are prepared through a dual-phase polymerization mechanism. This dual-reactive approach allows one to tune the hydrogel matrix in which some hydrophilic vinyl polymer chains have a greater ability to move or migrate within the hydrogel polymeric framework than other hydrophilic vinyl polymer chains, particularly in a physiological aqueous environment.
- dual-phase polymerization allows for inherent wetting and lubricity through the selective use of monomers with very different reactivity ratios. It also allows for the incorporation within each phase of specific functionalities.
- Conventional and silicone hydrogel polymer formulations that include two or more free-radical, vinyl monomers with two very different reactivity ratios typically provide a polymer in which the two vinyl monomers coexist as essentially two homopolymers.
- the theoretical composition of the polymer formed by the reaction of two different vinyl monomers and the initial monomer mixture is determined by the following:
- dn 1 /dn 2 ( N 1 /N 2 )( r 1 N 1 +N 2 )/( r 2 N 2 +N 1 )
- n 1 is the moles of vinyl monomer 1 in the copolymer
- n 2 is the moles of vinyl monomer 2 in the copolymer
- N 1 and N 2 are the number of moles of vinyl monomers 1 and 2, respectively, in the monomer mixture
- r 1 and r 2 are the vinyl monomer reactivity ratios.
- the reactivity ratios are defined in terms of propagation rate constants, k 11 , k 12 , k 22 and k 21 , according to the following polymerization reactions.
- methacrylate-based siloxane and conventional hydrophilic monomers were copolymerized with N-vinyl pyrrolidone (r 1 and r 2 ).
- NVP N-vinyl pyrrolidone
- the reactivity of the monomers allows for the fast polymerization and complete polymerization of the methacrylate functionality followed by NVP.
- high molecular weight covalently linked PVP chains are formed that create an interpenetrating network of hydrophilic polymer embedded within a silicone mesh.
- Crosslinking density is paramount in that it will impact the overall wetting, lubricity and level of extractables.
- These poly(NVP) chains tend to leach out from the polymer over time. The leaching of the poly(NVP) reduces the hydrophilic character of the polymer, and a reduction in water content and wettability is observed. It also can compromise dimensional stability.
- a composition comprising at least one vinyl containing monomer, methacrylate(acrylate) monomer, methacrylate (acrylate) prepolymers, crosslinking agents and monomers having the structure as shown in Formula 1:
- R 1 is selected from the group as shown below (II-VIII):
- Y 1 and Y 2 are independent of one other and each one of Y 1 and Y 2 is a linkage selected from the group consisting of a direct bond, H, C 1 -C 6 divalent radical, O, NR a , C(O), C(O)NR a , NR a C(O), OC(O)NH, NHC(O)O, NR a C(O)NH, NHC(O)NR a , C(O)O, OC(O), NHC(O)NHZ 0 —NH—C(O)NH, OC(O)NHZ 0 —NH—C(O)O, OC(O)NHZ 0 —NH—C(O)NH, and NHC(O)NHZ 0 —NH—C(O)O; where R a is H, C 1 -C 4 alkyl or C 1 -C 3 alkanol, and Z 0 is a linear or branched C 2 -C 12 alkylene divalent
- Z 2 is selected from the group consisting of a direct bond, a C 1 -C 12 unsubstituted or substituted, linear or branched alkylene divalent radical, where each alkylene divalent radical can optionally include one or more linkages of O, NR a , and C(O), an unsubstituted phenylene divalent radical, a C 5 -C 7 cycloaliphatic divalent radical, and a C 7 -C 12 arylalkylene divalent radical, with the proviso that at least two of the groups Y 1 , Y 2 , and Z 2 is not a direct bond.
- R 2 for structures II-VII is selected from the group of zwitterionic functionality as shown in the following formulas:
- R is a group consisting of a direct bond, C 1 -C 6 divalent radical, O, NR a , C(O), C(O)NR a , NR a C(O), OC(O)NH, NHC(O)O, NR a C(O)NH, NHC(O)NR a , C(O)O, OC(O), NHC(O)NHZ 0 —NH—C(O)NH, OC(O)NHZ 0 —NH—C(O)O, OC(O)NHZ 0 —NH—C(O)NH, and NHC(O)NHZ 0 —NH—C(O)O;
- R a is H, C 1 -C 4 alkyl or C 1 -C 3 alkanol
- Z 0 is a linear or branched C 2 -C 12 alkylene divalent radical, or a C 5 -C 7 cycloaliphatic divalent radical, each of which can optionally include
- R 2 can be selected from the following anionic groups to provide a zwitterionic monomer capable of cyclo-copolymerizing:
- R is a group consisting of a direct bond, H, C 1 -C 6 divalent radical, O, NR a , C(O), C(O)NR a , NR a C(O), OC(O)NH, NHC(O)O, NR a C(O)NH, NHC(O)NR a , C(O)O, OC(O), NHC(O)NHZ 0 —NH—C(O)NH, OC(O)NHZ 0 —NH—C(O)O, OC(O)NHZ 0 —NH—C(O)NH, and NHC(O)NHZ 0 —NH—C(O)O; where R a is H, C 1 -C 4 alkyl or C 1 -C 3 alkanol, and Z 0 is a linear or branched C 2 -C 12 alkylene divalent radical, or a C 5 -C 7 cycloaliphatic divalent radical, each of which can optionally
- This invention is directed to a biomedical device, such as a contact lens comprising a polymer prepared from at least one (meth)acrylic monomer, at least one vinyl containing monomer, at least one crosslinking agent and the monomer of formula I.
- the monomer is:
- the monomer is:
- the monomer is:
- the monomer is:
- the monomer is:
- the monomer is:
- the invention is directed to a composition
- a composition comprising the monomer of Formula 1, at least one (meth)acrylic monomer, at least one vinyl containing monomer and a crosslinking agent.
- the crosslinking agent may include at least one free-radical reactive site for vinyl-containing monomer and at least one free-radical reactive site for meth(acrylic)-containing monomer.
- a preferred composition will include a dual-reactive crosslink agent, such as allyl methacrylate, and may also include a diallyl crosslinker, such as O-diallyl ethyl diester.
- compositions will include a (meth)acrylate crosslink agent to provide the necessary structural stability to the hydrogel polymer framework.
- the (meth)acrylate crosslink agents include, but are not limited to, any one difunctional or multifunctional crosslink agent, and any one mixture thereof.
- Representative examples of such crosslinkers include, but are not limited to, tripropylene glycerol diacrylate, ethylene glycol dimethacrylate, tetraethylene glycol dimethacrylate, poly(ethylene glycol diacrylate) (PEG400 or PEG600), allyl methacrylate and the like.
- hydrogel material that includes a proper balance of desired properties
- the need for a stable hydrogel polymer framework must be balanced with the wettability and lubricity of the hydrogel surface in a physiological aqueous environment. Accordingly, in the investigation of many different compositions, one generally observes that an ideal concentration of crosslinking agent exists to obtain the desired set of properties.
- the described dual-reactive monomers are particularly designed for hydrogel formulations that include at least one N-vinyl lactam monomer as the at least one vinyl monomer.
- N-vinyl lactams that are present in the hydrogel formulations, include but not limited to, N-vinyl-2-pyrrolidinone (NVP), N-(1-methyl vinyl) pyrrolidinone, N-vinyl-2-piperidone and N-vinyl-2-caprolactam, each of which can be substituted in the lactam ring by one or more lower alkyl groups such as methyl, ethyl or propyl, e.g., N-vinyl-5-methyl pyrrolidinone, N-vinyl-3,3-dimethyl pyrrolidinone, N-vinyl-5-ethyl pyrrolidinone and N-vinyl-6-methyl piperidone.
- a preferred monomer is N-vinyl-2-pyrrolidinone.
- Any one of the above N-vinyl lactams can be used alone or in admixture with other lactam monomers to provide hydrogel materials with the properties of interest.
- Illustrative of the other lactam monomers are, for example, N-vinyl imidazole, N-vinyl succinimide, N-vinyl diglycolylimide, N-vinyl glutarimide, N-vinyl-3-morpholinone and N-vinyl-5-methyl-3-morpholinone.
- the N-vinyl lactam monomer(s) will be used in conjunction with one or more hydrophobic and/or hydrophilic comonomers. If used in conjunction with a comonomer, the N-vinyl lactam will constitute at least 60% of the copolymer and more preferably from 70% to 90% by weight of the total monomers present in the monomer formulation. Furthermore, the ratio of hydrophobic comonomer to hydrophilic comonomer present in a monomer formulation in preparing the N-vinyl lactam, can be varied as desired to obtain the combination of polymer properties desired for the particular application. The preferred amount of N-vinyl lactam in the polymer composition is 70 to 90 percent by weight to achieve a relatively high-water content of 70% to 90% by weight.
- the (meth)acrylate monomers polymerize very rapidly while the at least one vinyl monomer, polymerizes relatively slowly and fail to effectively copolymerize resulting in a high level of uncrosslinked poly(NVP), the latter of which is released from the hydrogel resulting in a loss of dimensional stability and a loss of surface wettability.
- the dual-reactive crosslink agents such as allyl methacrylate or methacrylate vinyl carbonate allows one to control the amount of crosslinking of the formed poly(NVP) with the hydrogel network, and in particular the crosslinking with the (meth)acrylate polymers of the network.
- crosslink density is important because it affects the wettability, lubricity, tear strength, extractables and dimensional stability of the resulting hydrogel material. Due to the dual-reactive sites of the described crosslink agents, the agents form a crosslink between the essentially (meth)acrylate homopolymer and the essentially vinyl homopolymer resulting in hydrogel materials that possess low extractables and excellent dimensional stability.
- the resulting hydrogel materials possess a highly wettable hydrogel “surface” enriched with the slow reacting monomer/polymer component. This is a particularly important strategy for silicone hydrogels, since wetting in these systems due to the hydrophobic nature of silicone can be problematic.
- the dual reactivity approach also allows for the surface enrichment, or exposure, of chemical functionality capable of providing for improved clinical performance.
- This functionality can be bioinspired in nature and is a key advantage of this invention.
- a monomer such as those described within this application, which copolymerizes well with NVP, will result in a zwitterionic enriched lens surface. Hydrogel materials with this surface functionality are known to exhibit such characteristics as a low affinity for proteins, lipids, and bacteria.
- bioinspired fast reacting methacrylate-based monomer combined with a silicone-based monomer can provide for improved wetting and compatibility with the PVP reacting phase.
- hydrogels The chemistry of hydrogels is well known and there exists a variety of monomers that can be used to make the hydrogel materials.
- Monomers of interest to the contact lens art include acrylate, acrylamide, methacrylate, methacrylamide, styrene-containing monomers, dimethacrylate and dimethacrylamide monomers, vinyl amide-containing monomers, vinyl carbonate/carbamate/urea monomers, and (meth)acrylate/(meth) acrylamide-capped prepolymers.
- All of the above-mentioned monomers and prepolymers may further include polysiloxanes and polyfluorosiloxanes, such as ethylenically terminated methacrylate capped urethane-containing polysiloxane prepolymers, fluorine containing polysiloxanes, polyether containing siloxanes, and polysiloxanes monomers, such as, ⁇ , ⁇ -bis(methacryloxybutyl) polysiloxane (M 2 D 25 ).
- polysiloxanes and polyfluorosiloxanes such as ethylenically terminated methacrylate capped urethane-containing polysiloxane prepolymers, fluorine containing polysiloxanes, polyether containing siloxanes, and polysiloxanes monomers, such as, ⁇ , ⁇ -bis(methacryloxybutyl) polysiloxane (M 2 D 25 ).
- Suitable monomers may be represented by the general formulae:
- X is O or NR a , where R a is hydrogen, C 1 -C 4 alkyl or C 1 -C 3 alkanol; R 1 is H or CH 3 ; and R 2 and R 3 are independently hydrogen, a C 1 -C 18 alkyl, C 3 -C 18 cycloalkyl, C 3 -C 18 cycloalkylalkyl, C 3 -C 18 cycloalkenyl, C 5 -C 30 aryl, C 5 -C 30 arylalkyl, C 1 -C 18 alkyl siloxysilane or C 1 -C 18 alkyl siloxane, each of which can be optionally substituted, linear or branched, or R 2 and R 3 together with the nitrogen atom to which they are bonded are joined together to form a heterocyclic group.
- compositions of interest can also include other hydrophilic monomers that are well known in the contact lens art, and include, but not limited to, 2-hydroxyethyl methacrylate (HEMA), glyceryl monomethacrylate (GM) and 2-acrylamido-2-methyl propane sulfonic acid (AMPS).
- HEMA 2-hydroxyethyl methacrylate
- GM glyceryl monomethacrylate
- AMPS 2-acrylamido-2-methyl propane sulfonic acid
- hydrophilic monomers useful for polymerization with the vinyl monomer include, but are not limited to, unsaturated carboxylic acids, e.g., acrylic acids, methacrylic acids and the like; (meth)acrylic substituted alcohols, e.g., 3-hydroxypropyl methacrylate, 3-hydroxypropyl acrylate and the like.
- Still other hydrophilic monomers include the azetidinium and the oxazolone-based monomers disclosed in U.S. Pat.
- the additional hydrophilic monomers are typically (meth)acrylate monomer, and therefore, will preferentially copolymerize with other (meth)acrylate monomer in the composition with a similar free-radical rate of reactivity.
- Hydrophilic monomer with hydroxyl functionality is of interest because the hydroxyl functionality can provide additional surface wettability of the resulting hydrogel material.
- a particular monomer of interest is 2-hydroxyl ethyl methacrylate, which can be present in the composition from 5% to 30% by weight.
- the N-vinyl-2-pyrrolidone is present from 30% to 90% by weight
- the 2-hydroxyl ethyl methacrylate is present from 0.5% to 30% by weight.
- silicone hydrogels In the absence of any one silicone-containing monomer, the hydrogels formed are referred to in the art as conventional hydrogels.
- silicone hydrogels is another class of hydrogel materials of importance in the field of medical devices. Accordingly, it can be of interest to include one or more silicone-containing monomers in a composition of interest.
- Some well-known silicone-containing monomers include the TRIS-like and trisiloxane (siloxy silane) monomers represented by the following structures:
- h is 1 to 18 and each R 3 independently denotes a lower alkyl radical, or phenyl radical.
- Representative examples of such acrylate ester and/or methacrylate ester-containing monomers include 3-methacryloyloxypropyltris(trimethylsiloxy)silane or (3-methacryloyloxy-2-hydroxypropyloxy)propylbis(trimethylsiloxy)-methylsilane), sometimes referred to as TRIS and SIGMA, respectively, and are commercially available from such sources as Gelest, Inc. (Morrisville, PA).
- siloxy silanes include, pentamethyldisiloxanyl methylmethacrylate, phenyltetramethyl-disiloxanylethyl acrylate, methyldi(trimethylsiloxy) methacryloyloxymethyl silane, 3-[tris(trimethylsiloxy)silyl]propyl vinyl carbamate, 3[tris(trimethylsiloxy)silyl]propyl allyl carbamate, and 3-tris(trimethylsiloxy)silyl] propyl vinyl carbonate.
- Silicone monomers referred in the art as silicone monofunctional monomer can also be included in the described compositions. See, U.S. Pat. No. 8,937,110 to Vanderlaan, the disclosure of which is herein incorporated by reference.
- silicone monofunctional monomer include monomethacryloyloxyalkyl-polydimethylsiloxane methacrylates selected from the group consisting of monomethacryloyloxypropyl terminated mono-n-butyl terminated polydimethylsiloxane, monomethacryloyloxypropyl terminated mono-methyl terminated polydimethylsiloxane, monomethacryloyloxypropyl terminated mono-n-butyl terminated polydiethylsiloxane, monomethacryloyloxypropyl terminated mono-n-methyl terminated polydiethylsiloxane, N-(2,3-dihydroxypropane)-N′-(propyltetra(dimethylsiloxy
- the silicone monofunctional monomer is selected from the group consisting of monomethacryloyloxypropyl terminated mono-n-butyl terminated polydimethylsiloxane, monomethacryloyloxypropyl terminated mono-n-methyl terminated polydimethylsiloxane, N-(2,3-dihydroxypropane)-N′-(propyl tetra(dimethylsiloxy) dimethylbutylsilane)acrylamide, ⁇ -(2-hydroxy-l-methacryloxypropyloxypropyl)-o-butyl-decamethyl-lpentasiloxane, and mixtures thereof.
- the at least one silicone-containing monomer is present in the silicone hydrogel described compositions in an amount sufficient to provide the desired oxygen permeability. It is a benefit of the present invention that oxygen permeabilities greater than about 60 Barrers, greater than about 80 Barrers, and in some embodiments greater than about 90 Barrers can be achieved. Suitable amounts will depend on the length of the siloxane chain included in the silicone-containing monomers, with silicone-containing monomers having longer chains requiring less monomer. Amounts include from 20% to 60% by weight, and in some embodiments from about 30% to 55% by weight.
- one or more of the silicone-containing monomers above are present in a composition from 25% to 80% by weight, or from 20% to 80% by weight.
- the N-vinyl-2-pyrrolidone is present from 50% to 90% by weight
- 2-hydroxyl ethyl methacrylate is present from 0.5% to 25% by weight
- the silicone-containing monomer is present from 30% to 70% by weight.
- bioinspired monomers include, but not limited to, carboxybetaines, sulfobetaines and phosphobetaines, such as methacryloyloxy phosphatidyl choline (MPC), N-vinylcarboxy ethyl phosphatidyl choline, 0-vinyl ethyl phosphatidyl choline carbonate, 1-(3-sulfopropyl)-2-vinylpyridinium betaine, 3-dimethyl(acryloyloxyethyl) ammonium propyl sulfonate, functional sugars and proteins, or any one mixture of bioinspired monomer.
- suitable bioinspired hydrophilic monomers will be apparent to one skilled in the art.
- Useful hydrophobic monomers for use herein include, but are not limited to, alkyl acrylates and methacrylates, 4-t-butyl-2-hydroxy cyclohexyl methacrylate (TBE), tert-butyl cyclohexyl methacrylate, isopropylcyclopentyl acrylate, tert-butylcyclohexyl acrylate, isobornyl methacrylate and the like; 2-ethylhexyl methacrylate, 2-phenyloxyethyl methacrylate, partially fluorinated acrylates, partially fluorinated methacrylates and the like and mixtures thereof.
- TBE 4-t-butyl-2-hydroxy cyclohexyl methacrylate
- tert-butyl cyclohexyl methacrylate isopropylcyclopentyl acrylate
- tert-butylcyclohexyl acrylate isobornyl meth
- the copolymerization reaction can be conducted neat or with a suitable cosolvent.
- the monomeric mixture and optional crosslinking agent(s) are combined in the desired ratio, and then exposed to, for example, ultraviolet (UV) light or electron beams in the presence of one or more photo initiator(s) or at a suitable temperature, for a time sufficient to form the copolymer.
- UV ultraviolet
- Heat may also be employed to initiate the polymerization in which case a series of Vazo, peroxide or peroxy initiators, well-known in the art, may be used.
- Suitable reaction times will ordinarily range from about 1 minute to about 24 hours and preferably from about 1 hour to about 10 hours.
- UV or visible light in combination with photo initiators is well known in the art and is particularly suitable for formation of the copolymer.
- Numerous photo initiators of the type in question here are commercial products. Photo initiators enhance the rapidity of the curing process when the photo curable compositions are exposed to, for example, ultraviolet radiation.
- Suitable photo initiators which are useful for polymerizing the polymerizable mixture of monomers can be commercially available photo initiators. They are generally compounds which can initiate the radical reaction of olefinically unsaturated double bonds on exposure to light with a wavelength of, for example, about 260 to about 480 nm.
- photo initiators for use herein include, but are not limited to, one or more photo initiators commercially available under the “IRGACURE®”, “DAROCURC®” and “SPEEDCURE®” trade names (manufactures by Ciba Specialty Chemicals, also obtainable under a different name from BASF, Fratelli Lamberti and Kawaguchi), e.g., “IRGACUREC®” 184 (1-hydroxycyclohexyl phenyl ketone), 907 (2-methyl-1-[4-(methylthio)phenyl]-2-morpholino propan-1-one), 369 (2-benzyl-2-N,N-dimethylamino-1-(4-morpholinophenyl)-1-butanone), 500 (the combination of 1-hydroxy cyclohexyl phenyl ketone and benzophenone), 651 (2,2-dimethoxy-2-phenyl acetophenone), 1700 (the combination of bis(2,6-dimethoxybenzoy
- photo initiators for use herein include, but are not limited to, alkyl pyruvates such as methyl, ethyl, propyl, and butyl pyruvates, and aryl pyruvates such as phenyl, benzyl, and appropriately substituted derivatives thereof.
- the amount of photo initiator can range from about 0.05% w/w to about 5% w/w and preferably from about 0.1% w/w to about 1% w/w.
- thermal initiators for use herein include, but are not limited to, include the azo and peroxy type compounds, such as 2,2-azobisisobutyronitrile (VAZO 64), 4,4-azobis(4-cyanovaleric acid), 1,1-azobis(cyclohexanecarbonitrile), benzoyl peroxide, 1,1-bis(tert-butylperoxy)cyclohexane, tert-butyl hydroperoxide, tert-butyl peroxybenzoate and dicumyl peroxide.
- the amount of thermal initiator can range from about 0.05% w/w to about 5% w/w and preferably from about 0.1% w/w to about 1% w/w.
- organic diluent can be included in any one composition of interest.
- organic diluent encompasses organic compounds which minimize incompatibility of the components in the monomeric mixture and are substantially nonreactive with the components in the mixture. Additionally, the organic diluent serves to minimize phase separation of polymerized products produced by polymerization of the monomeric mixture. Also, the organic diluent will generally be relatively non-flammable. Contemplated organic diluents include alcohols such as tert-butanol (TBA), tert-amyl alcohol, diols, such as ethylene glycol; and polyols, such as glycerol.
- TSA tert-butanol
- diols such as ethylene glycol
- polyols such as glycerol.
- the organic diluent is water soluble and can be removed easily through a water extraction process. Other suitable organic diluents would be apparent to a person of ordinary skill in the art.
- the organic diluent is included in an amount effective to provide the desired effect (for example, minimal phase separation of polymerized products).
- the diluent is included at 0 to 60% by weight of the monomeric mixture, with 1 to 40% by weight being more preferred, 2 to 30% by weight being even more preferred and 3 to 25% by weight being especially preferred.
- compositions described can also include at least one UV absorbing compound.
- Suitable UV absorbers may be derived from 2-(2′-hydroxyphenyl)benzotriazoles, 2-hydroxybenzophenones, 2-hydroxyphenyltriazines, cyanoacrylates, salicylates and 4-hydroxybenzoates; which may be further reacted to incorporate reactive polymerizable groups, such as (meth)acrylates.
- UV absorbers which include polymerizable groups include 2-(2′-hydroxy-5-methacryloyloxyethylphenyl)-2H-benzotriazole (Norbloc), 5-vinyl and derivatives of 2-(2,4-dihydroxyphenyl)-2H-benzotriazole and 4-acrylates or 4-methacrylates of 2-(2,4-dihydroxyphenyl)-2H-benzotriazole or 2-(2,4-dihydroxyphenyl)-1,3-2H-dibenzotriazole, mixtures thereof and the like.
- a UV absorber When a UV absorber is included, it may be included in amounts between 0.5% and 4% by weight, and suitably between 1% and 2% by weight.
- the present invention relates to monomeric formulations useful in the manufacture of biocompatible medical devices. More particularly, the present invention relates to hydrogel formulations capable of polymerization to form polymeric compositions having desirable physical characteristics useful in the manufacture of contact lenses. Such properties include low modulus of elasticity, a high level of oxygen permeability, wettability, lubricity, and a low level of extractables. Further, the monomers possess unique zwitterionic functionally designed to minimize attachment of bacteria, viruses, and other environment debris.
- compositions described herein can be used to make hydrogel materials for a biomedical device such as artificial heart valves, films, surgical devices, vessel substitutes, intrauterine devices, membranes, diaphragms, surgical implants, artificial blood vessels, artificial ureters, artificial breast tissue and membranes intended to come into contact with body fluid outside of the body, e.g., membranes for kidney dialysis and heart/lung machines and the like, catheters, mouth guards, denture liners, ophthalmic devices, and especially hydrogel contact lenses.
- a biomedical device such as artificial heart valves, films, surgical devices, vessel substitutes, intrauterine devices, membranes, diaphragms, surgical implants, artificial blood vessels, artificial ureters, artificial breast tissue and membranes intended to come into contact with body fluid outside of the body, e.g., membranes for kidney dialysis and heart/lung machines and the like, catheters, mouth guards, denture liners, ophthalmic devices, and especially hydrogel contact lenses.
- a “biomedical device” is any article that is designed to be used while either in or on mammalian tissues or fluid, and in one embodiment in or on human tissue or fluids. Examples of these devices include but are not limited to catheters, implants, stents, and ophthalmic devices such as intraocular lenses, punctal plugs and contact lenses.
- lens formation can be by free radical polymerization such as azobisisobutyronitrile (AIBN) and peroxide catalysts using initiators and under conditions such as those set forth in U.S. Pat. No. 3,808,179, incorporated herein by reference.
- Photoinitiation of polymerization of the monomer mixture as is well known in the art may also be used in the process of forming an article as disclosed herein.
- the manufacture of contact lenses is performed via cast molding, spin casting, or rod-lathing techniques-all well-known in the industry.
- NVP N-vinyl pyrrolidinone
- TAA t-amyl alcohol diluent
- Vazo 64 2,2′-azobis (2-methyl propionitrile)
- N,N, Diallyl-N-methylamine (4) (0.9 mol), ethyl 4-bromobutyrate (0.99 mol), and acetonitrile (500 mL) were de-aerated by multiple freeze-pump-thaw cycles, combined, and allowed to react under reflux with stirring for 60 h.
- Acetonitrile was removed under vacuum, and the resulting oil was washed continuously with ether for 5 days utilizing a liquid-liquid extractor. The oil was then lyophilized to remove any associated water.
- the ammonium bromide solid (mp 47-49° C.), was obtained in 85% yield. Elemental microanalysis for C 12 H 24 NO 2 Br.
- diallyl methyl amine and 1,4, butane sultone 1.0 equivalent
- the flask is heated to 70° C. for 5 hours at which time the diallyl sulfobetaine precipitate was collected via filtration, washed with acetone and vacuum dried resulting in an 80% yield of product.
- the starting material dimethyl amino ethyl allyl ester was prepared in high yield and purity via the esterification of the dimethyl amino ethyl methyl ester.
- the resultant product was added to propiolactone (1.2 equivalent) in acetone at 15° C. for five hours.
- the resultant ring-opened product was devolatilized under high vacuum to remove the unreacted cyclic lactone.
- the final product was obtained in in 85% yield with structure confirmation via H-NMR.
- the starting material dimethyl amino ethyl N-vinyl carbamate was prepared in high yield and purity via the reaction of vinyl isocyanate with hydroxyl ethyl dimethylamine.
- the resultant product was added to propiolactone (1.2 equivalent) in acetone at 15° C. for five hours.
- the resultant ring-opened product was devolatilized under high vacuum to remove the unreacted cyclic lactone.
- the final product was obtained in in 85% yield with structure confirmation via H-NMR.
- the starting material dimethyl amino ethyl N-vinyl carbamate was prepared in high yield and purity via the reaction of vinyl chloro formate with hydroxyl ethyl dimethylamine.
- the resultant product was added to propiolactone (1.2 equivalent) in acetone at 15° C. for five hours.
- the resultant ring-opened product was devolatilized under high vacuum to remove the unreacted cyclic lactone.
- the final product was obtained in high yield with structure confirmation via H-NMR.
- Hydrogel contact lenses are prepared with the inventive chemistry.
- the monomer formulation mixture is prepared in a dry box (rel. hum. of approx. 10%).
- the mixed formulation is added to polypropylene lens molds in the dry box, and the filled molds are placed in an oven at room temperature and purged with nitrogen for 30 minutes. The nitrogen atmosphere is maintained for the entire cure protocol at a level of 100 ppm.
- the oven temperature is raised to 60° C. (10° C./min ramp rate) and the temperature maintained at 60° C. for 2 hrs.
- the oven temperature is raised to 80° C. (10° C./min ramp rate) and the temperature maintained at 80° C. for 2 hrs.
- the oven temperature is raised to 100° C. (10° C./min ramp rate) and the temperature maintained at 100° C.
- the oven temperature is then lowered to 55° C. over the next hour.
- the lenses are removed from the oven and allowed to cool to room temperature in the dry box.
- the lenses are dry released from the molds.
- the lenses can be wet released from the mold. Dry release or wet release methods are well known to those of ordinary skill in the contact lens art.
- the lenses are extracted 3 ⁇ /10 min with distilled water with exchange of fresh water per cycle.
- the lenses are then extracted 3 ⁇ /10 min with borate-buffered saline (pH 6.8-7.2, osmolality 270-320) with exchange of fresh BBS per cycle and packaged in BBS.
- Monomer mixtures, 9A through 9E, as shown in Table 1 are prepared by mixing the following components: NVP, TBCM, allyl ester carboxy betaine from example 3, HEMA, allyl methacrylate and Vazo 64 initiator.
- the resultant monomeric mixture is cast in a polypropylene contact lens mold and thermally cured in accordance with the procedure as described in Example 8.
- the resultant contact lens materials are transparent and highly wettable.
- Monomer mixtures, 10A through 10E, as shown in Table 2 are prepared by mixing the following components: NVP, Tris Methacrylate, Sigma, Mono the allyl ester carboxy betaine or the diallyl carboxy betaine together with the crosslinkers TEGDMA and allyl methacrylate and a Vazo 64 initiator.
- the resultant monomeric mixture is cast in a polypropylene contact lens mold and thermally cured in accordance with the procedure as described in Example 8.
- the resultant contact lens materials are transparent and highly wettable.
Abstract
Hydrogel materials used in the manufacture of biocompatible medical devices, for example, hydrogel materials having desirable physical properties for use as a contact lens. A composition contains at least one vinyl containing monomer, a methacrylate(acrylate) monomer, methacrylate (acrylate) prepolymers, crosslinking agents and monomers having the structure as shown in Formula 1:where R1 is a vinyl functionality capable of radical polymerization with specific preference for N-vinyl lactam derivatives and R2 is a zwitterionic functionality. The materials utilize a two-phase polymerization strategy.
Description
- This application claims priority under 35 USC 119(e) from U.S. Provisional Application Ser. No. 63/391,056, filed on Jul. 21, 2022, the disclosure of which is herein incorporated by reference.
- This invention is directed to zwitterionic hydrogel materials that are useful in the manufacture of biocompatible medical devices, for example, hydrogel materials having desirable physical properties for use as a contact lens. The contact lens incorporates novel zwitterionic monomers that provide unique functionality to enhance wettability, lubricity, and chemical attributes such as a low affinity for bacteria, viruses, lipids, proteins and other environmental materials. The zwitterionic materials are prepared through a dual-phase polymerization mechanism.
- Hydrogels are hydrophilic polymers that absorb water, and are essentially insoluble in water at physiologic temperature, pH, and ionic strength due to the presence of a three-dimensional polymeric network. The three-dimensional network includes crosslinks between polymer chains of the network, and these crosslinks can be formed by covalent bonds, electrostatic, hydrophobic, or dipole-dipole interactions. The hydrophilicity of the hydrogel materials is in large part due to the presence of hydrophilic groups, including, but not limited to, hydroxyl, carboxyl, acid, amide, sulfonic or phosphonic groups, in some instances, along the polymer backbone, and in other instances, as functional side groups that extend from the polymer backbone. Generally, a hydrogel is a crosslinked polymer that absorbs water to an equilibrium value of at least 10% water. The water-swollen equilibrated state of a hydrogel results from a balance between an osmotic force that drives the water to enter the hydrophilic polymer network, and a cohesive force exerted by the polymer chains in resisting expansion. In some fashion, both the osmotic force and the cohesive force correlates with the type of monomers used to prepare the hydrogel polymeric material and the crosslink density of the polymeric hydrogel material. In general, a person of ordinary skill would expect a greater degree of crosslinking for a given hydrogel polymeric material will result in a corresponding decrease in water content, i.e., at equilibrium, the weight percentage of water absorbed by the polymeric network under physiological conditions relative to its total weight. Water content (%) is simply: {[wet lens (g)−dry lens (g)]/wet lens (g)}×100 at equilibrium.
- Hydrogels can be classified as synthetic or natural according to their origin; degradable or stable depending on their stability characteristics, and intelligent or conventional depending on their ability to exhibit significant dimensional changes with variations in pH, temperature, or electric field. One class of conventional synthetic hydrogels is prepared by free-radical polymerization of vinyl or (meth)acrylate monomers. Several important classes of monomers are recognized by persons of skill with an interest to prepare hydrogel polymeric materials. There are the neutral monomers, for example, but not limited to, methacrylates and acrylates, e.g., 2-hydroxyethyl methacrylate (HEMA), acrylamide/methacrylamides, e.g., dimethyl acrylamide (DMA), glycerol methacrylate (GMA) and cyclic lactams, e.g., N-vinyl-2-pyrrolidone (NVP). At times, the term N-vinylpyrrolidone is used interchangeably with N-vinyl-2-pyrrolidone, and both chemical terms are well recognized by persons of ordinary skill to mean the same vinyl monomer. Another class of monomers is the ionic or charged (under physiological conditions) monomers, including, but not limited to, methacrylic acid, acrylic acid, methylpropylsulfonic acid and p-styrene sulfonate. Typically, in the making of contact lenses the ionic class of monomer is present at low concentration relative to the neutral class of monomer, but the former can have a dramatic effect on water content of the material. The ionic functionality in a buffered saline environment can significantly increase the water content of a hydrogel. For example, copolymerization of 2% w/w methacrylic acid with HEMA results in a hydrogel possessing a water content of 58% (compared with 38% water content for HEMA alone). As used herein “(meth)” refers to an optional methyl substitution. Thus, a term such as “(meth)acrylate” denotes both methacrylic and acrylic radicals.
- Hydrogel materials prepared with vinyl cyclic lactams. e.g., N-vinyl-2-pyrrolidone (NVP) can have relatively high-water content, and thus, an acceptable level of oxygen permeability. For example, NVP is often copolymerized with an alkyl acrylate or methacrylate such as methyl methacrylate to provide lens materials that typically have a water content of 50% to 80% by weight. However, such copolymers are difficult to synthesize in a controlled manner because of the difference in their respective rates of polymerization between the N-vinyl groups of NVP and the acryloyl or methacryloyl groups of the alkyl acrylate or methacrylate. During free-radical polymerization, the methacryate monomers polymerize relatively quickly while the vinyl cyclic lactam monomer polymerize more slowly, and therefore, only small amounts of the two comonomers actually react with the other. What one finds is that the polymer network is essentially an interpenetrating network of poly(vinyl monomer) and poly((meth)acrylate)).
- It is also observed, and not to be overlooked, that in a conventional poly(vinyl monomer) and poly((meth)acrylate)) hydrogel framework a minimum of crosslinking occurs between the two essentially homopolymers. In the absence of a suitable crosslinking agent to link the two dual phase polymers, high levels of extractables and dimensional instability results. There have been attempts to prepare high water content hydrogels using two different crosslink agents, i.e., allyl methacrylate (AMA) or divinylethylene urea (DVEU), to incorporate the vinyl (cyclic lactam) monomer into the hydrogel polymer network. The AMA crosslink agent works quite well with monomers systems where a fast polymerizing (meth)acrylate and a slow NVP are used. An ideal level of dual crosslinker is vital in that the mobility of the NVP-phase can not be compromised. For example, as films or lenses are being made, or as water enters the framework, the resulting hydrogel material can exhibit loss of lubricity at the surface of the hydrogel due to a reduction in the mobility of the PVP phase. For application of a contact lens, the loss of lubricity will result in reduced on-eye wearing comfort.
- Silicone hydrogels combine the high oxygen permeability of polydimethylsiloxane and the excellent water absorption characteristics of a hydrogel. However, for the application of a contact lens, one well known issue with preparing silicone hydrogels is that silicone-based monomers are hydrophobic, and relatively, incompatible in regard to forming a homogeneous polymerization mixture with the hydrophilic monomers present in the mixture. The copolymerization of (meth)acrylate functionalized silicones with hydrophilic monomers generally results in opaque, phase separated materials. Technical approaches to minimize such mix incompatibility can include the use of a solubilizing co-solvent or incorporating hydrophilic groups to the silicone backbone.
- The design of a silicone hydrogel involves several important considerations. The development involves not only the design of a material possessing excellent physical properties such as modulus, tear strength, and oxygen permeability, but also the design of a material possessing excellent wetting and lubricity without the use of a secondary plasma treatment to impart wettability. The first silicone hydrogels that were commercially introduced in the mid 1990's utilized a plasma treatment to render the surface wettable. This technique is extremely costly and provides marginal clinical performance. Another approach makes use of hydrophilic molds for casting.
- A next generation silicone hydrogel material included the addition of a high molecular weight, hydrophilic polymer directly mixed in with the monomer mix formulation. See, McCabe et al. (U.S. Pat. Nos. 6,367,929 and 7,052,131). McCabe takes a somewhat different approach to incorporating poly(NVP). McCabe describe a process of making a polymeric, ophthalmic lens material from a high molecular weight hydrophilic polymer and a silicone monomer. The McCabe process polymerizes the silicon monomer in the presence of an already formed hydrophilic polymer, e.g., poly(NVP) having a molecular weight of no less than about 100,000 Daltons. The PVP is entrapped within the matrix and not covalently linked.
- Still another approach relies upon the use of a dual phase or a dual network polymerization. The wetting of a dual-phase silicone hydrogel material is achieved through the selective use of monomers with very different reactivity rates as described above. It is when two or more free-radically polymerizable monomers with two very different reactivity rates form a polymer system containing essentially two homopolymers, such as a polymethacrylate (fast) and poly(NVP) (slow). The reactivity of the monomers allows for the fast and complete polymerization of the methacrylate functionality followed by NVP. Through careful control of the polymerization rate and degree of crosslinking, high molecular weight poly vinyl pyrrolidone (PVP) chains embedded within a silicone mesh are created. The PVP chains are essentially free to migrate within the silicone matrix and, and in an aqueous environment, are driven to the surface of the lens resulting in good wetting and lubricity. This has been an important discovery in the ophthalmic filed, and it has allowed for improved wetting of a contact lens without the need for plasma or other complicated surface-treatment processes.
- The use of the dual phase polymerization has been described several times in the patent literature. It has been used by various research groups for cast molded silicone hydrogel lenses and was first described in a series of U.S. Pat. Nos. 5,387,662, 5,539,016 and 5,321,108, and later in U.S. Pat. Nos. 7,176,268, 7,074,873. In these systems a fast-polymerizing methacrylate-based silicone is copolymerized with NVP. Recently, U.S. Pat. No. 7,528,208 describes the dual phase polymerization of a monofunctional silicone with NVP. The technical issue with this material, however, is that the crosslinker used for this system is ineffective in maintaining poly(NVP) within the silicone polymer network. This leads to high extractables and poor dimensional stability. U.S. Pat. No. 9,039,174 describes the use of a dual phase polymerization in which a methacrylate-based silicone reacts with NVP resulting in a hydrogel material of reported good wetting and lubricity. It is also reported that a discrete network of PVP can be seen within a silicone network using SEM.
- This invention is directed to zwitterionic hydrogel materials that are useful in the manufacture of biocompatible medical devices, for example, hydrogel materials having desirable physical properties for use as a contact lens through the incorporation of novel zwitterionic monomers provide unique functionality to enhance wettability and other chemical attributes such as a low affinity for bacteria, viruses, lipids proteins and other environmental materials. The zwitterionic monomers are well-suited for materials polymerized through a dual-phase mechanism.
- The invention relates primarily to a monomer having the structure as shown in Formula 1:
- wherein:
- R1 is selected from the group as shown below (II-VIII):
- Y1 and Y2 are independent of one other and each one is a linkage selected from the group consisting of a direct bond, H, C1-C6 divalent radical, O, NRa, C(O), C(O)NRa, NRaC(O), OC(O)NH, NHC(O)O, NRaC(O)NH, NHC(O)NRa, C(O)O, OC(O), NHC(O)NHZ0—NH—C(O)NH, OC(O)NHZ0—NH—C(O)O, OC(O)NHZ0—NH—C(O)NH, and NHC(O)NHZ0—NH—C(O)O; where Ra is H, C1-C4 alkyl or C1-C3 alkanol, and Z0 is a linear or branched C2-C12 alkylene divalent radical, or a C5-C7 cycloaliphatic divalent radical, each of which can optionally include one or more linkages of O, NRa and C(O); and
- Z2 is selected from the group consisting of a direct bond, a C1-C12 unsubstituted or substituted, linear or branched alkylene divalent radical, where each alkylene divalent radical can optionally include one or more linkages of O, NRa, and C(O), an unsubstituted phenylene divalent radical, a C5-C7 cycloaliphatic divalent radical, and a C7-C12 arylalkylene divalent radical, with the proviso that at least two of the groups Y1, Y2, and Z2 is not a direct bond.
- R2 for structures II-VII is selected from the group of zwitterionic functionality as shown in the following formulas:
- Where R is a group consisting of a direct bond, C1-C6 divalent radical, O, NRa, C(O), C(O)NRa, NRaC(O), OC(O)NH, NHC(O)O, NRaC(O)NH, NHC(O)NRa, C(O)O, OC(O), NHC(O)NHZ0—NH—C(O)NH, OC(O)NHZ0—NH—C(O)O, OC(O)NHZ0—NH—C(O)NH, and NHC(O)NHZ0—NH—C(O)O; where Ra is H, C1-C4 alkyl or C1-C3 alkanol, and Z0 s a linear or branched C2-C12 alkylene divalent radical, or a C5-C7 cycloaliphatic divalent radical, each of which can optionally include one or more linkages of O, NRa and C(O).
- Or in the case of the diallyl quat structure VIII, R2 can be selected from the following anionic groups to provide a zwitterionic monomer capable of cyclo-copolymerizing:
- Where R is a group consisting of a direct bond, C1-C6 divalent radical, O, NRa, C(O), C(O)NRa, NRaC(O), OC(O)NH, NHC(O)O, NRaC(O)NH, NHC(O)NRa, C(O)O, OC(O), NHC(O)NHZ0—NH—C(O)NH, OC(O)NHZ0—NH—C(O)O, OC(O)NHZ0—NH—C(O)NH, and NHC(O)NHZ0—NH—C(O)O; where Ra is H, C1-C4 alkyl or C1-C3 alkanol, and Z0 is a linear or branched C2-C12 alkylene divalent radical, or a C5-C7 cycloaliphatic divalent radical, each of which can optionally include one or more linkages of O, NRa and C(O).
- This invention is also directed to a biomedical device, such as a contact lens comprising a polymer prepared from a composition comprising the monomer of Formula 1 and at least one (meth)acrylic monomer, at least one vinyl containing monomer, and at least one crosslinking agent.
- This invention overcomes the above technical shortcomings of past attempts to prepare either a conventional hydrogel material or silicon hydrogel materials for contact lens application. This invention is directed to zwitterionic hydrogel materials that are useful in the manufacture of biocompatible medical devices, for example, hydrogel materials having desirable physical properties for use as a contact lens. The contact lens incorporates novel zwitterionic monomers that provide unique functionality to enhance wettability, lubricity, and chemical attributes such as a low affinity for bacteria, viruses, lipids, proteins and other environmental materials, all important features to enhance lens comfort. The zwitterionic materials are prepared through a dual-phase polymerization mechanism. This dual-reactive approach allows one to tune the hydrogel matrix in which some hydrophilic vinyl polymer chains have a greater ability to move or migrate within the hydrogel polymeric framework than other hydrophilic vinyl polymer chains, particularly in a physiological aqueous environment.
- Specifically, dual-phase polymerization allows for inherent wetting and lubricity through the selective use of monomers with very different reactivity ratios. It also allows for the incorporation within each phase of specific functionalities. Conventional and silicone hydrogel polymer formulations that include two or more free-radical, vinyl monomers with two very different reactivity ratios typically provide a polymer in which the two vinyl monomers coexist as essentially two homopolymers. The theoretical composition of the polymer formed by the reaction of two different vinyl monomers and the initial monomer mixture is determined by the following:
-
dn 1 /dn 2=(N 1 /N 2)(r 1 N 1 +N 2)/(r 2 N 2 +N 1) - where n1 is the moles of vinyl monomer 1 in the copolymer, n2 is the moles of vinyl monomer 2 in the copolymer, N1 and N2 are the number of moles of vinyl monomers 1 and 2, respectively, in the monomer mixture, and r1 and r2 are the vinyl monomer reactivity ratios. The reactivity ratios are defined in terms of propagation rate constants, k11, k12, k22 and k21, according to the following polymerization reactions.
-
M 1 *+M 1 →M 1 M 1 *k 11 -
M 1 *+M 2 →M 1 M 2 *k 12 -
M 2 *+M 2 →M 2 M 2 *k 22 -
M 2 *+M 1 →M 2 M 1 *k 21 - In these systems methacrylate-based siloxane and conventional hydrophilic monomers were copolymerized with N-vinyl pyrrolidone (r1 and r2). The reactivity of the monomers allows for the fast polymerization and complete polymerization of the methacrylate functionality followed by NVP. Through careful control of the polymerization rate and type crosslinker, high molecular weight covalently linked PVP chains are formed that create an interpenetrating network of hydrophilic polymer embedded within a silicone mesh. Crosslinking density is paramount in that it will impact the overall wetting, lubricity and level of extractables. These poly(NVP) chains tend to leach out from the polymer over time. The leaching of the poly(NVP) reduces the hydrophilic character of the polymer, and a reduction in water content and wettability is observed. It also can compromise dimensional stability.
- A composition comprising at least one vinyl containing monomer, methacrylate(acrylate) monomer, methacrylate (acrylate) prepolymers, crosslinking agents and monomers having the structure as shown in Formula 1:
- wherein:
- R1 is selected from the group as shown below (II-VIII):
- Y1 and Y2 are independent of one other and each one of Y1 and Y2 is a linkage selected from the group consisting of a direct bond, H, C1-C6 divalent radical, O, NRa, C(O), C(O)NRa, NRaC(O), OC(O)NH, NHC(O)O, NRaC(O)NH, NHC(O)NRa, C(O)O, OC(O), NHC(O)NHZ0—NH—C(O)NH, OC(O)NHZ0—NH—C(O)O, OC(O)NHZ0—NH—C(O)NH, and NHC(O)NHZ0—NH—C(O)O; where Ra is H, C1-C4 alkyl or C1-C3 alkanol, and Z0 is a linear or branched C2-C12 alkylene divalent radical, or a C5-C7 cycloaliphatic divalent radical, each of which can optionally include one or more linkages of O, NRa and C(O); and
- Z2 is selected from the group consisting of a direct bond, a C1-C12 unsubstituted or substituted, linear or branched alkylene divalent radical, where each alkylene divalent radical can optionally include one or more linkages of O, NRa, and C(O), an unsubstituted phenylene divalent radical, a C5-C7 cycloaliphatic divalent radical, and a C7-C12 arylalkylene divalent radical, with the proviso that at least two of the groups Y1, Y2, and Z2 is not a direct bond.
- R2 for structures II-VII is selected from the group of zwitterionic functionality as shown in the following formulas:
- Where R is a group consisting of a direct bond, C1-C6 divalent radical, O, NRa, C(O), C(O)NRa, NRaC(O), OC(O)NH, NHC(O)O, NRaC(O)NH, NHC(O)NRa, C(O)O, OC(O), NHC(O)NHZ0—NH—C(O)NH, OC(O)NHZ0—NH—C(O)O, OC(O)NHZ0—NH—C(O)NH, and NHC(O)NHZ0—NH—C(O)O; where Ra is H, C1-C4 alkyl or C1-C3 alkanol, and Z0 is a linear or branched C2-C12 alkylene divalent radical, or a C5-C7 cycloaliphatic divalent radical, each of which can optionally include one or more linkages of O, NRa and C(O).
- Or in the case of the diallyl quat structure VIII, R2 can be selected from the following anionic groups to provide a zwitterionic monomer capable of cyclo-copolymerizing:
- Where R is a group consisting of a direct bond, H, C1-C6 divalent radical, O, NRa, C(O), C(O)NRa, NRaC(O), OC(O)NH, NHC(O)O, NRaC(O)NH, NHC(O)NRa, C(O)O, OC(O), NHC(O)NHZ0—NH—C(O)NH, OC(O)NHZ0—NH—C(O)O, OC(O)NHZ0—NH—C(O)NH, and NHC(O)NHZ0—NH—C(O)O; where Ra is H, C1-C4 alkyl or C1-C3 alkanol, and Z0 is a linear or branched C2-C12 alkylene divalent radical, or a C5-C7 cycloaliphatic divalent radical, each of which can optionally include one or more linkages of O, NRa and C(O).
- This invention is directed to a biomedical device, such as a contact lens comprising a polymer prepared from at least one (meth)acrylic monomer, at least one vinyl containing monomer, at least one crosslinking agent and the monomer of formula I.
- In another embodiment, the monomer is:
- In another embodiment, the monomer is:
- In another embodiment, the monomer is:
- In another embodiment, the monomer is:
- In another embodiment, the monomer is:
- In another embodiment, the monomer is:
- The invention, as stated, is directed to a composition comprising the monomer of Formula 1, at least one (meth)acrylic monomer, at least one vinyl containing monomer and a crosslinking agent. The crosslinking agent may include at least one free-radical reactive site for vinyl-containing monomer and at least one free-radical reactive site for meth(acrylic)-containing monomer. Accordingly, a preferred composition will include a dual-reactive crosslink agent, such as allyl methacrylate, and may also include a diallyl crosslinker, such as O-diallyl ethyl diester.
- As stated, preferred compositions will include a (meth)acrylate crosslink agent to provide the necessary structural stability to the hydrogel polymer framework. Many of these (meth)acrylate crosslink agents are known in the art of hydrogel materials. The (meth)acrylate crosslink agents include, but are not limited to, any one difunctional or multifunctional crosslink agent, and any one mixture thereof. Representative examples of such crosslinkers include, but are not limited to, tripropylene glycerol diacrylate, ethylene glycol dimethacrylate, tetraethylene glycol dimethacrylate, poly(ethylene glycol diacrylate) (PEG400 or PEG600), allyl methacrylate and the like. In addition, diacrylates and dimethacrylates of triethylene glycol, butylene glycol, neopentyl glycol, ethylene glycol, hexane-1,6-diol and thio-diethylene glycol; trimethylolpropane triacrylate, N,N′-dihydroxyethylene bisacrylamide, diallyl phthalate, triallyl cyanurate, divinylbenzene, ethylene glycol divinyl ether, or N,N′-methylene-bis-(meth)acrylamide, sulfonated divinylbenzene, divinylsulfone.
- In general, to achieve a hydrogel material that includes a proper balance of desired properties, particularly, if the hydrogel material is to be a material for a contact lens, the need for a stable hydrogel polymer framework must be balanced with the wettability and lubricity of the hydrogel surface in a physiological aqueous environment. Accordingly, in the investigation of many different compositions, one generally observes that an ideal concentration of crosslinking agent exists to obtain the desired set of properties.
- The described dual-reactive monomers are particularly designed for hydrogel formulations that include at least one N-vinyl lactam monomer as the at least one vinyl monomer. Illustrative examples of N-vinyl lactams that are present in the hydrogel formulations, include but not limited to, N-vinyl-2-pyrrolidinone (NVP), N-(1-methyl vinyl) pyrrolidinone, N-vinyl-2-piperidone and N-vinyl-2-caprolactam, each of which can be substituted in the lactam ring by one or more lower alkyl groups such as methyl, ethyl or propyl, e.g., N-vinyl-5-methyl pyrrolidinone, N-vinyl-3,3-dimethyl pyrrolidinone, N-vinyl-5-ethyl pyrrolidinone and N-vinyl-6-methyl piperidone. A preferred monomer is N-vinyl-2-pyrrolidinone. Any one of the above N-vinyl lactams can be used alone or in admixture with other lactam monomers to provide hydrogel materials with the properties of interest. Illustrative of the other lactam monomers are, for example, N-vinyl imidazole, N-vinyl succinimide, N-vinyl diglycolylimide, N-vinyl glutarimide, N-vinyl-3-morpholinone and N-vinyl-5-methyl-3-morpholinone.
- In a preferred non-silicone hydrogel material, the N-vinyl lactam monomer(s) will be used in conjunction with one or more hydrophobic and/or hydrophilic comonomers. If used in conjunction with a comonomer, the N-vinyl lactam will constitute at least 60% of the copolymer and more preferably from 70% to 90% by weight of the total monomers present in the monomer formulation. Furthermore, the ratio of hydrophobic comonomer to hydrophilic comonomer present in a monomer formulation in preparing the N-vinyl lactam, can be varied as desired to obtain the combination of polymer properties desired for the particular application. The preferred amount of N-vinyl lactam in the polymer composition is 70 to 90 percent by weight to achieve a relatively high-water content of 70% to 90% by weight.
- As stated, the (meth)acrylate monomers polymerize very rapidly while the at least one vinyl monomer, polymerizes relatively slowly and fail to effectively copolymerize resulting in a high level of uncrosslinked poly(NVP), the latter of which is released from the hydrogel resulting in a loss of dimensional stability and a loss of surface wettability. The dual-reactive crosslink agents such as allyl methacrylate or methacrylate vinyl carbonate allows one to control the amount of crosslinking of the formed poly(NVP) with the hydrogel network, and in particular the crosslinking with the (meth)acrylate polymers of the network. The control of crosslink density is important because it affects the wettability, lubricity, tear strength, extractables and dimensional stability of the resulting hydrogel material. Due to the dual-reactive sites of the described crosslink agents, the agents form a crosslink between the essentially (meth)acrylate homopolymer and the essentially vinyl homopolymer resulting in hydrogel materials that possess low extractables and excellent dimensional stability.
- The resulting hydrogel materials possess a highly wettable hydrogel “surface” enriched with the slow reacting monomer/polymer component. This is a particularly important strategy for silicone hydrogels, since wetting in these systems due to the hydrophobic nature of silicone can be problematic. The dual reactivity approach also allows for the surface enrichment, or exposure, of chemical functionality capable of providing for improved clinical performance. This functionality can be bioinspired in nature and is a key advantage of this invention. For example, the addition of a monomer, such as those described within this application, which copolymerizes well with NVP, will result in a zwitterionic enriched lens surface. Hydrogel materials with this surface functionality are known to exhibit such characteristics as a low affinity for proteins, lipids, and bacteria. In addition, the use of bioinspired fast reacting methacrylate-based monomer combined with a silicone-based monomer can provide for improved wetting and compatibility with the PVP reacting phase.
- The chemistry of hydrogels is well known and there exists a variety of monomers that can be used to make the hydrogel materials. Monomers of interest to the contact lens art include acrylate, acrylamide, methacrylate, methacrylamide, styrene-containing monomers, dimethacrylate and dimethacrylamide monomers, vinyl amide-containing monomers, vinyl carbonate/carbamate/urea monomers, and (meth)acrylate/(meth) acrylamide-capped prepolymers. All of the above-mentioned monomers and prepolymers may further include polysiloxanes and polyfluorosiloxanes, such as ethylenically terminated methacrylate capped urethane-containing polysiloxane prepolymers, fluorine containing polysiloxanes, polyether containing siloxanes, and polysiloxanes monomers, such as, α,ω-bis(methacryloxybutyl) polysiloxane (M2 D25).
- Suitable monomers may be represented by the general formulae:
- wherein X is O or NRa, where Ra is hydrogen, C1-C4 alkyl or C1-C3 alkanol; R1 is H or CH3; and R2 and R3 are independently hydrogen, a C1-C18 alkyl, C3-C18 cycloalkyl, C3-C18 cycloalkylalkyl, C3-C18 cycloalkenyl, C5-C30 aryl, C5-C30 arylalkyl, C1-C18 alkyl siloxysilane or C1-C18 alkyl siloxane, each of which can be optionally substituted, linear or branched, or R2 and R3 together with the nitrogen atom to which they are bonded are joined together to form a heterocyclic group.
- The compositions of interest can also include other hydrophilic monomers that are well known in the contact lens art, and include, but not limited to, 2-hydroxyethyl methacrylate (HEMA), glyceryl monomethacrylate (GM) and 2-acrylamido-2-methyl propane sulfonic acid (AMPS). Examples of other hydrophilic monomers useful for polymerization with the vinyl monomer include, but are not limited to, unsaturated carboxylic acids, e.g., acrylic acids, methacrylic acids and the like; (meth)acrylic substituted alcohols, e.g., 3-hydroxypropyl methacrylate, 3-hydroxypropyl acrylate and the like. Still other hydrophilic monomers include the azetidinium and the oxazolone-based monomers disclosed in U.S. Pat. No. 4,910,277, the disclosure of which is herein incorporated by reference.
- As noted, the additional hydrophilic monomers are typically (meth)acrylate monomer, and therefore, will preferentially copolymerize with other (meth)acrylate monomer in the composition with a similar free-radical rate of reactivity. Hydrophilic monomer with hydroxyl functionality is of interest because the hydroxyl functionality can provide additional surface wettability of the resulting hydrogel material. A particular monomer of interest is 2-hydroxyl ethyl methacrylate, which can be present in the composition from 5% to 30% by weight. In a preferred composition, the N-vinyl-2-pyrrolidone is present from 30% to 90% by weight, and the 2-hydroxyl ethyl methacrylate is present from 0.5% to 30% by weight.
- In the absence of any one silicone-containing monomer, the hydrogels formed are referred to in the art as conventional hydrogels. However, silicone hydrogels is another class of hydrogel materials of importance in the field of medical devices. Accordingly, it can be of interest to include one or more silicone-containing monomers in a composition of interest. Some well-known silicone-containing monomers include the TRIS-like and trisiloxane (siloxy silane) monomers represented by the following structures:
- wherein h is 1 to 18 and each R3 independently denotes a lower alkyl radical, or phenyl radical. Representative examples of such acrylate ester and/or methacrylate ester-containing monomers include 3-methacryloyloxypropyltris(trimethylsiloxy)silane or (3-methacryloyloxy-2-hydroxypropyloxy)propylbis(trimethylsiloxy)-methylsilane), sometimes referred to as TRIS and SIGMA, respectively, and are commercially available from such sources as Gelest, Inc. (Morrisville, PA). Other examples of siloxy silanes include, pentamethyldisiloxanyl methylmethacrylate, phenyltetramethyl-disiloxanylethyl acrylate, methyldi(trimethylsiloxy) methacryloyloxymethyl silane, 3-[tris(trimethylsiloxy)silyl]propyl vinyl carbamate, 3[tris(trimethylsiloxy)silyl]propyl allyl carbamate, and 3-tris(trimethylsiloxy)silyl] propyl vinyl carbonate.
- Silicone monomers referred in the art as silicone monofunctional monomer can also be included in the described compositions. See, U.S. Pat. No. 8,937,110 to Vanderlaan, the disclosure of which is herein incorporated by reference. Examples of some silicone monofunctional monomer include monomethacryloyloxyalkyl-polydimethylsiloxane methacrylates selected from the group consisting of monomethacryloyloxypropyl terminated mono-n-butyl terminated polydimethylsiloxane, monomethacryloyloxypropyl terminated mono-methyl terminated polydimethylsiloxane, monomethacryloyloxypropyl terminated mono-n-butyl terminated polydiethylsiloxane, monomethacryloyloxypropyl terminated mono-n-methyl terminated polydiethylsiloxane, N-(2,3-dihydroxypropane)-N′-(propyltetra(dimethylsiloxy)-dimethylbutylsilane) acrylamide, α-(2-hydroxy-1-methacryloyloxypropyloxypropyl)-o-butyl-decamethyl-pentasiloxane, and mixtures thereof.
- In another embodiment the silicone monofunctional monomer is selected from the group consisting of monomethacryloyloxypropyl terminated mono-n-butyl terminated polydimethylsiloxane, monomethacryloyloxypropyl terminated mono-n-methyl terminated polydimethylsiloxane, N-(2,3-dihydroxypropane)-N′-(propyl tetra(dimethylsiloxy) dimethylbutylsilane)acrylamide, α-(2-hydroxy-l-methacryloxypropyloxypropyl)-o-butyl-decamethyl-lpentasiloxane, and mixtures thereof.
- The at least one silicone-containing monomer is present in the silicone hydrogel described compositions in an amount sufficient to provide the desired oxygen permeability. It is a benefit of the present invention that oxygen permeabilities greater than about 60 Barrers, greater than about 80 Barrers, and in some embodiments greater than about 90 Barrers can be achieved. Suitable amounts will depend on the length of the siloxane chain included in the silicone-containing monomers, with silicone-containing monomers having longer chains requiring less monomer. Amounts include from 20% to 60% by weight, and in some embodiments from about 30% to 55% by weight.
- In certain silicone hydrogel compositions, one or more of the silicone-containing monomers above are present in a composition from 25% to 80% by weight, or from 20% to 80% by weight. In a preferred composition, the N-vinyl-2-pyrrolidone is present from 50% to 90% by weight, 2-hydroxyl ethyl methacrylate is present from 0.5% to 25% by weight, and the silicone-containing monomer is present from 30% to 70% by weight.
- Specific bioinspired monomers include, but not limited to, carboxybetaines, sulfobetaines and phosphobetaines, such as methacryloyloxy phosphatidyl choline (MPC), N-vinylcarboxy ethyl phosphatidyl choline, 0-vinyl ethyl phosphatidyl choline carbonate, 1-(3-sulfopropyl)-2-vinylpyridinium betaine, 3-dimethyl(acryloyloxyethyl) ammonium propyl sulfonate, functional sugars and proteins, or any one mixture of bioinspired monomer. Other suitable bioinspired hydrophilic monomers will be apparent to one skilled in the art.
- Useful hydrophobic monomers for use herein include, but are not limited to, alkyl acrylates and methacrylates, 4-t-butyl-2-hydroxy cyclohexyl methacrylate (TBE), tert-butyl cyclohexyl methacrylate, isopropylcyclopentyl acrylate, tert-butylcyclohexyl acrylate, isobornyl methacrylate and the like; 2-ethylhexyl methacrylate, 2-phenyloxyethyl methacrylate, partially fluorinated acrylates, partially fluorinated methacrylates and the like and mixtures thereof.
- In general, the copolymerization reaction can be conducted neat or with a suitable cosolvent. The monomeric mixture and optional crosslinking agent(s) are combined in the desired ratio, and then exposed to, for example, ultraviolet (UV) light or electron beams in the presence of one or more photo initiator(s) or at a suitable temperature, for a time sufficient to form the copolymer. Heat may also be employed to initiate the polymerization in which case a series of Vazo, peroxide or peroxy initiators, well-known in the art, may be used. Suitable reaction times will ordinarily range from about 1 minute to about 24 hours and preferably from about 1 hour to about 10 hours.
- The use of UV or visible light in combination with photo initiators is well known in the art and is particularly suitable for formation of the copolymer. Numerous photo initiators of the type in question here are commercial products. Photo initiators enhance the rapidity of the curing process when the photo curable compositions are exposed to, for example, ultraviolet radiation. Suitable photo initiators which are useful for polymerizing the polymerizable mixture of monomers can be commercially available photo initiators. They are generally compounds which can initiate the radical reaction of olefinically unsaturated double bonds on exposure to light with a wavelength of, for example, about 260 to about 480 nm.
- Examples of suitable photo initiators for use herein include, but are not limited to, one or more photo initiators commercially available under the “IRGACURE®”, “DAROCURC®” and “SPEEDCURE®” trade names (manufactures by Ciba Specialty Chemicals, also obtainable under a different name from BASF, Fratelli Lamberti and Kawaguchi), e.g., “IRGACUREC®” 184 (1-hydroxycyclohexyl phenyl ketone), 907 (2-methyl-1-[4-(methylthio)phenyl]-2-morpholino propan-1-one), 369 (2-benzyl-2-N,N-dimethylamino-1-(4-morpholinophenyl)-1-butanone), 500 (the combination of 1-hydroxy cyclohexyl phenyl ketone and benzophenone), 651 (2,2-dimethoxy-2-phenyl acetophenone), 1700 (the combination of bis(2,6-dimethoxybenzoyl-2,4,4-trimethyl pentyl)phosphine oxide and 2-hydroxy-2-methyl-1-phenyl-propan-1-one), and 819 [bis(2,4,6-trimethyl benzoyl)phenyl phosphine oxide] and “DAROCUR®” 1173 (2-hydroxy-2-methyl-1-phenyl-1-propan-1-one) and 4265 (the combination of 2,4,6-trimethylbenzoyldiphenyl-phosphine oxide and 2-hydroxy-2-methyl-1-phenyl-propan-1-one); and the like and mixtures thereof. Other suitable photo initiators for use herein include, but are not limited to, alkyl pyruvates such as methyl, ethyl, propyl, and butyl pyruvates, and aryl pyruvates such as phenyl, benzyl, and appropriately substituted derivatives thereof. Generally, the amount of photo initiator can range from about 0.05% w/w to about 5% w/w and preferably from about 0.1% w/w to about 1% w/w.
- Examples of suitable thermal initiators for use herein include, but are not limited to, include the azo and peroxy type compounds, such as 2,2-azobisisobutyronitrile (VAZO 64), 4,4-azobis(4-cyanovaleric acid), 1,1-azobis(cyclohexanecarbonitrile), benzoyl peroxide, 1,1-bis(tert-butylperoxy)cyclohexane, tert-butyl hydroperoxide, tert-butyl peroxybenzoate and dicumyl peroxide. Generally, the amount of thermal initiator can range from about 0.05% w/w to about 5% w/w and preferably from about 0.1% w/w to about 1% w/w.
- An organic diluent (solvent) can be included in any one composition of interest. As used herein, the term “organic diluent” encompasses organic compounds which minimize incompatibility of the components in the monomeric mixture and are substantially nonreactive with the components in the mixture. Additionally, the organic diluent serves to minimize phase separation of polymerized products produced by polymerization of the monomeric mixture. Also, the organic diluent will generally be relatively non-flammable. Contemplated organic diluents include alcohols such as tert-butanol (TBA), tert-amyl alcohol, diols, such as ethylene glycol; and polyols, such as glycerol. Preferably, the organic diluent is water soluble and can be removed easily through a water extraction process. Other suitable organic diluents would be apparent to a person of ordinary skill in the art.
- The organic diluent is included in an amount effective to provide the desired effect (for example, minimal phase separation of polymerized products). Generally, the diluent is included at 0 to 60% by weight of the monomeric mixture, with 1 to 40% by weight being more preferred, 2 to 30% by weight being even more preferred and 3 to 25% by weight being especially preferred.
- The compositions described can also include at least one UV absorbing compound. Suitable UV absorbers may be derived from 2-(2′-hydroxyphenyl)benzotriazoles, 2-hydroxybenzophenones, 2-hydroxyphenyltriazines, cyanoacrylates, salicylates and 4-hydroxybenzoates; which may be further reacted to incorporate reactive polymerizable groups, such as (meth)acrylates. Specific examples of UV absorbers which include polymerizable groups include 2-(2′-hydroxy-5-methacryloyloxyethylphenyl)-2H-benzotriazole (Norbloc), 5-vinyl and derivatives of 2-(2,4-dihydroxyphenyl)-2H-benzotriazole and 4-acrylates or 4-methacrylates of 2-(2,4-dihydroxyphenyl)-2H-benzotriazole or 2-(2,4-dihydroxyphenyl)-1,3-2H-dibenzotriazole, mixtures thereof and the like. When a UV absorber is included, it may be included in amounts between 0.5% and 4% by weight, and suitably between 1% and 2% by weight.
- The present invention relates to monomeric formulations useful in the manufacture of biocompatible medical devices. More particularly, the present invention relates to hydrogel formulations capable of polymerization to form polymeric compositions having desirable physical characteristics useful in the manufacture of contact lenses. Such properties include low modulus of elasticity, a high level of oxygen permeability, wettability, lubricity, and a low level of extractables. Further, the monomers possess unique zwitterionic functionally designed to minimize attachment of bacteria, viruses, and other environment debris.
- The compositions described herein can be used to make hydrogel materials for a biomedical device such as artificial heart valves, films, surgical devices, vessel substitutes, intrauterine devices, membranes, diaphragms, surgical implants, artificial blood vessels, artificial ureters, artificial breast tissue and membranes intended to come into contact with body fluid outside of the body, e.g., membranes for kidney dialysis and heart/lung machines and the like, catheters, mouth guards, denture liners, ophthalmic devices, and especially hydrogel contact lenses.
- As used herein, a “biomedical device” is any article that is designed to be used while either in or on mammalian tissues or fluid, and in one embodiment in or on human tissue or fluids. Examples of these devices include but are not limited to catheters, implants, stents, and ophthalmic devices such as intraocular lenses, punctal plugs and contact lenses.
- The examples should not be read as limiting the scope of the invention as defined in the claims. Unless clearly stated otherwise all numerical percentages, e.g., percentage amounts of monomer in a polymerization mixture, are listed as weight percent.
- As described earlier, lens formation can be by free radical polymerization such as azobisisobutyronitrile (AIBN) and peroxide catalysts using initiators and under conditions such as those set forth in U.S. Pat. No. 3,808,179, incorporated herein by reference. Photoinitiation of polymerization of the monomer mixture as is well known in the art may also be used in the process of forming an article as disclosed herein. The manufacture of contact lenses is performed via cast molding, spin casting, or rod-lathing techniques-all well-known in the industry.
- The examples should not be read as limiting the scope of the invention as defined in the claims. Unless clearly stated otherwise all numerical percentages, e.g., percentage amounts of monomer in a polymerization mixture, are listed as weight percent.
- TRIS: 3-methacryloyloxy propyl tris (trimethyl siloxy) silane
- Sigma: 3-(3-methacryloyloxy-2-hydroxypropoxybis (trimethylsiloxy) methyl silane
- Mono: methacryloyloxy ethyl ether propyl mono capped polysiloxane (average DP of 15) possessing a mono butyl terminus.
- HEMA: 2-hydroxyethyl methacrylate
- NVP: N-vinyl pyrrolidinone
- TBCM: 4-t-butyl cyclohexyl methacrylate
- XL TEGDMA: cross-linker tetra ethylene glycol dimethacrylate
- XL AMa: Allyl methacrylate: dual phase cross-linker methacrylic acid allyl ester
- TAA: t-amyl alcohol diluent
- Vazo 64: 2,2′-azobis (2-methyl propionitrile)
-
- N,N, Diallyl-N-methylamine (4) (0.9 mol), ethyl 4-bromobutyrate (0.99 mol), and acetonitrile (500 mL) were de-aerated by multiple freeze-pump-thaw cycles, combined, and allowed to react under reflux with stirring for 60 h. Acetonitrile was removed under vacuum, and the resulting oil was washed continuously with ether for 5 days utilizing a liquid-liquid extractor. The oil was then lyophilized to remove any associated water. The ammonium bromide solid (mp 47-49° C.), was obtained in 85% yield. Elemental microanalysis for C12H24NO2Br. Calculated: C, 50.99%; H, 7.90%; N, 4.57%; Br, 26.09%. Found: C, 50.85%; H, 7.97%; N, 4.58%; Br, 26.33%. The ammonium bromide intermediate was then dissolved in deionized water and passed over an Amberlite IRA-400-(OH—) ion-exchange resin to yield the carboxy betaine monomer, in quantitative yield. The structure was confirmed by 1H and 13C NMR spectroscopy.
-
- To a flame-dried, round bottom flask is added diallyl methyl amine and 1,4, butane sultone (1.0 equivalent) in toluene under a N2 atmosphere. The flask is heated to 70° C. for 5 hours at which time the diallyl sulfobetaine precipitate was collected via filtration, washed with acetone and vacuum dried resulting in an 80% yield of product.
-
- The starting material dimethyl amino ethyl allyl ester was prepared in high yield and purity via the esterification of the dimethyl amino ethyl methyl ester. The resultant product was added to propiolactone (1.2 equivalent) in acetone at 15° C. for five hours. The resultant ring-opened product was devolatilized under high vacuum to remove the unreacted cyclic lactone. The final product was obtained in in 85% yield with structure confirmation via H-NMR.
-
- To a flame-dried, round bottom flask is added the reaction product of allyl alcohol and the cyclic lactone prepared using identical reaction conditions as described in example 3 together with an equivalent amount of triethylamine and acetonitrile. The solution is cooled to −15 C and the chloro phospholane is added slowly in a solution of acetonitrile. After five hours of reaction, the amine precipitate is removed by filtration and the solution is evaporated under reduced pressure. To the residue, 50 ml of dry ethyl ether were added to precipitate a small amount of remaining triethylammonium chloride which was removed by filtration The allyl ester phosphatidyl choline product is obtained in high yield and purity as determined by H-NMR.
-
- The starting material dimethyl amino ethyl N-vinyl carbamate was prepared in high yield and purity via the reaction of vinyl isocyanate with hydroxyl ethyl dimethylamine. The resultant product was added to propiolactone (1.2 equivalent) in acetone at 15° C. for five hours. The resultant ring-opened product was devolatilized under high vacuum to remove the unreacted cyclic lactone. The final product was obtained in in 85% yield with structure confirmation via H-NMR.
-
- The starting material dimethyl amino ethyl N-vinyl carbamate was prepared in high yield and purity via the reaction of vinyl chloro formate with hydroxyl ethyl dimethylamine. The resultant product was added to propiolactone (1.2 equivalent) in acetone at 15° C. for five hours. The resultant ring-opened product was devolatilized under high vacuum to remove the unreacted cyclic lactone. The final product was obtained in high yield with structure confirmation via H-NMR.
- Hydrogel contact lenses are prepared with the inventive chemistry. The monomer formulation mixture is prepared in a dry box (rel. hum. of approx. 10%). The mixed formulation is added to polypropylene lens molds in the dry box, and the filled molds are placed in an oven at room temperature and purged with nitrogen for 30 minutes. The nitrogen atmosphere is maintained for the entire cure protocol at a level of 100 ppm. The oven temperature is raised to 60° C. (10° C./min ramp rate) and the temperature maintained at 60° C. for 2 hrs. The oven temperature is raised to 80° C. (10° C./min ramp rate) and the temperature maintained at 80° C. for 2 hrs. The oven temperature is raised to 100° C. (10° C./min ramp rate) and the temperature maintained at 100° C. for 2 hrs. The oven temperature is then lowered to 55° C. over the next hour. The lenses are removed from the oven and allowed to cool to room temperature in the dry box. The lenses are dry released from the molds. Alternatively, the lenses can be wet released from the mold. Dry release or wet release methods are well known to those of ordinary skill in the contact lens art.
- Once released from the molds, the lenses are extracted 3×/10 min with distilled water with exchange of fresh water per cycle. The lenses are then extracted 3×/10 min with borate-buffered saline (pH 6.8-7.2, osmolality 270-320) with exchange of fresh BBS per cycle and packaged in BBS.
- Monomer mixtures, 9A through 9E, as shown in Table 1 are prepared by mixing the following components: NVP, TBCM, allyl ester carboxy betaine from example 3, HEMA, allyl methacrylate and Vazo 64 initiator. The resultant monomeric mixture is cast in a polypropylene contact lens mold and thermally cured in accordance with the procedure as described in Example 8. The resultant contact lens materials are transparent and highly wettable.
-
TABLE 1 Non-silicone Hydrogel Formulations Example 9A 9B 9C 9D 9E NVP 83.9 80.9 78.9 85.9 80.9 TBCM 10 10 10 8 8 Allyl ester carboxy betaine (Example 3) 1 3 5 1 5 HEMA 5 5 5 5 5 XL AMa 0.1 0.1 0.1 0.1 0.1 Vazo 64 0.1 0.1 0.1 0.1 0.1 - Monomer mixtures, 10A through 10E, as shown in Table 2 are prepared by mixing the following components: NVP, Tris Methacrylate, Sigma, Mono the allyl ester carboxy betaine or the diallyl carboxy betaine together with the crosslinkers TEGDMA and allyl methacrylate and a Vazo 64 initiator. The resultant monomeric mixture is cast in a polypropylene contact lens mold and thermally cured in accordance with the procedure as described in Example 8. The resultant contact lens materials are transparent and highly wettable.
-
TABLE 2 Siloxy Silane Hydrogel Formulations Example 10A 10B 10C 10D 10E NVP 49 47 45 49 45 TRIS 15 15 15 15 15 Sigma 20 20 20 20 20 Mono 15 15 15 15 15 Allyl ester carboxy 1 3 5 0 0 betaine (Example 3) Diallyl carboxy 0 0 0 1 5 betaine (Example 1) Allyl methacrylate 0.1 0.1 0.1 0.1 0.1 XL TEGDMA 0.5 0.5 0.5 0.5 0.5 TAA 2.5 2.5 2.5 2.5 2.5 Vazo 64 0.5 0.5 0.5 0.5 0.5
Claims (12)
1. A composition comprising a monomer having the structure as shown in Formula
wherein:
R1 is selected from the group as shown below in formulas (II)-(VIII):
wherein Y1 and Y2 are independent of one other and each on of Y1 and Y2 is a linkage selected from the group consisting of a direct bond, C1-C6 divalent radical, O, NW, C(O), C(O)NRa, NRaC(O), OC(O)NH, NHC(O)O, NRaC(O)NH, NHC(O)NRa, C(O)O, OC(O), NHC(O)NHZ0—NH—C(O)NH, OC(O)NHZ0—NH—C(O)O, OC(O)NHZ0—NH—C(O)NH, and NHC(O)NHZ0—NH—C(O)O; where Ra is H, C1-C4 alkyl or C1-C3 alkanol, and Z0 is a linear or branched C2-C12 alkylene divalent radical, or a C5-C7 cycloaliphatic divalent radical;
wherein Z1 is selected from the group consisting of a direct bond, a C1-C12 unsubstituted or substituted, linear or branched alkylene divalent radical, an unsubstituted phenylene divalent radical, a C5-C7 cycloaliphatic divalent radical, and a C7-C12 arylalkylene divalent radical, wherein at least two of the groups Y1, Y2, Z1 and Z2 is not a direct bond,
wherein R2 for formulas II-VII is selected from the group of zwitterionic functionality as shown in the following formulas:
where R is selected from the group consisting of a direct bond, C1-C6 divalent radical, O, NRa, C(O), C(O)NRa, NRaC(O), OC(O)NH, NHC(O)O, NRaC(O)NH, NHC(O)NRa, C(O)O, OC(O), NHC(O)NHZ0—NH—C(O)NH, OC(O)NHZ0—NH—C(O)O, OC(O)NHZ0—NH—C(O)NH, and NHC(O)NHZ0—NH—C(O)O; where Ra is H, C1-C4 alkyl or C1-C3 alkanol, and Z0 is a linear or branched C2-C12 alkylene divalent radical, or a C5-C7 cycloaliphatic divalent radical;
wherein in the case of the structure VIII, R2 is selected from the following anionic groups to provide a zwitterionic monomer capable of cyclo-copolymerizing:
where R is selected from the group consisting of a direct bond, C1-C6 divalent radical, O, NRa, C(O), C(O)NRa, NRaC(O), OC(O)NH, NHC(O)O, NRaC(O)NH, NHC(O)NRa, C(O)O, OC(O), NHC(O)NHZ0—NH—C(O)NH, OC(O)NHZ0—NH—C(O)O, OC(O)NHZ0—NH—C(O)NH, and NHC(O)NHZ0—NH—C(O)O; where Ra is H, C1-C4 alkyl or C1-C3 alkanol, and Z0 is a linear or branched C2-C12 alkylene divalent radical, or a C5-C7 cycloaliphatic divalent radical.
2. The composition of claim 1 further comprising at least one vinyl monomer selected from the group consisting of N-vinyl-2-pyrrolidone, N-vinyl piperidone, N-vinyl-caprolactam, N-vinylimidazolidone, N-vinylsuccinimide, N-vinylformamide, N-vinyl urea, N-vinylcarbamate, O-vinyl carbonate and any one mixture thereof.
3. The composition of claim 1 , further comprising at least one (meth)acrylic monomer.
4. The composition of claim 3 , wherein the (meth)acrylic monomer is 4-t-butyl-2-hydroxycyclohexylmethacrylate or another cycloaliphatic strengthening agents.
5. The composition of claim 3 , wherein the(meth)acrylic monomers include functional monomers selected from the group consisting of carboxybetaines, sulfobetaines and phosphobetaines.
6. The composition of claim 1 further comprising silicone monomers selected from the group consisting of Tris-(trimethylsiloxy)-3-methacryloxypropyl methacrylate (Tris), 3-methacryloxy-2-hydroxypropyloxy) propylbis(trimethylsiloxy)-methylsilane (Sigma), and other siloxy silane monomers, and mixture thereof, wherein the mixture thereof is present from 8% to 60% by weight of the composition.
7. The composition of claim 1 further comprising silicone prepolymers selected from the group consisting of mono or difunctional polydimethyl siloxanes and mixtures thereof present from 8% to 60% by weight of the composition.
8. The composition of claim 1 , wherein Z1 is a branched alkylene divalent radical that includes one or more linkages of O, NRa, and C(O).
9. The composition of claim 1 , further comprising a crosslinking agent.
10. A hydrogel polymer prepared from the composition of claim 1 .
11. The hydrogel polymer of claim 10 with a water content of 30 to 90 wt percent.
12. A contact lens prepared with the hydrogel polymer according to claim 10 .
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