WO2013020917A1 - Ophthalmologic composition comprising an aqueous solution of at least one viscoelastic polysaccharide - Google Patents
Ophthalmologic composition comprising an aqueous solution of at least one viscoelastic polysaccharide Download PDFInfo
- Publication number
- WO2013020917A1 WO2013020917A1 PCT/EP2012/065248 EP2012065248W WO2013020917A1 WO 2013020917 A1 WO2013020917 A1 WO 2013020917A1 EP 2012065248 W EP2012065248 W EP 2012065248W WO 2013020917 A1 WO2013020917 A1 WO 2013020917A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- polysaccharide
- dye
- alkoxy
- alkyl
- crc
- Prior art date
Links
- 239000005017 polysaccharide Substances 0.000 title claims abstract description 95
- 229920001282 polysaccharide Polymers 0.000 title claims abstract description 94
- 239000000203 mixture Substances 0.000 title claims abstract description 91
- 239000007864 aqueous solution Substances 0.000 title claims abstract description 10
- 150000004676 glycans Chemical class 0.000 title abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 150000004804 polysaccharides Chemical class 0.000 claims description 91
- 239000000975 dye Substances 0.000 claims description 90
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 36
- 229920002674 hyaluronan Polymers 0.000 claims description 33
- 229960003160 hyaluronic acid Drugs 0.000 claims description 33
- -1 aminophenyl Chemical group 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 125000003277 amino group Chemical group 0.000 claims description 23
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 238000006058 Ugi-reaction Methods 0.000 claims description 15
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 12
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 12
- 239000000985 reactive dye Substances 0.000 claims description 12
- 125000000524 functional group Chemical group 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 229910021653 sulphate ion Inorganic materials 0.000 claims description 7
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 125000004104 aryloxy group Chemical group 0.000 claims description 6
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 229940047889 isobutyramide Drugs 0.000 claims description 6
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 6
- 229940080818 propionamide Drugs 0.000 claims description 6
- 150000003254 radicals Chemical class 0.000 claims description 6
- BUSZLIXFVJAMHW-UHFFFAOYSA-N 3-aminoanthracene-1,2-dione Chemical compound C1=CC=C2C=C(C(=O)C(C(N)=C3)=O)C3=CC2=C1 BUSZLIXFVJAMHW-UHFFFAOYSA-N 0.000 claims description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- 125000006850 spacer group Chemical group 0.000 claims description 5
- IEWUCHDAMHJMRT-UHFFFAOYSA-N 3-nitro-2-phenyldiazenylaniline Chemical class NC1=CC=CC([N+]([O-])=O)=C1N=NC1=CC=CC=C1 IEWUCHDAMHJMRT-UHFFFAOYSA-N 0.000 claims description 4
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 229920001287 Chondroitin sulfate Polymers 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- FPJHWYCPAOPVIV-VOZMEZHOSA-N (2R,3S,4R,5R,6R)-6-[(2R,3R,4R,5R,6R)-5-acetamido-2-(hydroxymethyl)-6-methoxy-3-sulfooxyoxan-4-yl]oxy-4,5-dihydroxy-3-methoxyoxane-2-carboxylic acid Chemical compound CO[C@@H]1O[C@H](CO)[C@H](OS(O)(=O)=O)[C@H](O[C@@H]2O[C@H]([C@@H](OC)[C@H](O)[C@H]2O)C(O)=O)[C@H]1NC(C)=O FPJHWYCPAOPVIV-VOZMEZHOSA-N 0.000 claims description 2
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 claims description 2
- 229920000945 Amylopectin Polymers 0.000 claims description 2
- 229920000856 Amylose Polymers 0.000 claims description 2
- 229920000018 Callose Polymers 0.000 claims description 2
- 229920001661 Chitosan Polymers 0.000 claims description 2
- 229920000045 Dermatan sulfate Polymers 0.000 claims description 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- 229920002683 Glycosaminoglycan Polymers 0.000 claims description 2
- 229920002971 Heparan sulfate Polymers 0.000 claims description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 2
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 claims description 2
- 229920000288 Keratan sulfate Polymers 0.000 claims description 2
- 239000000783 alginic acid Substances 0.000 claims description 2
- 229920000615 alginic acid Polymers 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
- 229960001126 alginic acid Drugs 0.000 claims description 2
- 150000004781 alginic acids Chemical class 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 239000007853 buffer solution Substances 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920003086 cellulose ether Polymers 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229920000669 heparin Polymers 0.000 claims description 2
- 229960002897 heparin Drugs 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- KXCLCNHUUKTANI-RBIYJLQWSA-N keratan Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@H](COS(O)(=O)=O)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@H](O[C@@H](O[C@H]3[C@H]([C@@H](COS(O)(=O)=O)O[C@@H](O)[C@@H]3O)O)[C@H](NC(C)=O)[C@H]2O)COS(O)(=O)=O)O[C@H](COS(O)(=O)=O)[C@@H]1O KXCLCNHUUKTANI-RBIYJLQWSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000003586 protic polar solvent Substances 0.000 claims description 2
- 229920001285 xanthan gum Polymers 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- 229920000609 methyl cellulose Polymers 0.000 claims 1
- 239000001923 methylcellulose Substances 0.000 claims 1
- 238000011161 development Methods 0.000 description 15
- 230000018109 developmental process Effects 0.000 description 15
- 210000001519 tissue Anatomy 0.000 description 13
- 238000001356 surgical procedure Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- 210000000695 crystalline len Anatomy 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- 210000002159 anterior chamber Anatomy 0.000 description 6
- 239000008154 viscoelastic solution Substances 0.000 description 6
- 208000002177 Cataract Diseases 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- 239000004971 Cross linker Substances 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- 0 *c(c(*)c1*)c(*)c(C(c2c3c(*)c(*)c(*)c2*)=O)c1C3=O Chemical compound *c(c(*)c1*)c(*)c(C(c2c3c(*)c(*)c(*)c2*)=O)c1C3=O 0.000 description 3
- DVCMHLZPRDGHKK-UHFFFAOYSA-N 1-amino-4-hydroxy-2-(2-methoxyethoxy)anthracene-9,10-dione Chemical compound C1=CC=C2C(=O)C3=C(N)C(OCCOC)=CC(O)=C3C(=O)C2=C1 DVCMHLZPRDGHKK-UHFFFAOYSA-N 0.000 description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000008033 biological extinction Effects 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 238000007306 functionalization reaction Methods 0.000 description 3
- 238000003541 multi-stage reaction Methods 0.000 description 3
- KUIXZSYWBHSYCN-UHFFFAOYSA-L remazol brilliant blue r Chemical compound [Na+].[Na+].C1=C(S([O-])(=O)=O)C(N)=C2C(=O)C3=CC=CC=C3C(=O)C2=C1NC1=CC=CC(S(=O)(=O)CCOS([O-])(=O)=O)=C1 KUIXZSYWBHSYCN-UHFFFAOYSA-L 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000004593 Epoxy Substances 0.000 description 2
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- VPKDCDLSJZCGKE-UHFFFAOYSA-N carbodiimide group Chemical group N=C=N VPKDCDLSJZCGKE-UHFFFAOYSA-N 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 229940059329 chondroitin sulfate Drugs 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical class C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 2
- 210000000871 endothelium corneal Anatomy 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 150000003138 primary alcohols Chemical group 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 2
- RRETZLLHOMHNNB-UHFFFAOYSA-M sodium;1-amino-9,10-dioxo-4-(2,4,6-trimethylanilino)anthracene-2-sulfonate Chemical compound [Na+].CC1=CC(C)=CC(C)=C1NC1=CC(S([O-])(=O)=O)=C(N)C2=C1C(=O)C1=CC=CC=C1C2=O RRETZLLHOMHNNB-UHFFFAOYSA-M 0.000 description 2
- 230000004304 visual acuity Effects 0.000 description 2
- FRASJONUBLZVQX-UHFFFAOYSA-N 1,4-naphthoquinone Chemical compound C1=CC=C2C(=O)C=CC(=O)C2=C1 FRASJONUBLZVQX-UHFFFAOYSA-N 0.000 description 1
- VERRKUAVICFWGH-UHFFFAOYSA-N 1-[(4-nitrophenyl)diazenyl]naphthalen-2-amine Chemical compound NC1=CC=C2C=CC=CC2=C1N=NC1=CC=C([N+]([O-])=O)C=C1 VERRKUAVICFWGH-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- YCMLQMDWSXFTIF-UHFFFAOYSA-N 2-methylbenzenesulfonimidic acid Chemical compound CC1=CC=CC=C1S(N)(=O)=O YCMLQMDWSXFTIF-UHFFFAOYSA-N 0.000 description 1
- MMNWSHJJPDXKCH-UHFFFAOYSA-N 9,10-dioxoanthracene-2-sulfonic acid Chemical compound C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 MMNWSHJJPDXKCH-UHFFFAOYSA-N 0.000 description 1
- 229920002567 Chondroitin Polymers 0.000 description 1
- ASMQGLCHMVWBQR-UHFFFAOYSA-N Diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(=O)(O)OC1=CC=CC=C1 ASMQGLCHMVWBQR-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- VERRKUAVICFWGH-VHEBQXMUSA-N Nc1ccc2ccccc2c1\N=N\c1ccc([N+]([O-])=O)cc1 Chemical compound Nc1ccc2ccccc2c1\N=N\c1ccc([N+]([O-])=O)cc1 VERRKUAVICFWGH-VHEBQXMUSA-N 0.000 description 1
- 206010036346 Posterior capsule opacification Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- DLGJWSVWTWEWBJ-HGGSSLSASA-N chondroitin Chemical compound CC(O)=N[C@@H]1[C@H](O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@H](O)C=C(C(O)=O)O1 DLGJWSVWTWEWBJ-HGGSSLSASA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- VBWIZSYFQSOUFQ-UHFFFAOYSA-N cyclohexanecarbonitrile Chemical compound N#CC1CCCCC1 VBWIZSYFQSOUFQ-UHFFFAOYSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 150000002009 diols Chemical group 0.000 description 1
- 125000000600 disaccharide group Chemical group 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000004406 elevated intraocular pressure Effects 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- KIWBPDUYBMNFTB-UHFFFAOYSA-M ethyl sulfate Chemical compound CCOS([O-])(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-M 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 230000004438 eyesight Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229920006158 high molecular weight polymer Polymers 0.000 description 1
- 150000002527 isonitriles Chemical class 0.000 description 1
- ZBKFYXZXZJPWNQ-UHFFFAOYSA-N isothiocyanate group Chemical group [N-]=C=S ZBKFYXZXZJPWNQ-UHFFFAOYSA-N 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000006452 multicomponent reaction Methods 0.000 description 1
- BXIGAWRFDMDLTL-UHFFFAOYSA-N n-(4-amino-3-methoxy-9,10-dioxoanthracen-1-yl)-4-methylbenzenesulfonamide Chemical compound C=12C(=O)C3=CC=CC=C3C(=O)C2=C(N)C(OC)=CC=1NS(=O)(=O)C1=CC=C(C)C=C1 BXIGAWRFDMDLTL-UHFFFAOYSA-N 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 238000007344 nucleophilic reaction Methods 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000001585 trabecular meshwork Anatomy 0.000 description 1
- 239000003190 viscoelastic substance Substances 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
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- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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Abstract
The invention relates to an ophthalmologic composition, comprising an aqueous solution of at least one viscoelastic polysaccharide, wherein the at least one polysaccharide is covalently bound to at least one dye. The invention also relates to a method for producing an ophthalmologic composition, in which at least one dye is covalently bound to at least one water-soluble, viscoelastic polysaccharide.
Description
Description
Ophthalmologic composition comprising an aqueous solution of at least one viscoelastic polysaccharide
Field of the invention
The invention relates to an ophthalmologic composition, comprising an aqueous 5 solution of at least one viscoelastic polysaccharide. The invention further relates to a method for producing an ophthalmologic composition.
Prior art
Cataract is a common disease especially in elderly people, where the crystalline lens gradually becomes less transparent. This opacity of the natural lens leads to the loss of visual acuity. To restore vision, cataract surgery has to be performed. In 10 a surgical step called phacoemulsification, the natural lens is destroyed and the pieces are aspirated out of the eye. In the next step, an artificial lens is injected into the eye and visual acuity is re-established.
Immediately before phacoemulsification, the anterior chamber is usually filled with an ophthalmologic composition, comprising a transparent viscoelastic solution. The i s viscoelastic ophthalmologic composition is used as a surgical aid to protect intraocular tissues (for example the corneal endothelium during phacoemulsification), as a space maintainer (for example to maintain the anterior chamber of the eye) and to facilitate intraocular maneuvers, for example to make a controlled capsulorhexis.
Viscoelastic compositions are water based solutions containing a polysaccharide 20 like hyaluronic acid, hydroxypropylmethylcellulose, chondroitin sulfate or mixtures thereof that are routinely used in cataract surgery. The viscoelastic composition might differentiate in the molecular weight of the polysaccharide dissolved in the solution, in the concentration of the polysaccharide and in the viscosity of the solution. They are generally well tolerated following brief exposure to intraocular tissues.
Most currently available ophthalmologic compositions comprising viscoelastic polysaccharides are transparent. A disadvantage of the transparency is that it is difficult to determine or control the amount and location of the ophthalmologic compositions in the eye. It is of importance that at the end of the surgery all of the ophthalmologic 5 composition is removed from the eye to prevent a trabecular meshwork obstruction and thus the elevation of intraocular pressure which may lead to glaucoma. Due to the transparency of the used polysaccharides, it is difficult to judge if residual ophthalmologic composition is still left in the eye. Furthermore, poor visibility of the viscoelastic ophthalmologic composition within the eye also prohibits exact visualiza- 10 tion of the amount injected.
EP 1 263 363 B1 suggests the use of a viscoelastic ophthalmologic composition based on aqueous solutions of hyaluronic acid and hydroxypropylmethylcellulose. To avoid the above-named problems associated with transparency the ophthalmologic solution also contains trypan blue to stain the viscoelastic solution. i s From WO 01 /66053 A1 , a further ophthalmologic composition is known, which is composed of a mixture of a viscoelastic polysaccharide with a vital dye, that is with a dye, which can be applied to living cells without killing them.
However, therein, both the trypan blue and the vital dye have to possess a substantially higher solubility in the ophthalmologic composition than in the surrounding tis- 20 sue in order not to stain the tissue. However, in particular upon longer dwell of the ophthalmologic composition in the eye, for example during surgery, it cannot be excluded that a certain proportion of the dye diffuses into the surrounding tissue and stains it. Moreover, there exist only comparatively few dyes, which can be applied to living cells without permanently damaging them.
25 It has been proposed to formulate a viscoelastic material containing fluorescein as a dye in the past (Zirm et al, British Journal of Ophthalmology 67, 1983, 259-263). These materials however did not have the desired advantages in ocular surgery. Dyes like fluorescein can diffuse out of the ophthalmologic composition, too, as a result of which they also stain the surrounding tissue. Another problem is that fluo-
30 rescein has to be irradiated with UV-light to show fluorescence and to make the viscoelastic solution visible. In order to minimize the diffusion of the dye from the ophthalmologic composition, US 4764360 A1 uses a high molecular weight polymer dye
with a molecular weight preferably exceeding 30,000 Dalton (u) to maintain the dye in the ophthalmologic solution.
Detailed description of the invention
It is the object of the present invention to improve an ophthalmologic composition of the initially mentioned type such that it is simpler and safer in application. A further 5 object of the invention is to provide a method for producing such an ophthalmologic composition.
According to the invention, the objects are solved by an ophthalmologic composition having the features of claim 1 as well as by a method for producing an ophthalmologic composition according to claim 1 1 . Advantageous developments of the inven- 10 tion are specified in the respective dependent claims, wherein advantageous developments of the ophthalmologic composition are to be regarded as advantageous developments of the method and vice versa.
In an ophthalmologic composition according to the invention, comprising an aqueous solution of at least one viscoelastic polysaccharide, it is provided that the at i s least one polysaccharide is covalently bound to at least one dye. Therein, within the scope of the invention, chemical compounds are to be understood by dye, which include at least one chromophore molecule structure, which absorbs light in the wavelength range visible to the human between about 380 nm and about 800 nm and preferably does not exhibit any fluorescence or phosphorescence. By the cova-
20 lent bond of the dye to the at least one viscoelastic polysaccharide, it is reliably excluded that the dye diffuses into adjoining tissue and undesirably stains it during use of the ophthalmologic composition. Moreover, unlike fluorescent dyes such as fluorescein, rhodamine or the like, it is not required to irradiate the ophthalmologic composition with UV light to visualize it. This allows a substantially simpler handling of
25 the ophthalmologic composition. In addition, there is a priori no risk that the concerned tissue is damaged by the irradiation with high-energy UV light. Further, a user - for example a surgeon - can even recognize minor traces without additional auxiliary means such as UV lamps or the like due to the integral coloration of the ophthalmologic composition, whereby the use of the ophthalmologic composition
30 according to the invention in addition becomes substantially simpler and safer - for example within the scope of eye surgeries. In simplest configuration, the ophthalmo-
logic composition is composed of an aqueous solution of a single viscoelastic polysaccharide, to which the dye is covalently bound. Alternatively, the ophthalmologic composition can include plural different viscoelastic polysaccharides and/or further additives. Independently thereof, it can also be provided that two or more different dyes are covalently bound to a viscoelastic polysaccharide.
In an advantageous development of the invention, it is provided that the polysaccharide is cellulose, a cellulose ether with methyl and/or ethyl and/or propyl groups, in particular hydroxypropyl methylcellulose, hydroxyethyl methylcellulose and/or me- thylcellulose, a glycosaminoglycan, in particular hyaluronic acid, chondroitin sul- phate, dermatan sulphate, heparin, heparan sulphate, keratan sulphate, alginic acid, polymannuronic acid, polyguluronic acid, polyglucuronic acid, amylose, amylopectin, callose, chitosan, polygalactomannan, dextran, xanthan and/or a mixture thereof. Hereby, in particular the viscoelastic properties of the ophthalmologic composition can be adapted to the respective purpose of employment and use in optimum man- ner. Therein, basically, it can also be provided that the ophthalmologic composition includes two or more polysaccharides of the same type, which only differ with regard to the molecular proportion of covalently bound dye.
In a further advantageous development of the invention, it is provided that the at least one dye is bound directly and/or via a spacer to the polysaccharide. Hereby, the dye can be particularly simply adapted to the present reactive groups of the concerned polysaccharide and be covalently bound to it. The use of a spacer is for example advantageous if the reactive group of the dye could not be bound to a corresponding reactive group of the polysaccharide or only within the scope of multistage reactions. Furthermore, the use of a spacer is advantageous if the absorption behavior of the dye would otherwise be affected in undesired manner by the cova- lent binding to the polysaccharide. Finally, by the use of a spacer the viscoelastic properties of the polysaccharide can be influenced as needed.
In a further advantageous development of the invention, it is provided that the at least one polysaccharide is obtainable by a reaction of the polysaccharide with at least one reactive dye from the group of modified and/or unmodified aminoanthra- cenedione and/or modified and/or unmodified nitrophenyldiazenylbenzenamine. The use of an aminoanthracenedione or of an aminoanthracenedione derivative and/or of a nitrophenyldiazenylbenzenamine or of a nitrophenyldiazenylbenzenamine de-
rivative as a dye, which is covalently bound to the polysaccharide, therein offers the advantage that the color of the viscoelastic polysaccharide and thereby of the ophthalmologic composition is specifically adjustable nearly in the entire visible wavelength range. Furthermore, these two dyes or dye groups are characterized by a great fastness to washing and light. Thus, the ophthalmologic composition is particularly simply and safely to handle and additionally has high storage stability.
In a further advantageous development of the invention, it is provided that the at least one polysaccharide is obtainable by reaction with at least one reactive dye of the general formula (I),
wherein in the general formula (I) at least one of the substituents Ri to R8 is an amino group, and the remaining substituents Ri to R8, which are different from the amino group are selected from hydrogen, halogen, d-C4-alkyl, CrC4-alkoxy, C C4- alkoxy-CrC4-alkyl, CrC4-alkyl-CrC4-alkoxy, CrC4-alkoxy-CrC4-alkoxy, aryloxy, acetamide, propionamide, butyramide, isobutyramide, sulphonate, (aminophenyl)-N- alkylacetamide, (aminophenylsulphonyl)alkyl sulphate, alkylbenzenesulphonamide, tri(alkyl)benzenamine, hydroxy, (alkylsulphonyl)benzenamine, and (alkenylsul- phonyl)benzenamine, and/or wherein at least two adjacent substituents Rx, Rx+i with x=1 to 3 and/or 5 to 7 form a 3-, 4-, 5-, 6- or 7-membered homocyclic or heterocyclic radical, wherein said cyclic radical can be unsaturated or aromatic. Therein, all of the stereoisomers, racemic mixtures and position isomers are to be considered as included. With the aid of a dye of the general formula (I), the color properties of the polysaccharide covalently bound to it can be varied within wide limits, wherein combinations of different dyes of the general formula (I) can basically also be used to achieve a specific coloration. By at least one of the radicals Ri to R8 being an amino group, the dye can additionally be coupled to a plurality of functional groups in chemically particularly simple manner. Therefore, different viscoelastic polysaccha-
rides with correspondingly different functional groups can also quickly and simply be coupled to the dye of the general formula (I) without the requirement of costly multistage reactions, thereby resulting significant cost advantages. All reactive dyes of the general formula (I) exhibit a high extinction coefficient in the visible range of the light spectrum.
In a further advantageous development of the invention, it is provided that the at least one polysaccharide is obtainable through reaction with at least one reactive dye of the general formula (II),
wherein in the general formula (II) at least one of the substituents Ri to R5 is an amino group and at least one of the substituents R6 to R 0 is a nitro group, and wherein the remaining radicals Ri to R 0, which are different from the amino group and the nitro group are selected from hydrogen, halogen, d-C4-alkyl, d-C4-alkoxy, Ci-C4-alkoxy-CrC4-alkyl, CrC4-alkyl-CrC4-alkoxy, CrC4-alkoxy-CrC4-alkoxy, ary- loxy, acetamide, propionamide, butyramide, isobutyramide, sulphonate, (amino- phenyl)-N-alkylacetamide, (aminophenylsulphonyl)alkyl sulphate, alkylbenzenesul- phonamide, tri(alkyl)benzenamine, hydroxy, (alkylsulphonyl)benzenamine, and (al- kenylsulphonyl)benzenamine, and/or wherein at least two adjacent substituents Ry, Ry+i with y=1 to 4 and/or 6 to 9 form the cyclic radical
with:
R=hydrogen, halogen, amino, hydroxyl, nitro, CrC4-alkyl, CrC4-alkoxy, C C4- alkoxy-CrC4-alkyl, CrC4-alkyl-CrC4-alkoxy, and/or CrC4-alkoxy-CrC4-alkoxy.
Therein, all of the stereoisomers, racemic mixtures and position isomers are to be considered as included. With the aid of a dye of the general formula (II), the color properties of the polysaccharide covalently bound to it can also be varied within wide limits, wherein combinations of different dyes of the general formula (II) can 5 basically also be used to achieve a specific coloration. By at least one of the radicals Ri to R5 being an amino group and at least one of the radicals R6 to R 0 being a nitro group, a particularly high extinction coefficient in the visible range of the light spectrum results. With the aid of the at least one amino group, the dye can additionally be covalently bound to a plurality of functional groups in chemically particularly sim- 10 pie manner. Therefore, different viscoelastic polysaccharides with correspondingly different functional groups can also quickly, simply be coupled to the dye of the general formula (II) without the requirement of costly multi-stage reactions, thereby resulting significant cost advantages.
Further advantages arise by the zero-shear viscosity of the aqueous solution being i s between 20,000 and 8,000,000 mPa.s, preferably between 50,000 and 500,000 mPa.s. Hereby, the ophthalmologic composition has a particularly good flow behavior and is correspondingly well to handle in typical applications.
In a further advantageous development of the invention it is provided that the molecular weight of the colored polysaccharide is between 500,000 u and 5,000,000 u, 20 preferably between 800,000 u and 2,500,000 u. Hereby too, a particularly good flow behavior and a correspondingly good manageability of the ophthalmologic composition is achieved. In addition, plural dye molecules can be covalently coupled to a polysaccharide molecule without this resulting in substantial variations of the properties of the viscoelastic polysaccharide.
25 In a further advantageous development of the invention, it is provided that the concentration of the colored polysaccharide in the ophthalmologic composition is between 0.5% and 5% (w/w), preferably between 1 % and 3% (w/w). By a concentration between 0.5% and 5% (w/w), within the scope of the invention, in particular concentrations of 0.5 %, 0.6 %, 0.7 %, 0.8 %, 0.9 %, 1 .0 %, 1 .1 %, 1 .2 %, 1 .3 %,
30 1 .4 %, 1 .5 %, 1 .6 %, 1 .7 %, 1 .8 %, 1 .9 %, 2.0 %, 2.1 %, 2.2 %, 2.3 %, 2.4 %, 2.5 %, 2.6 %, 2.7 %, 2.8 %, 2.9 %, 3,0 %, 3,1 %, 3,2 %, 3,3 %, 3,4 %, 3,5 %, 3,6 %, 3,7 %, 3,8 %, 3,9 %, 4.0 %, 4.1 %, 4.2 %, 4.3 %, 4.4 %, 4.5 %, 4.6 %, 4.7 %, 4.8 %, 4.9 %, and 5.0 % as well as corresponding intermediate values are to be understood.
Therein, within the scope of the invention, percentage information is to be understood as mass percent unless otherwise stated. By use of the polysaccharide in the indicated range of concentration, a particularly good flow behavior and a correspondingly good manageability of the ophthalmologic composition is achieved for 5 typical application cases.
In a further advantageous development of the invention, it is provided that the ophthalmologic composition is prepared for use in ophthalmology, in particular for use in a phacoemulsification method. Due to the integral, non-washable and simply adjustable coloration of the ophthalmologic composition, the viscoelastic solution can be 10 introduced into the eye in a particularly simple and controlled manner without herein being the risk of washout of the dye or of undesired coloration of the surrounding tissue. The entire ophthalmologic composition can be removed from the eye without residue in correspondingly simple and safe manner for example after a cataract surgery. i s A further aspect of the invention relates to a method for producing an ophthalmologic composition, in which at least one dye is covalently bound to at least one water-soluble, viscoelastic polysaccharide. By the covalent binding of the at least one dye to the at least one viscoelastic polysaccharide, it is reliably excluded that the dye diffuses into adjoining tissue and undesirably stains it during the use of the oph-
20 thalmologic composition. Moreover, unlike fluorescent dyes such as fluorescein, rhodamine or the like, it is not required to irradiate the ophthalmologic composition with UV light to render it visible. This allows a substantially simpler handling of the ophthalmologic composition. In addition, there is a priori no risk that the concerned tissue is damaged by the irradiation with high-energy UV light. Furthermore, a user -
25 for example a surgeon - can even recognize minor traces without additional auxiliary means such as UV lamps or the like due to the integral coloration of the ophthalmologic composition, whereby the use of the ophthalmologic composition according to the invention - for example within the scope of eye surgeries- additionally becomes substantially simpler and safer. In simplest configuration, the ophthalmo-
30 logic composition is produced with a viscoelastic polysaccharide, to which a single dye type is covalently bound. Alternatively, it can be provided that plural different viscoelastic polysaccharides and/or further additives are used to produce the ophthalmologic composition. Independently thereof, it can also be provided that two or
more different dyes are covalently bound to a viscoelastic polysaccharide, whereupon the colored viscoelastic polysaccharide - optionally with further additives - is used for producing the ophthalmologic composition.
Furthermore, it can be provided that a dye with plural reactive groups is used. Hereby, the dye advantageously can be used as a cross-linker for cross-linking plural polysaccharides, whereby the viscoelastic properties of the polysaccharide can be specifically adjusted among other things. Alternatively or additionally, of course, non-colored cross-linkers such as for example divinyl sulphones or diepoxies can also be used for cross-linking for example alcohol or other functional groups of plural polysaccharides.
In a further advantageous development of the invention, it is provided that the at least one dye is used in a molar ratio between 1:10 and 1 :30 with regard to the polysaccharide and/or in a concentration of between 0.0005% and 1%, preferably between 0.01 and 0.3%, based on the weight of the ophthalmologic composition. Therein, within the scope of the invention, by a molar ratio between 1 :10 and 1 :30, in particular molar ratios of 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1 :20, 1:21, 1 :22, 1 :23, 1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, and 1 :30 as well as corresponding intermediate values are to be understood. Within the scope of the invention, by a concentration of between 0.0005% and 1%, in particular concentrations of 0.0005%, 0.001 %, 0.011 %, 0.021 %, 0.031 %, 0.041 %, 0.051 %, 0.061 %, 0.071 %, 0.081 %, 0.091 %, 0.101 %, 0.111 %, 0.121 %, 0.131 %, 0.141 %, 0.151 %, 0.161 %, 0.171 %, 0.181 %, 0.191 %, 0.201 %, 0.211 %, 0.221 %, 0.231 %, 0.241 %, 0.251 %, 0.261 %, 0.271 %, 0.281 %, 0.291 %, 0.301 %, 0.311 %, 0.321 %, 0.331 %, 0.341 %, 0.351 %, 0.361 %, 0.371 %, 0.381 %, 0.391 %, 0.401 %, 0.411 %, 0.421 %, 0.431 %, 0.441 %, 0.451 %, 0.461 %, 0.471 %, 0.481 %, 0.491 %, 0.501 %, 0.511 %, 0.521 %, 0.531 %, 0.541 %, 0.551 %, 0.561 %, 0.571 %, 0.581 %, 0.591 %, 0.601 %, 0.611 %, 0.621 %, 0.631 %, 0.641 %, 0.651 %, 0.661 %, 0.671 %, 0.681 %, 0.691 %, 0.701 %, 0.711 %, 0.721 %, 0.731 %, 0.741 %, 0.751 %, 0.761 %, 0.771 %, 0.781 %, 0.791 %, 0.801 %, 0.811 %, 0.821 %, 0.831 %, 0.841 %, 0.851 %, 0.861 %, 0.871 %, 0.881 %, 0.891 %, 0.901 %, 0.911 %, 0.921 %, 0.931 %, 0.941 %, 0.951 %, 0.961 %, 0.971 %, 0.981 %, 0.991 %, and 1.000 % as well as corresponding intermediate values are to be understood. By the use of the dye in the specified
molar ratios and/or concentrations, the ophthalmologic composition has an optimum colorfulness for typical applications.
In a further advantageous development of the invention, it is provided that a dye with an amino group is used and covalently bound to the polysaccharide by way of an Ugi reaction. The Ugi reaction is a multi-component reaction involving a ketone or aldehyde, an amine, an isocyanide and a carboxylic acid. The products of the Ugi reaction are bis-amides. The Ugi reaction is an uncatalyzed reaction but is usually complete within minutes after adding the isocyanide. The main advantages of using an Ugi reaction are the inherent high atom economy as only a molecule of water is lost and the high product yields. Accordingly, the dye including the amino group can be bound quickly, simply and with high yields to polysaccharides comprising functional keto groups, aldehyde groups and/or carboxylic acid groups. An example for a suitable polysaccharide is hyaluronic acid. Hyaluronic acid is a polysaccharide with repeating disaccharide units of glucuronosyl-β-1 ,3-N-acetylglucosamine linked by β- 1 ,4-glycoside (glycosidic) bonds and has the general formula
In a further advantageous development of the invention, it is provided that for producing the ophthalmologic composition the polysaccharide coupled to the dye and/or a physiologically acceptable salt thereof is dissolved and/or dispersed in an amount of between 0.05 percent by weight and 5 percent by weight possibly together with a buffer system and/or with further agents and/or excipients in a protic solvent, in particular in water. Within the scope of the invention, by an amount of between 0.05 percent by weight and 5 percent by weight, in particular amounts of 0.05 %, 0.15 %, 0.25 %, 0.35 %, 0.45 %, 0.55 %, 0.65 %, 0.75 %, 0.85 %, 0.95 %, 1 .05 %, 1 .15 %, 1 .25 %, 1 .35 %, 1 .45 %, 1 .55 %, 1 .65 %, 1 .75 %, 1 .85 %, 1 .95 %, 2.05 %, 2.15 %, 2.25 %, 2.35 %, 2.45 %, 2.55 %, 2.65 %, 2.75 %, 2.85 %, 2.95 %,
3.05 %, 3.15 %, 3.25 %, 3.35 %, 3.45 %, 3.55 %, 3.65 %, 3.75 %, 3.85 %, 3.95 %, 4.05 %, 4.15 %, 4.25 %, 4.35 %, 4.45 %, 4.55 %, 4.65 %, 4.75 %, 4.85 %, 4.95 %, and 5.00 % as well as corresponding intermediate values are to be understood. Hereby, the property profile of the ophthalmologic composition can be adapted to different purposes of application in optimum manner.
In a further advantageous development of the invention, it is provided that in order to bond the at least one dye, the viscoelastic polysaccharide is functionalized and the at least one dye is covalently bound to the added functional group of the polysaccharide. In other words, first, a functional group is introduced into the viscoelastic polysaccharide, which is subsequently reacted with the at least one dye, in order to covalently bind the at least one dye to the polysaccharide. In this manner, the at least one dye can be simply bound to different polysaccharides with correspondingly specific functional groups largely independent of its precisely present reactive group. Alternatively or additionally, it can be provided that the at least one dye is first func- tionalized and subsequently covalently bound to the viscoelastic polysaccharide via its newly created functional group by means of a desired type of reaction.
Further features of the invention appear from the claims as well as based on the following embodiments. The features and feature combinations mentioned above in the description as well as the features and feature combinations mentioned below in the embodiments are usable not only in the respectively specified combination, but also in other combinations without departing from the scope of the invention.
Preferred embodiments of the invention
The present invention generally provides a colored ophthalmologic composition which can be completely removed after cataract surgery. The ophthalmologic composition comprises a viscoelastic solution based on a polysaccharide to which at least one dye is covalently bound. This means for example that a surgeon can visualize even very small traces of the viscoelastic ophthalmologic composition. By way of covalently binding the dye to the polysaccharide it is also ensured that the dye does not diffuse out of the solution and therefore does not stain the surrounding tissues.
The ophthalmologic composition according to the invention can for example be used as eye drops. The viscoelastic property of the solution of the color labeled polysaccharide therein provides for a stable and long lasting tear film. Alternatively, it can be provided that the ophthalmologic composition according to the invention is used as caring solutions for contact lenses. Hereby, uncolored or colored contact lenses can be better recognized and simpler be removed from the contact lens container.
In the ophthalmic surgery, the ophthalmologic composition according to the invention can be used for filling up the vitreous body as well as for stabilizing the anterior chamber and for protection of the highly sensible endothelial cell layer of the cornea during surgery on the anterior eye portions, especially the surgery of the cataract. As the viscoelastic polysaccharide, to which the dye is covalently bound, for example hyaluronic acid is suited.
Suitable dyes that can be covalently bound to hyaluronic acid or another polysaccharide are based on aminoanthracenedione derivatives of the general formula (I):
wherein in the general formula (I) at least one of the substituents Ri to R8 is an amino group, and the remaining substituents Ri to R8, which are different from the amino group, are selected from: hydrogen, halogen, d-C4-alkyl, CrC4-alkoxy, CrC4-alkoxy-CrC4-alkyl, CrC4-alkyl- CrC4-alkoxy, CrC4-alkoxy-CrC4-alkoxy, aryloxy, acetamide, propionamide, bu- tyramide, isobutyramide, sulphonate, (aminophenyl)-N-alkylacetamide, (aminophen- ylsulphonyl)alkyl sulphate, alkylbenzenesulphonamide, tri(alkyl)benzenamine, hydroxy, (alkylsulphonyl)benzenamine, and (alkenylsulphonyl)benzenamine, and/or
wherein at least two adjacent substituents Rx, Rx+i with x=1 to 3 and/or 5 to 7 form a 3-, 4-, 5-, 6- or 7-membered homocyclic or heterocyclic, unsaturated or aromatic radical.
Alternatively or additionally a reactive dye from the group of ((nitro- phenyl)diazenyl)benzenamine derivatives having the general formula (II)
may be covalently bound to the polysaccharide, wherein in the general formula (II) at least one of the substituents Ri to R5 is an amino group and at least one of the substituents R6 to R 0 is a nitro group, and wherein the remaining radicals Ri to R 0, which are different from the amino group and the nitro group, are selected from: hydrogen, halogen, d-C4-alkyl, CrC4-alkoxy, Ci-C4-alkoxy-Ci-C4-alkyl, CrC4-alkyl- CrC4-alkoxy, Ci-C4-alkoxy-Ci-C4-alkoxy, aryloxy, acetamide, propionamide, bu- tyramide, isobutyramide, sulphonate, (aminophenyl)-N-alkylacetamide, (aminophen- ylsulphonyl)alkyl sulphate, alkylbenzenesulphonamide, tri(alkyl)benzenamine, hydroxy, (alkylsulphonyl)benzenamine, and (alkenylsulphonyl)benzenamine, and/or wherein at least two adjacent substituents Ry, Ry+i with y=1 to 4 and/or 6 to 9 form the cyclic radical
with: R=hydrogen, halogen, amino, hydroxyl, nitro, CrC4-alkyl, CrC4-alkoxy, CrC4- alkoxy-CrC4-alkyl, Ci-C4-alkyl-Ci-C4-alkoxy, and/or Ci-C4-alkoxy-Ci-C4-alkoxy.
Since both the dyes of the general formula (I) and the dyes of the general formula (II) have free amino groups, they can be bound to a polysaccharide having free keto, aldehyde and/or carboxyl groups without further derivatization or functionalization with the aid of the so-called Ugi reaction. The Ugi reaction is a 4 component con- 5 densation (U-4CC), which allows the synthesis of -aminoacylamide derivatives from aldehydes, amines, carboxylic acids and isocyanides. Therein, the Ugi reaction proceeds according to the general reaction scheme:
In the specific case, thus, the dyes of the general formulas (I) und (II) function as the 10 amino component and the hyaluronic acid functions as the carboxylic acid component of the Ugi reaction. For example, acetaldehyde can be used as the aldehyde. For example, cyclohexanenitrile is suitable as the isocyanide. Generally, low molecular alcohols have proven as the solvent in the Ugi reaction.
Preferably, the reactants are prepared in high concentrations with cooling and react i s very fast, that is within a few minutes at room temperature. Lewis acids known per se can be employed in the conversion in particular of sterically demanding educts for catalysis.
In the case of hyaluronic acid, which has the general formula
th e dyes of the general formulas (I) and (II) thus can react with the free carboxyl groups of the hyaluronic acid with the aid of their amino groups in a reaction step and hereby be covalently bound to the hyaluronic acid. The carboxylic acids employed within the scope of an Ugi reaction can advantageously be diversely varied such that other polysaccharides with free carboxyl groups can also be used without previous functionalization within the scope of an Ugi reaction. Polysaccharides without carboxyl groups can be subjected to a preceding derivatization or functionalization for later use in the Ugi reaction. Conversely, polysaccharides with free amino groups can of course also be reacted with dyes having free carboxyl groups.
An advantage of the dyes of the general formulas (I) and (II) is in their basically very high extinction coefficient in the visible range of the light spectrum (about 400 nm to about 800 nm). Furthermore, the color of the dyes of the general formulas (I) and (II) can be simply varied in a wide color range by use of corresponding substituents and/or position isomers, whereby the ophthalmologic composition can be simply adapted to different purposes of use.
In the following table 1 , various embodiments for dyes of the general formula (I) are specified.
Table 1 : Embodiments for dyes of the general formula (I)
Example 1
Name and sodium 1 -amino-4-(4-(N-methyl-acetamido)phenylamino)-9,10-
Synonyms dioxo-9,10-dihydroanthracene-2-sulfonate; Acid Blue 41 ; CAS
2666-17-3
Example 2
Name and sodium 2-(3-(4-amino-9,10-dioxo-3-sulfonato-9,10-
Synonyms dihydroanthracen-1 -ylamino)phenylsulfonyl)ethyl sulphate; Reactive Blue 19 (Remazol Brilliant Blue R); CAS 2580-78-1
Example 3
Name and N-(4-amino-3-methoxy-9,10-dioxo-9,10-dihydroanthracen-1 -yl)-4- Synonyms methylbenzenesulfonamide; Disperse Red 86; CAS 81 -68-5
Name and 1 -amino-4-hydroxy-2-(2-methoxyethoxy)anthracene-9, 10-dione;
Synonyms Disperse Red 59; CAS 17869-10-2
Example 5
Name and sodium 1 -amino-4-(mesitylamino)-9,10-dioxo-9,10-
In the following table 2, various embodiments for dyes of the general formula (II) are specified.
Table 2: Embodiments for dyes of the general formula (II)
Example 1 o
3;
Name and (E)-1 -((4-nitrophenyl)diazenyl)naphthalene-2-amine; 1 -(4'-
Synonyms Nitrophenylazo)-2-naphthylamine; Solvent Red 5; CAS 3025-77-
2
Example 1 1
Name and (E)-4-amino-3-((4-nitrophenyl)diazenyl)naphthalene-1 -sulphonic
Synonyms acid; Acid Red 74; CAS 6300-18-1
However, it is to be emphasized that besides the Ugi reaction, basically, other chemical reaction types can also be used for covalently binding the concerned dye to the concerned viscoelastic polysaccharide. For example, dyes with a free alcohol group can be bound to hyaluronic acid by an esterification reaction.
Labeling of hyaluronic acid (HA) can for example also be obtained by the reaction of CNBr-activated HA at vicinal diols and a dye comprising a reactive amine group according to the following reaction scheme:
wherein HA denotes hyaluronic acid and NH2-R denotes the reactive dye comprising an amine group. The reaction may also involve the hydroxyl groups in two hyaluronic acid molecules.
It is also possible to use a dye comprising an isothiocyanate group (denoted by SCN-R), which targets mostly the primary hydroxyl groups of HA or other viscoelas- tic polysaccharides:
The reaction is conducted at 37 °C overnight. The resulting color labeled polysaccharide is stable for over a month.
A further type of reaction for covalently binding a dye to hyaluronic acid includes activation of a hyaluronic acid derivative with N-hydroxysuccinimide coupled di- phenylphosphoric acid. The resulting adduct is reacted with a dye comprising a reactive hydrazide group (denoted by [R]CC(NN)=0) according to the following general reaction scheme:
Another method to chemically bond a reactive dye to hyaluronic acid (HA) or other polysaccharides comprising carboxylic groups is depicted in the following reaction scheme:
The reaction employs a dye comprising a hydrazide group. The first step is to form an O-acylurea of HA by reaction of HA with 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC) having the formula
The resulting intermediate is then reacted with the reactive dye to form the color labeled HA.
Another possibility is the reaction between the carboxylic groups of HA and dyes comprising a carbodiimide group in the presence or absence of primary amines at pH 4.5 according to the general reaction scheme:
The reaction of carbodiimides proceeds rapidly at room temperature. The final group is an N-acylurea or O-acylurea. The carbodiimides are synthesized in a 2-step reaction: the reaction of a dye comprising a primary amine and isothiocyanate to form a thiourea and the reaction of said thiourea and HgO to produce the reactive dye comprising a carbodiimide group.
HA esters can also be produced by a nucleophilic reaction of a reactive dye comprising a halide with a quaternary salt of hyaluronic acid:
Another way to molecularly label the viscoelastic polysaccharide is given by the cross-linking of HA with diepoxies:
In acidic conditions, the ester of HA is formed by linking the epoxy to HA at the acidic position. In basic conditions, the ether is produced by linking the epoxy to HA at the primary alcohol position.
Another way to crosslink and therefore functionalize HA at the primary alcohol posi- tion is to use divinylsulfone as cross-linker:
Alternatively, it can be provided herein that a dye with a free hydroxy group is used and bound to the hyaluronic acid with the aid of the cross-linker.
Alternatively or additionally to hyaluronic acid, basically, other viscoelastic polysaccharides such as for example hydroxypropylmethylcellulose, chondroitin sulfate or mixtures thereof can also be used.
An ophthalmologic composition comprising an aqueous solution of a viscoelastic polysaccharide which is covalently bound to one or several dyes of the general formulas (I) and/or (II) may be used in a phacoemulsification method. During the phacoemulsification, the anterior chamber of the eye is filled with the ophthalmologic composition comprising the colored viscoelastic solution. The viscoelastic ophthalmologic composition is used as a surgical aid to protect intraocular tissues, for ex- ample the corneal endothelium, during the phacoemulsification, as a space main- tainer to maintain the anterior chamber of the eye, and to facilitate intraocular maneuvers, for example to make a controlled capsulorhexis. Because the dye is covalently bound to the polysaccharide, the dye does not diffuse out of the solution and therefore does not stain the surrounding tissues. After the capsulorhexis the colored ophthalmologic composition may be completely removed from the anterior chamber as the surgeon can visualize even very small traces of the viscoelastic ophthalmologic composition.
Claims
Claims
1 . Ophthalmologic composition, comprising an aqueous solution of at least one viscoelastic polysaccharide,
characterized in that
the at least one polysaccharide is covalently bound to at least one dye.
The ophthalmologic composition according to claim 1 ,
characterized in that
the polysaccharide is cellulose, a cellulose ether with methyl and/or ethyl and/or propyl groups, in particular hydroxypropyl methylcellulose, hydroxyethyl methylcellulose and/or methylcellulose, a glycosaminoglycan, in particular hyaluronic acid, chondroitin sulphate, dermatan sulphate, heparin, heparan sulphate, keratan sulphate, alginic acid, polymannuronic acid, polyguluronic acid, polyglucuronic acid, amylose, amylopectin, callose, chitosan, polygalac- tomannan, dextran, xanthan and/or a mixture thereof.
The ophthalmologic composition according to claim 1 or 2,
characterized in that
the at least one dye is bound to the polysaccharide directly and/or
spacer.
The ophthalmologic composition according to any one of claims 1 to 3, characterized in that
the at least one polysaccharide is obtainable by a reaction of the polysaccharide with at least one reactive dye from the group of modified and/or unmodi-
tied aminoanthracenedione and/or of modified and/or unmodified nitro- phenyldiazenylbenzenamine.
The ophthalmologic composition according to claim 4,
characterized in that
the at least one polysaccharide is obtainable by reaction with at least active dye of the general formula (I),
wherein in the general formula (I) at least one of the substituents Ri to R8 is an amino group, and the remaining substituents Ri to R8, which are different from the amino group:
- are selected from: hydrogen, halogen, d-C4-alkyl, CrC4-alkoxy, C C4-alkoxy-CrC4-alkyl, CrC4-alkyl-CrC4-alkoxy, CrC4-alkoxy-CrC4- alkoxy, aryloxy, acetamide, propionamide, butyramide, isobutyra- mide, sulphonate, (aminophenyl)-N-alkylacetamide, (aminophenyl- sulphonyl)alkyl sulphate, alkylbenzenesulphonamide, tri(alkyl)benzenamine, hydroxy, (alkylsulphonyl)benzenamine, and (alkenylsulphonyl)benzenamine; and/or wherein at least two adjacent substituents Rx, Rx+i with x=1 to 3 and/or 5 to 7 form a 3-, 4-, 5-, 6- or 7-membered homocyclic or heterocyclic, unsaturated or aromatic radical.
6. The ophthalmologic composition according to claim 4 or 5, characterized in that
the at least one polysaccharide is obtainable by reaction with at least one reactive dye of the general formula (II),
R7 fie
wherein in the general formula (II) at least one of the substituents Ri to R5 is an amino group and at least one of the substituents R6 to Ri0 is a nitro group, and wherein the remaining radicals Ri to R 0, which are different from the amino group and the nitro group:
- are selected from hydrogen, halogen, d-C4-alkyl, CrC4-alkoxy, C C4-alkoxy-CrC4-alkyl, Ci-C4-alkyl-Ci-C4-alkoxy, Ci-C4-alkoxy-Ci-C4- alkoxy, aryloxy, acetamide, propionamide, butyramide, isobutyra- mide, sulphonate, (aminophenyl)-N-alkylacetamide, (aminophenyl- sulphonyl)alkyl sulphate, alkylbenzenesulphonamide,
tri(alkyl)benzenamine, hydroxy, (alkylsulphonyl)benzenamine, and (alkenylsulphonyl)benzenamine; and/or
- wherein at least two adjacent substituents Ry, Ry+i with y=1 to 4 and/or 6 to 9 form the cyclic radical
with:
R=hydrogen, halogen, amino, hydroxyl, nitro, CrC4-alkyl, CrC4- alkoxy, Ci-C4-alkoxy-Ci-C4-alkyl, Ci-C4-alkyl-Ci-C4-alkoxy, and/or C C4-alkoxy-CrC4-alkoxy.
7. The ophthalmologic composition according to any one of claims 1 to 6, characterized in that
the zero-shear viscosity of the aqueous solution is between 20,000 and 8,000,000 mPa.s, preferably between 50,000 and 500,000 mPa.s.
The ophthalmologic composition according to any one of claims 1 to 7, characterized in that
the molecular weight of the colored polysaccharide is between 500,000 5,000,000 u, preferably between 800,000 u and 2,500,000 u.
9. The ophthalmologic composition according to any one of claims 1 to 8,
characterized in that
the concentration of the colored polysaccharide in the ophthalmologic composition is between 0.5% and 5% (w/w), preferably between 1 % and 3% (w/w).
10. The ophthalmologic composition according to any one of claims 1 to 9,
characterized in that
it is prepared for use in ophthalmology, in particular for use in a phacoemulsification method.
1 1 . A method for producing an ophthalmologic composition, in which at least one dye is covalently bound to at least one water-soluble, viscoelastic polysaccharide.
The method according to claim 1 1 ,
characterized in that
the at least one dye is used in a molar ratio between 1 :10 and 1 :30 with regard to the polysaccharide and/or in a concentration of between 0.0005% and 1 %,
preferably between 0.01 and 0.3%, based on the weight of the ophthalmologic composition.
The method according to claim 1 1 or 12,
characterized in that
a dye with an amino group is used and covalently bound to the polysaccharide by way of an Ugi reaction.
The method according to any one of claims 1 1 to 13,
characterized in that
for producing the ophthalmologic composition the polysaccharide coupled to the dye and/or a physiologically acceptable salt thereof is dissolved and/or dispersed in an amount of between 0.05 percent by weight and 5 percent by weight possibly together with a buffer system and/or with further agents and/or excipients in a protic solvent, in particular in water.
The method according to any one of claims 1 1 to 14,
characterized in that
in order to bond the at least one dye, the viscoelastic polysaccharide is func- tionalized and the at least one dye is covalently bound to the added functional group of the polysaccharide.
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