MXPA96005188A - Use of amidoamines in oftalmi compositions - Google Patents
Use of amidoamines in oftalmi compositionsInfo
- Publication number
- MXPA96005188A MXPA96005188A MXPA/A/1996/005188A MX9605188A MXPA96005188A MX PA96005188 A MXPA96005188 A MX PA96005188A MX 9605188 A MX9605188 A MX 9605188A MX PA96005188 A MXPA96005188 A MX PA96005188A
- Authority
- MX
- Mexico
- Prior art keywords
- methyl
- hydrogen
- further characterized
- saturated
- composition
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 86
- 150000001875 compounds Chemical class 0.000 claims abstract description 77
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 38
- 239000001257 hydrogen Substances 0.000 claims abstract description 25
- 239000011780 sodium chloride Substances 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims abstract description 6
- 239000001301 oxygen Substances 0.000 claims abstract description 6
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 6
- 238000011109 contamination Methods 0.000 claims abstract description 5
- 230000000813 microbial Effects 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 claims abstract 7
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 230000000249 desinfective Effects 0.000 claims description 25
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- -1 hydroxyethyl Chemical group 0.000 claims description 14
- 238000004659 sterilization and disinfection Methods 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000004094 surface-active agent Substances 0.000 claims description 6
- 230000000845 anti-microbial Effects 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 239000004599 antimicrobial Substances 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims 4
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 4
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 4
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 4
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 4
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 4
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 4
- 125000003282 alkyl amino group Chemical group 0.000 claims 3
- 125000005065 undecenyl group Chemical group C(=CCCCCCCCCC)* 0.000 claims 3
- BIQKRILZMDQPHI-UHFFFAOYSA-N heptadec-8-ene Chemical compound CCCCCCCCC=CCCCCCCC BIQKRILZMDQPHI-UHFFFAOYSA-N 0.000 claims 1
- 125000004171 alkoxy aryl group Chemical group 0.000 abstract description 2
- 125000004417 unsaturated alkyl group Chemical group 0.000 abstract 2
- 125000002877 alkyl aryl group Chemical group 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 81
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 31
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Inorganic materials [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- 238000004140 cleaning Methods 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 235000017557 sodium bicarbonate Nutrition 0.000 description 15
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
- 125000000520 N-substituted aminocarbonyl group Chemical group [*]NC(=O)* 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 238000000921 elemental analysis Methods 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- 239000000126 substance Substances 0.000 description 10
- 238000007792 addition Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 8
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 230000002335 preservative Effects 0.000 description 6
- 239000003755 preservative agent Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- NQGIJDNPUZEBRU-UHFFFAOYSA-N dodecanoyl chloride Chemical compound CCCCCCCCCCCC(Cl)=O NQGIJDNPUZEBRU-UHFFFAOYSA-N 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 5
- 238000004321 preservation Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 101700067048 CDC13 Proteins 0.000 description 3
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 229920002892 amber Polymers 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 125000006355 carbonyl methylene group Chemical group [H]C([H])([*:2])C([*:1])=O 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000008079 hexane Substances 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N Boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 208000001860 Eye Infections Diseases 0.000 description 2
- 229940082054 Sodium Bicarbonate / Sodium Chloride Drugs 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000006295 amino methylene group Chemical group [H]N(*)C([H])([H])* 0.000 description 2
- 230000000844 anti-bacterial Effects 0.000 description 2
- 230000000843 anti-fungal Effects 0.000 description 2
- 229940027983 antiseptics and disinfectants Quaternary ammonium compounds Drugs 0.000 description 2
- 239000000607 artificial tear Substances 0.000 description 2
- 244000052616 bacterial pathogens Species 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000000645 desinfectant Substances 0.000 description 2
- 201000009910 diseases by infectious agent Diseases 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 238000007654 immersion Methods 0.000 description 2
- 229910001410 inorganic ion Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 239000001187 sodium carbonate Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000010339 sodium tetraborate Nutrition 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing Effects 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 2
- 239000004034 viscosity adjusting agent Substances 0.000 description 2
- RNHWYOLIEJIAMV-UHFFFAOYSA-N 1-chlorotetradecane Chemical compound CCCCCCCCCCCCCCCl RNHWYOLIEJIAMV-UHFFFAOYSA-N 0.000 description 1
- RWYHOIUBWBDNSP-UHFFFAOYSA-N 1-oxidanylpyrrolidine-2,5-dione Chemical compound ON1C(=O)CCC1=O.ON1C(=O)CCC1=O RWYHOIUBWBDNSP-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 description 1
- 101700061322 ATG4 Proteins 0.000 description 1
- 101710034283 CG12163 Proteins 0.000 description 1
- OMFHQUCUWSMFOJ-FMONCPFKSA-N COMP protocol Chemical compound ClCCN(CCCl)P1(=O)NCCCO1.O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1.C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1.C([C@H](C[C@]1(C(=O)OC)C=2C(=C3C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)=CC=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 OMFHQUCUWSMFOJ-FMONCPFKSA-N 0.000 description 1
- SZXQTJUDPRGNJN-UHFFFAOYSA-N Dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 241000282619 Hylobates lar Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- LUJNJZRJFYGHKD-UHFFFAOYSA-N N-(1-morpholin-4-ylpropyl)dodecanamide Chemical compound CCCCCCCCCCCC(=O)NC(CC)N1CCOCC1 LUJNJZRJFYGHKD-UHFFFAOYSA-N 0.000 description 1
- FODYHSRHUPEHKP-UHFFFAOYSA-N N-[3-(4-methylpiperazin-1-yl)propyl]tetradecanamide Chemical compound CCCCCCCCCCCCCC(=O)NCCCN1CCN(C)CC1 FODYHSRHUPEHKP-UHFFFAOYSA-N 0.000 description 1
- CEUPSWZDQFEYHG-UHFFFAOYSA-N N-[3-(dimethylamino)propyl]tridecanamide Chemical compound CCCCCCCCCCCCC(=O)NCCCN(C)C CEUPSWZDQFEYHG-UHFFFAOYSA-N 0.000 description 1
- VXSKOADGMONUGO-UHFFFAOYSA-N N-[3-[4-(2-hydroxyethyl)piperazin-1-yl]propyl]dodecanamide Chemical compound CCCCCCCCCCCC(=O)NCCCN1CCN(CCO)CC1 VXSKOADGMONUGO-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-hydroxy-Succinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 206010052143 Ocular discomfort Diseases 0.000 description 1
- 241001644482 Onyx Species 0.000 description 1
- 229920001451 Polypropylene glycol Polymers 0.000 description 1
- 229920000289 Polyquaternium Polymers 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M Potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- FDRCDNZGSXJAFP-UHFFFAOYSA-M Sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N TiO Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- YEDTWOLJNQYBPU-UHFFFAOYSA-N [Na].[Na].[Na] Chemical compound [Na].[Na].[Na] YEDTWOLJNQYBPU-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000003732 agents acting on the eye Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003212 astringent agent Substances 0.000 description 1
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N benzohydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L cacl2 Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 235000019804 chlorophyll Nutrition 0.000 description 1
- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical compound C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 description 1
- 229930002875 chlorophylls Natural products 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000012459 cleaning agent Substances 0.000 description 1
- 230000000295 complement Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L disodium;2-[2-[carboxylatomethyl(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 150000004676 glycans Polymers 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 125000006357 methylene carbonyl group Chemical group [H]C([H])([*:1])C([*:2])=O 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 101700084105 num-1 Proteins 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920001987 poloxamine Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- JCMLRUNDSXARRW-UHFFFAOYSA-N trioxouranium Chemical compound O=[U](=O)=O JCMLRUNDSXARRW-UHFFFAOYSA-N 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
Abstract
The present invention relates to a preserved pharmaceutical composition, characterized in that it comprises an aqueous ophthalmic composition and 0.00001 to 0.05% by weight of a compound of the following formula for preserving said ophthalmic composition from microbial contamination: R1- (OCH2CH2) mX- (CH2) nY where: Z is oxygen or NR4, R1 is C6-C18 saturated or unsaturated alkyl, alkylaryl or alkoxyaryl, m is zero to 16, n is 2 to 16, R2, R3 and R4 are independently hydrogen , C 1 -C 8 saturated or unsaturated alkyl or hydroxyalkyl, or a pharmaceutically acceptable salt thereof, provided that when: R 2 is H, Y is -N (R 3) 2, and R 3 is other than hydrogen, m can not be
Description
USE OF FLAMIDOAMINS IN OPHTHALMIC COMPOSITIONS
BACKGROUND OF THE INVENTION
The present invention relates to the field of ophthalmology. Very particularly, the invention is directed to compositions and methods for disinfecting contact lenses, and to the chemical preservation of various types of ophthalmic products. 1 > Contact lenses are exposed to a broad spectrum of microbes during normal use and get dirty relatively quickly. The routine cleaning and disinfection of the lenses is therefore * required. Although the frequency of cleaning and disinfection may vary somewhat between different
types of lenses and lens care regimens, cleaning and daily disinfection is normally required. If the lenses are not properly cleaned and disinfected, it can cause an inulity of problems ranging from uncomfortable discomfort when the lenses are used to infections.
? 0 severe eyepieces. Ocular infections caused by * microbes pair ICUL rmente fpolent-os such co or Pseudomoñ aerogni years, may lead to loss or I infec ed left untreated or allowed to reach one an + advanced stage is that the treatment is initiated . Therefore, it is extremely
It is important for patients to disinfect their contact lenses according to the regimen prescribed by their or? + Ome + i s or phtalmologist.
Unfortunately, patients often do not follow the prescribed regimens. Many patients find that the regimens are difficult to understand and / or complicated, and as a result they do not meet one or more aspects of the regimen. Other patients may have * a negative experience with the regimen, such as ocular discomfort atpbuible to the disinfectant agent, and as a result they do not routinely disinfect their lenses or in a way they move away from the present regimen. In any case, the risk of eye infections is exacerbated. "Despite the availability of several types of contact lens disinfection systems, such as heat, hydrogen peroxide and other chemical agents, there remains a need for improved systems that: 1) they are simple to use, 2) they have potent antimicrobial activity and 3) they are non-toxic (ie they do not produce ocular irritation as a result of binding to the lens material). Moreover, the chemical agents used in the contact lens disinfection systems currently marketed by * generally have limited antifungal activity. Also, many of the chemical agents currently used can interact with contact lens materials and / or produce irritation in some individuals. Therefore, there is a particular need in the fields of disinfection of contact lenses and preservation of ophthalmic composition for safe and effective chemical agents having better antibacterial activity, the present invention is directed to satisfy the needs
previously mentioned .
BRIEF DESCRIPTION OF THE INVENTION
The present invention is directed to methods for using certain drugs to disinfect contact lenses and to preserve ophthalmic compositions. The invention is also directed to contact lens disinfecting compositions containing one or more of the compounds herein, and to various types of ophthalmic compositions (eg, pharmaceutical drops, artificial tears and drops for comfort) containing the compounds for purposes of preserving the compositions against microbial contamination. In addition, of having antimicrobial activity, including antibacterial and antifungal activity, the compounds of the present invention are also surface active, as a result, the compounds can help to clean contact lenses by facilitating the removal of lens deposits. The nas arnidoan of the present invention retain their antimicrobial activity in the presence of Na +, Ca ++, Cl- and other inorganic ions produced by dissociation of alkali metal and alkaline earth metal (v .. g. Sodium and calcium chloride) , and are compatible with polymers and surfactants frequently used in ophthalmic products such as polyvinylpyrrolidone, and polyoxyethylene / polyoxypropylene copolymers of amines. These properties represent signi icant advantages, in relation
with many of the antimicrobial agents previously used in the ophthalmic field. DESCRIPTION OF THE PREFERRED MODALITIES
The compounds used in the present invention comprise one or more compounds of the following formula, or pharmaceutically acceptable salts thereof (v. G, salts of hydrohalogenides): R1- (0CH2CH2) m "- (CH2) nY (I) where:
And it is- -N (R3) 2 or -N Z
Z is oxygen or MR * l is alkyl, alkylated or saturated alkoxyaryl or Methylated Ce-C; rn is zero to 16; n is 2 to 16; R2, R3, and 4 are independently hydrogen, alkyl or hydroquinol to saturated or unsaturated chi-i, or a pharmaceutically acceptable salt thereof Compounds wherein rn is 0 to 5, n is 2 to 4, R2 < - > < -, hydrogen or methanol, methyl or ethyl R3 and R * is hydrogen, methyl or hydroxyethyl are particularly preferred, such as
compounds of table 1
TABLE 1: COMP. R1 m S & R3 R4
No. I C, 7 0 3 CONR 'H N (RJ). CH3 2 C, 3 0 2 CONR2 HN (R3) 2 CH, 3 c13 0 2 CONR2 HN (R3) 2 C2H5 4 C, 3 0 3 CONR2 HN (R3) 2 CH3 5 C, 0 3 CONR2 HN (R) 2 CH3 6 c ,, 0 3 CONR2 HN (R3) 2 C2H5 7 C "0 3 CONR2 H / \ ONZ \ / 8 C, 4 0 2 R2NCO H / \ - NHNZ \ / 9 C, 3 0 3 CONR2 H / \ - N CH, NZ \ / 10 C, 3 0 3 CONR2 CH3 N (R3) 2 CH3 11 C, j 0 3 CONR2 H / \ N CH OH NZ \ / 12 C, 2 5 3 CONR2 HN (R3) 2 CH3 13 C.2 4 R2NCO HN (R3) 2 CH3 14 C, 2 0 3 CONR2 II N (R3) 2 CH3 15 c, 0 3 CONR2 CH3 N (R3) 2 CH3 16 C "0 3 CONR2 H / \ N C2H4OH NZ \ /
17 c, 3 0 3 CONR2 H - O N Z
The most preferred compound is compound No. 4, which is known as N, N-Dimethyl-N'-tetradecanoyl-l, 3-? Ropylene-diarnin. Some of the compounds of the present invention are available from commercial sources. For example, compound No. 4 is available with MTRISTOCORR, myristamidopropyldirnethylamine phosphate from Hoff an-La Roche Inc. Nutley, New Jersey (E.U.A.) and as chercodine M from Scher Chemicals Inc., Clifton Ne? Jersey (E.U.fl.); Compound No. 5 is available as LEXAMINF "L-13, lauramidopropyl ethylamine from Inolex Chemical Cornpany, Philadelphia, Pennsylvania (EUfl.), and Compound No. 1 is available as L EXAMINE" S-13, ester-ararnidopropyl dimethiamine also of Inolex Chemical Cornpany. The compounds of the present invention can be synthesized according to the following two reaction schemes:
SCHEME 1:
The following reaction scheme can be used * to synthesize compounds where X is C0NR2;
In the above reaction scheme, A is a good residual group, such as chloride or N-hydroxysuccinimide. SCHEME II;
The following reaction scheme can be used to raise * to synthesize compounds where X is NR2C0:
The following article can be consulted * for additional details regarding the synthesis of the amino acids of formula I of scheme I: Muzyczl-o and others, "Fatty Amidoarnme Derivatives: N, ND? Rnethyl - N ~ (e-al ynrnidopropiDa ines and Their * Salts, "Journal of the American Qil Chemists' Society, volume 45, number 11, pages 720-725 (1968) All the contents of the aforesaid article are incorporated herein by reference herein.
descriptive The aforementioned article does not disclose the use of compounds of the formula T as disinfectants or preservatives in ophthalmic products, particularly products used in the care of contact lenses. The compounds of the formula I can be used individually, in combination with one or more other compounds of the formula I, or in combination with other disinfectants or preservatives. The compounds, for example, can be used in combination with the polymectic quaternary ammonium compounds described in US Patent No. 4,407,791, the entire contents of this patent therefore being incorporated herein by reference, as follows. describes in the '791 Patent those quaternary ammonium compounds polirnepcos are useful in the disinfection of contact lenses and in the preservation of ophthalmic compositions. The most preferred polymeric quaternary ammonium compound is polyquatern? U? N-1, which is also known as Onainer M ™ (non-cornoreial from Onyx Chemical Company) and Polyquad® (Registered Mark from Fll with Laboratories, TNC). The amount of polyquaternium um-l used generally to be in the range will be in the range of about 0.00005 to about 0.01% by weight, based on the total weight of the composition (X in weight). The amount of each compound used depends on the purpose of the use, v. gr .. disinfection of contact lenses or preservation of ophthalmic products and the absence or inclusion of other antirnicrobial agents. The concentrations
determined as necessary for the purposes stated above may be described functionally as "an effective amount to disinfect" and "an effective amount to conserve" or variations thereof. The concentrations used for disinfection will generally be on the scale of about 0.00005 to approximately 0.1% by weight. The concentrations used for preservation will generally be in the range of about 0.0001 to about 0.05% by weight. The compounds of the formula (I) can be included in various types of ophthalmic compositions as preservatives, as well as to prevent microbial contamination of the compositions. The types of compositions that may be preserved by the compounds of formula I include: ophthalmic pharmaceutical compositions, such as topical compositions used in the treatment of glaucoma infections, allergies or inflammation; compositions for treating contact lenses, such as cleaning products and products for increasing the ocular comfort of patients using contact lenses, and various other types of compositions. Such as ocular lubricant products, artificial tears, astringents, etc. The compositions can be aqueous or non-aqueous, but are generally aqueous. As will be appreciated by those skilled in the art, the compositions may contain a wide variety of ingredients, such as tonicity agents (v. G .odium chloride or mannitol).
surfactants (v. g., polyoxyethylene / pyoxypyr-opylene copolymers, such as Poloxamine ™), viscosity adjusting agents (e.g., hydroxypropyl ether, cellulose and other cellulose derivatives) and pH regulating agents ( v. gr. borates, citrates, phosphates and carbonates). The present invention is not limited with respect to the types of ophthalmic compositions in which the compounds of formula I can be contained as preservatives. In fact, as already indicated, the compatibility of the compounds of the formula I with other ingredients of ophthalmic compositions, such as inorganic ions, polymers and surfactants, is a distinct advantage of the present invention, in relation to anti-microbial agents. previously used in the ophthalmic field. As with the ophthalmic compositions of the present invention which contain one or more compounds of the formula T as preservatives, the form of the compositions of the present invention contains one or more of the compounds for Contact lens disinfection purposes is not limited. The contact lens disinfection compositions of the present invention will preferably be formulated as aqueous solutions, but can also be formulated as non-aqueous solutions, as well as suspensions, gels, etc. The compositions may contain a variety of tonicity agents, surfactants, viscosity adjusting agents and regular pH agents as described above.
The chemical compatibility of the compounds of the formula T is also a significant advantage over the use of these compounds in the contact lens disinfecting compositions of the present invention. The compositions described above can be used to disinfect contact lenses in accordance with procedures known to those skilled in the art. Very specifically, the lenses will first be removed from the eyes of the patients and then immersed in the compositions for a sufficient time to disinfect the lenses. This immersion will typically be achieved by soaking the lenses in a solution overnight (ie, approximately 6 to 8 hours). The lenses will then be rinsed and placed either o o o. In addition to immersion and disinfectant compositions, the lenses will preferably also be cleaned and rinsed. The compounds of formula T also have active surface properties. As a result of being-properties, the compounds are also useful for cleaning * contact lenses. Very specifically, the surfactant properties of the compounds facilitate the removal of deposits typically accumulated in contact lenses when used by human patients. These deposits vary from one patient to another, eg they will typically include proteins, lipids, polysaccharides and mixtures thereof, as well as some other dirt that may accumulate on the lenses.
during normal use and handling. The compounds will show some cleaning effect even at relatively low concentrations required for purposes of preserving ophthalmic compositions or disinfecting contact lenses. This cleaning effect is therefore useful as a complement to make other cleaning agents that can be contained in the compositions, such as ammonium or nonionic surfactants. In addition, when used at a concentration of 0.01% by weight or greater, the compounds show a more pronounced cleaning effect. The manner in which the cleaning effect of the compounds of the formula I used depends on the contact lens tLp being treated, the acceleration and type of the lens deposits and the overall treatment regime used by the lens. the patient. The selection of other components to be included in contact lens cleaning compositions of the present invention will also depend on their factors. The cleaning compositions will generally contain one or more compounds of the formula T in an amount of at least 0.01% by weight and preferably from about 0.01 to 1.0%. The compositions described above can be used to clean contact lenses according to known procedures. For example, lenses after being removed first from the eye and preferably also rinsed, may be lightly rubbed with a small amount of the compositions on the fingers or may be
Submerged in a little larger volume the compositions and then let it soak. The lenses are then rinsed and disinfected before being placed back in the patient's eyes. All of the compositions described above will be formulated to be compatible with the eye and / or contact lenses to be treated with the compositions. As will be appreciated by those skilled in the art, ophthalmic compositions designed for direct application to the eye will be formulated to have a pH and tonicity that are compatible with the oo. This will usually require a pH regulator to maintain the pH of the composition at or near physiological pH (i.e. 7.4) and may require a tonicity agent to bring the osnolality of the composition to about 300 rnillols. The formulation of disinfecting and / or contact lens cleaning compositions will involve similar considerations, as well as considerations related to the physical effect of contact lens materials and the potential for uni-absorption of contact lenses. the components of the composition by the len. The compositions and methods of the present invention may be used in conjunction with various types of contact lenses, including both lenses generally classified as "hard" and lenses generally classified as "soft." The following examples are presented to further illustrate the methods of synthesis of the aido-amines of the
present invention.
EXAMPLE 1
NN-Dimethyl-N-dodecanoyl-l, 3-propylenediamine (Compound No. 5) A round bottom flask of 500 nln containing a solution of lauroyl chloride (19.38 g, 09 mM) in dry chloroform (200 nl) cooled to 0 ° C on an ice bath .. A solution of N, N-dimet? 1-1, 3-pro? Andiam? Na (10.40 g., 51 rnM) and triethylamine (9.40 g, 93 mM) in dry chloroform was added dropwise to the cold solution through an addition funnel, then of heating to room temperature and stirring for 2 hours. The chloroform was removed or reduced pressure and the residue was redissolved in an ethanol / water mixture. And neutralized with baking soda. Extraction with chloroform (4 x 50 rnl). The combined extracts were dried (Mg TiO?), Concentrated and the residue was distilled under reduced pressure (bp 171 ° C, 10 μg) to give 23.92 g B68% of the compound as an amber solid *. 1 H NMR (200 MHz, CDCl 3): 63.33 (q, 2H, NH-CH?), 3.37 (t, 2H, CH 2 N (CH 3) 2), 2.23 (s, 6 H, N (CH 3) 2), 2.15 ( t, 2 H, CH2CO), 1.62 (m, 4H, CH? CH2C0, CH2 CH2 Ni CH3) 2), 1-26 (s, 16H, CH2-), 0.88 (t, 3H). Elemental analysis: Calculated for C17H30N2O; C,
71, 77; H, 12.75; N, 9.85.
Found: C, 72.06; H, 12.76; N, 9.94. IR (net): 3280, 2910, 2840, 2800, 2750, 1460, 1370, 1260, 1125, 1035 cpr 1"
EXAMPLE 2
N ^ -dimethyl-N'-Tetradecanoyl-1'-Propylenediamine (Compound No. 4) 2.0g (0.0196 moles) of 3-dirnethylanil? Nopro? Larn? 40 ml of chloroform was added dropwise to an ice-cold chloroform solution (50 ml) of myristyl chloride (4.17 g, 0.0169 mol). After the addition, the ice bath was stirred and the solution was stirred for 2 hours. An aqueous solution of 25 mmol of sodium bicarbonate was added and stirred for 30 minutes. An organic layer was then washed with
ml of aqueous solution of sodium bicarbonate / sodium chloride and dried with magnesium sulfate. The solution was concentrated in vacuo and the amide was crystallized from ethyl acetate to yield 3.29 g (0.0105 mol, 62.3%) of the present compound. 1 H NMR (200 HH, CDCl 3): & 6.9 (s, IH, NH), 3.3 (q, 3H, NHCH2), 2.4 (t, 2H, NCH2), 2.22 (s, 6H, NCH3), 2.15 (t, 2H, C0CH2), 1.7-1.5 (rn , 4H, C0CH2CH2 and NHCH2CH2), 1.25 (s, 20H, COCH2CH2 (CH2) 10), 0.88 (t, 3H, CH3). Elemental analysis: Calculated for C19H40N2O
(312.42): H, 12.90; N
Found: C, 72.96; H, 12.92; N, 8.93.
EXAMPLE 3
N, N-Diethyl-N'-Tetradecanoyl-l, 2- Ethylenediamine (Compound No. 3) 8.35 g (0.072 mole) of 3-d? Me? Lar? No? Rop? Larn? Na in 40 ml of chloroform is added dropwise to an ice-cold chloroform solution (60 rnl) of rniristol chloride (15.84 g, 0.064 mol). After the addition, the ice bath was stirred and the solution was stirred for 6 hours. The reaction mixture was then stirred with aqueous sodium bicarbonate solution for 10 minutes and the organic layer was washed with an aqueous solution of sodium bicarbonate / sodium chloride. The organic layer was then dried over magnesium sulfate and concentrated in vacuo leaving a white solid. The amide was recrystallized from ethyl acetate, filtered and dried to yield 16.58 g (0.051 mol, 79.1%) of the present compound. 1 H NMR (200 HHz, CDCL 3): 66.2 (s, 1 H, m), 3.3 (q,
2H, NHCH2), 2.6.-2.5 (rn, 6H, NCH2), 2.2 (t, 2H, C0CH2), 1.6 (rn,
2H, COCH2), 1.25 (s, 20H, COCH2 CH2 (CH_2) l?), 1.03 (t, 6H,
NCH2 CH2.CH3) • An ele i elemental: Calculated for C20H42N2C (326.54): H, 12.96; N Fncon: C, 73.44; H, 12.97; N, B ..56.
EXAMPLE 4
N, N-Diethyl-N'-Dodecanoyl-l, 3-Propylenediamine (compound No. 6).
A 500 ml round bottom flask containing a solution of lauroyl chloride (19.03 g, 87 rnM) in dry chloroform (200 rnl) was cooled to 0 ° C on an ice bath. A solution of N, N-diethyl 1-1, 3-propanediarnine (15.00 g, 115 mil) in dry chloroform (25 nmol) was added dropwise to the cold solution and then allowed to warm to room temperature and stirred for 2 hours. The chloroform was removed under reduced pressure and the residue redissolved in a mixture of ethanol / water (1: 1) and neutralized with sodium bicarbonate, followed by extraction with chloroform (4 x 50 ml). The combined extracts were Dried (MgSO) were concentrated and the residue was distilled under reduced pressure (bp 176 ° C, 20u) to give 41.47 g (79%) of the present compound as an amber oil. 1 H NMR (200 HHZ, CDCl 3): or 3.33 (q, 2 HNH-CH 2), 2.52 (III, 6 H, CH 2 N (CH 2 CH 3), 2.15 (t, CH 2 CO), 1.63 (m, 4 H, CH 2 CH 2 CO, CH 2 CH 2 N ( CH2CH3) 2, 1.25 (s, L6H, -CH2 -), 1.04 (t, 6H,
N (CH2CH3), 0.88 (t, 3H, -CH3). IR (net): 3280, 3080, 2910, 2840, 2800, 2750, 1640, 1550, 1460, 1370, 1280, 1100, 1060 cm-i MS (Cl): m / e 313 (MH +) "
EXAMPLE 5
N-Tetradecyl-3- (l-piperazino) propionamide (Compound No. 8)
. 6 g (0.0835 mole) of 3-chloropropionoyl chloride in 50 ml of chloroform was added dropwise to a 100 liter ice-cold chloroform solution containing 14.4 g (0.018 mmol) of te + radeci sheet and 11.3 g ( 0.112 mol) of tetylamine. The reaction mixture was stirred for 3 hours and washed with 3 x 75 rnl of aqueous sodium chloride followed by 75 ml of cold aqueous sodium chloride. The chloroform layer was dried (MgSO 2) and concentrated in vacuo resulting in a solid which was successively crystallized from ethyl acetate to yield 18.22 g (73.6%) of the chloropropioni lamide. 76. g. (0.025 moles) of the amide intermediate was reacted with 21.6 g. (0.25 moles) of piperazi a in 25 ml of dirnetilsul phoxide at 125 ° C for k hours. This reaction mixture was treated with 200 mL of ice-cold aqueous sodium bicarbonate containing sodium chloride and then, extracted with 3 x 70 L of chloroform, the combined chloroform layers were washed with aqueous sodium chloride (4 x 225 mL), dried (MgSO 4) filtered, concentrated in vacuo and dried at 80 ° C under reduced pressure. high vacuum to produce a white precipitate. The precipitate was successively crystallized from ethyl acetate to give 3.0 g 32.0%) of the present compound.
1 H NMR (200 HHz, CDCL 3): 63.2 - 3.3. (q, 2H, CH3 (CH2) nCH2CH_2), 2.9 (t, 4H, piperazine), 2.6 (t, 2H, C (= 0) CH2), 2.5 (, 4H, piperazine), 2.4 (t, 2H, C (= 0) CH2 CH2), 1.5 (n, 2H, CH3 (CH2) ll (CH2), 1.25 (width s, 22H, CH3 ICHj? N), and 0.88 (t, 3H, CH3). Elemental analysis: Calculated for C2iH /; 3N30 (MU 353.57): H, 71.33; H, 12.25; N, 11.88 Found: C, 71.26; H, 12.20; N 11.86.
EXAMPLE 6
3-Dimethylamino-N- (3,6,9,16-tetraoxa-tetracosyl) ropione ida (Compound No. 13) A chloroform solution of 60 rnl containing 3.7 g (0.0102 mole) of Ci 2 (PEO) 4 NH 2 (prepared by reaction of etherol? ox? et? in ~ 4-laupl? co with thionyl chloride followed by reaction with potassium phthalimide and then deprotection by h? dr * azma) and 2.25 g. (0.017 moles) of N, Nd? Soprop? Let? Larn? Na, was added dropwise to an ice-cold 50-chloroform solution containing 1.88 g (0.10148 mol) of 3-chloroprochloride? on it. The reaction mixture was stirred for 2 hours, washed with aqueous HCl (1 x 150 mL) and aqueous sodium chloride solution (2 x 75 mL) successively, dried
(MgSO 3), filtered and concentrated in vacuo to give 3.72 g. (80.7%) of the chloropropioni lo intermediary. A 50 mL tetrahydrofuran urane solution of 2.72 g
(0.006 moles) of the chloropropionyl intermediate was reacted with an excessive amount of direthylamine at 80 ° C overnight. The reaction mixture was concentrated in vacuo, dissolved in 50 ml of chloroform and washed with an aqueous solution of sodium chloride containing sodium bicarbonate solution (3 x 10 ml). The organic layer was dried (MgSO 4), filtered and concentrated in vacuo. This material was purified by ion exchange chromatography to give (12.7%) of the present compound. 1 H NMR (CDCl 3): 6 8.2 (broad, 1H, NH), 3.6-3.4
(width, L8H, PEO), 2.6 (app t, 2H, C (= 0) CH2), 2.3 (app t, 2H, NCH2), 2.2. (s, 6H, N (CH3) 2), 1-5 (m, 2H, (CH2) 9 (CH2), 1.2 (width s, 18H, (CH_2) 9) and 0.8 (app t, 3H, CH3) Elemental analysis: Calculated for C27H56N2O6 • 1/2 H2O (MU 513.76) C, 63.12 H, 11.18; N, 5.45 F, cont: C, 52.77; H, 10.92; N, 4.02
EXAMPLE 7
N ^ -Dimethyl-N '- (3,6,9,12,15-pentaoxa-heptacosanoyl) -1, 3-propylendia ina (compound No. 12) A mixture of 4.4 g (0.0104 moles) of
C12 (PEO) 4ÜCH2C00H (made from carboxy ether of etherol? Ox? Et? Len-4-lauryl with sodium hydroxide and sodium chloroacetate) and 1.26 g (0.011 moles) of N-hydroxysuccinimide N-hydroxysuccinimide he was made to react
with 2.31 g (0.0112 mol) of dicyclohexylcarbodurnide in an ice bath, under argon for 4 hours. The reaction mixture was treated with acetic acid several times, filtered and concentrated in vacuo to yield 5 g (86%) of the activated ester. A 20 L ice-cold ethyl acetate solution of 5 g (0.009 mole) of the activated intermediate was reacted with 1.86 g (0.0182 mole of N, N-dirnetiipropylendiarnine for 1 hour, and then for another 2 hours at room temperature The solution was then diluted with 60 mL of ethyl acetate and washed with aqueous sodium chloride (3 x 10 mL), the organic layer was concentrated in vacuo, redissolved in ethyl acetate, filtered, concentrated to a vacuum and dry over the vacuum pump to give 3.68 g (72.0%) of the present compound, 1 H NMR (CDCl 3): 7.5 (width 1 H, NH), 4.0 (< - ,,? II, C (-0) CH2), 3.6 (width, 18H, PEO), 3.4 (t, 2H, C (-OCH2OCH2), 3.3 (q, 2H, NHCH2), 2.3 (t, 2H, NCH2), 2.2. (S, 6H, N (CH3) 2), 1.7 (m, 2H, NHCH2CH2), 1.6 (rn, 2H, CH2), 1.3 (width s, 1TH, (CH2) 9), and 0.9 (t, 3H, CH3). Calculated for C28H58N2O6.5 (MU (525.78); C, 63.84; H, 11.10; N, 5.32, Found: C, 63.89; H, 11.01; N, 5.03.
EXAMPLE 8
4-Hydroxyethyl-N-dodecanoyl-l-piperazinepropylamine (Compound No. 16) A chloroform solution of 50 rnL of 2.45 g (0.0112 mole) of dodecanoyl chloride was added dropwise under argon to a chloroform solution of 50 nm cooled with ice of 2.12 g, (0.0113 moles) of N- (3-arn? No? Ropi 1) ~ N '- (2-hydroxyethyl) ??? eraz? Na and stirred for one hour maintaining the temperature between 2- ° C. This reaction mixture was then treated with 100 mL of aqueous sodium bicarbonate and extracted with chloroform (2 x 50 mL). The layers of chlorophyll cornbi were washed with aqueous sodium bicarbonate (2 x 50 mL), dried (MgSC), filtered and concentrated in vacuo. The remaining solid was crystallized from ethyl acetate / hexane to give 1.69 g (40.8%) of the present compound. 1 H NMR (CI) Cl 3): 3.6 (t, 2 H, HOCH?), 3.3. - 3.4 (, 2H, NHCH2), 2.4 - 2.7 (m, 12H, H0CH2CH2, piperazine), 2.1 -2.2 (t, 2H, C (= 0) CH2), 1.5 - 1.7 (, 4H, (CI-bßCH? , NHCH2CH2), 1.25 (s, 16H, (C ís), and 0.88 (t, 3H, CH3) - Elemental Analysis: Calculated for C21H43N3O2 (MU (369.59); C, 68.25; H, 11.73; N, 11.37. Found: C, 68.15; H, 11.82; N, 11.32.
EXAMPLE 9
N, N-Dimet? L-N'-dodecanoyl-N'-methyl-1,3-propylenediamine (compound No. 15)
A mixture of 3.89 g (0.0335 moles) of N, N, N '~ t r? Et? L-l, 3-propylene and ma and 4.33 g. (0.0355 moles) of N, N-diisopropylethiamine in 50 rnL of chloroform was added to 7.33 g (0.0335 moles) of lauroyl chloride dropwise, on an ice bath, and then reacted for another two hours at room temperature. ambient. 75 mL of aqueous sodium bicarbonate was then added to this reaction mixture, and the chloroform layer was separated and washed with 125 mL of aqueous sodium bicarbonate followed by 100 mL of water. The chloroform layer was then dried (MgSO 4), filtered and concentrated in vacuo. The acidified compound (with hydrochloric acid) was concentrated in vacuo and then crystallized from acetone t ryl to give 3.04 g (0.0102 mol, 30.4%) of the present compound. 1H NMR (CDC13) *: 6 3.5 (t, 2H, CO-NCH2), 3.1 (< = >, 1H,
N-CH3), 3.0 (t, 2H, N-CH2), 2.8 (s, 6H, N- (CH3) 2), 2.3 (t, 2H, CO-CH2), 2.2 (m,? H, NCH2CH2) , 1.6 (, 2H, C0CH2 CH2), 1.3
(width s, 16H, CH2), and Q.9U, 3H, CH3). Elemental Analysis: Calculated for C18H39 2OCI • (MU (334.47); C, 64.83; H, 11.94; N, 8.4f). Found: C, 54.59; H, 11.80; N, 8"27
EXAMPLE 10
N-N-Dimethyl-N * -dodecanoyl-N'-roethyl-l, 3-propylenediamine (Compound No. 10)
A mixture of 3.56 g (0.0306 moles) of N, N, N '~ tr? Rnet? L-1, 3-propaned? Amine and 3.96 g (0.0306 moles) of N, N-dn sopropí letilanina in 50 mL of chloroform on an ice bath was added dropwise to 7.55 g (0.0306 moles) of rninstoyl chloride, and then reacted for two hours.
The reaction mixture was then treated with 75 mL of aqueous sodium bicarbonate. The separated chloroform layer was washed with aqueous sodium bicarbonate and water successively. The dried chloroform layer (MgSC) was filtered and concentrated in vacuo. The acidified compound (with HCl) was crystallized (2x) from acetonitrile to yield 1.00 g (10%) of the present compound. 1 H NMR (CDCl 3): 6 3.5 (t, 2 H, CO-NCH 2), 3.1 (s, 3 H, N-CH 3), 3.0 (t, 2 H, N-CH 2), 2.8 (s, 6 H, N- (CH 3 ) 2), 2.3 (t, 2H, CO-CH2), 2.2 (m, 2H, NCH2CH2), 1.6 (rn, 2H), COCH2CH29, 1.3
(width, 20H, CH2), and 0.9 (t, 3H, CH3). Elemental Analysis: Calculated confident 0.2? H43N2? C? (MU (363.03); C, 66.17; H, 11.94; N, 7.72. Found: C, 65.96; H, 12.00; N, 7.67.
EXAMPLE 11
N, N-Dimethyl-N'-tridecanoyl-1, 3-propylenediamine (Compound No. 14) A mixture of methyl t-decanoate (11.4 g 0.05 mol) and N, Nd? Methylprop? Lend? Am? Na (7.7) g., 0.05 mole) was reacted at 180 ° C for 5 hours with removal of the ethanol from the reaction mixture and crystallized from acetonitrile to give (66.7%) of the present compound. PF: 39-40 ° C 1 H NMR (CDCl 3): 6.9 (broad, 1H, NH), 3.35 (app. Q, 2H, NHCH2), 2.4 (t, 2H, NCH2), 2.2 (s, 3H, N ( CH3) 2), 1.65 (m, 4H, CH2), 1.3 (app. S, 18H, CH2), 0.9 (t, 3H, CH3). Elemental analysis: Calculated for C18H38 2O (298.51); C, 72.43; H, 12.83; N, 9.38. Found: C, 72.54; H, 12.87; N, 9.40.
EXAMPLE 12
4-Hydroxyethyl-N-tetradecanoyl-l-piperazinepripylarnine (Compound No. 11) A chloroform solution of 50 rnL of 6.21 g (0.0251 mole) of mipstoal chloride was added dropwise under argon to a chloroform solution of 75 ml. cooled with ice of 4.79 g, (0.0256 mol) of N- (3-arnmopropyl) -N '- (2-hydroxyethi) piperazine. After stirring for 2 hours,
100 ml of aqueous sodium carbonate was added and stirred for 30 minutes. The layers were separated and the chloroform layer was washed with aqueous sodium carbonate (2 x 125 inL) followed by water (2 x 75 inL). The chloroform layer was concentrated in vacuo and the remaining amber liquid was successively crystallized from ethyl acetate to give 4.56 g,
(45.6%) of the present compound. 1 H NMR (CDCl 3): 6 3.6 (t, 2 H, H 0 CH 2), 3.3 - 3.4 (q,
2H, NHCH2), 2.4-2.6 (n, 12H, HOCH2CH2., NHCH2CH2CH2, piperazm), 2.1 (t, 2H, C (= 0) CH2, 1.5-1.7 (m, 4H,
CH3 (CH2) l? CH_2, NHCH2CH2), 1.25 (width S, 20H, CH3 (CH2)? O), 0.88
(t, 3H, CH3) - Elemental Analysis: Calculated for C23H47N3O2 • 1/2 H2O
(MU (406.65); C, 67.93; H, 11.89; N, 10.33.) Found: C, 67.84; H, 11.56; N, 10..35.
EXAMPLE 13
4-Methyl-N-tetradecanoyl-l-piperazinepropylamine (Compound No. 9) 4..7 g (0.03 mole) of N-met Ll -N '- (3-arn? Nopropyl) -piperazine (prepared from N -met ilpí perazma and acplonitrilo and subsequently reduction to the primary amine) in 200 mL of chloroform was cooled in a bath with luelo. To this was added 7.3 g (0.03 mole) of rnipstoyl chloride dropwise for 7 hours. The reaction mixture was brought to
room temperature and then allowed to react for another 4 hours. The reaction mixture was treated with 10 g of sodium bicarbonate in 100 ml of water and the separated chloroform layer was washed with water (2 x 200 ml). The organic layer was dried (Mg 0") filtered and concentrated in vacuo. Crystallization from acetonitrile gave 8g (72.3%) of the present product. MP 55-56 ° C 1H NMR (CDCl 3): 6 7.1 (broad, 1H NH), 3.35 (app. Q, 2H, NHCH2), 2.5 (app t, 8H, piperazine), 2.3 (s, 3H, NCH3) , 2.15 (t, 2H, COCH2), 1.65 (rn, 4H, CH2, 1.3 (app.s, 22H, CH2) and
0. 9 (t, 3H, CH3). Elemental analysis: Calculated for C22H45N3O (MU 367.62); C, 71.88; H, 12.34; N, 11.43. Found: C, 71.88; H, 12.10; N, 11.40 CG: 97.3%.
EXAMPLE 14
N-Dodecanoyl-1-morpholinopropylamine (Compound No. 7) To a 100 in.L round bottom flask equipped with a magnetic stir bar and an addition funnel, a mixture of 2.00 g was added. (9.14 rnM) of lauroyl chloride in chloroform (50 ml), cooled in an ice bath. Through the addition funnel, a solution of 1.32 g (9.15 mM) of 4- (3-arn? Noprop? L) yle dazol and 1.0 g (9.9 mM) of triethyl chloride in chloroform (10 mL) was then added drop drop to the solution
hectic cold. After the addition, the ice bath was removed and the reaction allowed to stir overnight at room temperature. The chloroform was removed by rotary evaporation and the residue redissolved in ethanol / water (1: 1). 2 g. (24 rnM) of sodium bicarbonate was then added, and the mixture was stirred for several hours. The aqueous mixture was extracted with ethyl acetate (3 x 50 rnL), the combined organic extracts were dried (MgSC) and the filtrate was concentrated. The residue was crystallized from hexane / ethyl acetate to give 1.57 g. 53%) of white crystals of the present compound.
MP: 52-54 ° c 1 H NMR (CDC13): 6 7.27 (S, 1H, NH), 3.72 (t, 4H, CH2 -O-CH2), 3.34 (t, 2H, CH2-NH), 2.46 (t , 6H, N (CH2) 3), 2.15 (t,? H, CH2, CH2-CO), 1.68 (ffl, 4H, CO-CH2-CH2 and N-CH2 ~ CH2 -CH2-NH),
1. 26 (s, 16H, C0-CH2-CH2- (CHj2)?), 0.88 (t, 3H, CH3). Elemental analysis: Calculated for C19H38N2O2 0.9H2? (342-72); C, 66.59; H, 11.70; N, 8.17. Found: C, 66061; H, 11.47; N, 8.03 CG: greater * of 99%.
EXAMPLE 15 N-Tetradecane l-1-morpholinopolyol (Compound No. 17) To a 100-mL round bottom flask equipped with
a magnetic stir bar and an addition funnel, a mixture of 2.67 g was added. (10.82 mM) of rnipstoyl chloride in chloroform (50 rnL), cooled in an ice bath, through the addition funnel, a solution of 1.60 g (11.09 M) of 4- (3-arn? Noprop? L) Rn? dazol and l.ll g (10.97) mM) of triethyia in chloroform (10 mL) was added dropwise to the cold stirred solution. After the addition, the ice bath was removed and the reaction allowed to stir overnight at room temperature. The chloroform was removed by rotary evaporation and the residue redissolved in ethanol / water (1: 1). 2g. (24 mM) of sodium bicarbonate was then added, and the mixture was stirred for several hours. The aqueous mixture was extracted with ethyl acetate (3 x 50 mL), the combined organic extracts were dried (MgSO) and the filtrate was concentrated. The residue was crystal LZO from hexane / ethyl acetate to give 3.0 g. (78%) of white crystals of the present compound. MP: 62 ~ 64 ° C 1 H RM- (CDC13): 6 7.27 (S, 1H, NH), 3.73 (t, 4H, CH2 -O-CH2), 3.36 (t, 2H, CH2-NH), 2.15 ( t, 6H, N (CH2) 3), 1.68 (? n, 4H, CO-CH2-CH2 and N-CH2-CH2-CH2-NH), 1.26 (s, 20H, C0 ~ CH2-CH2- (CH210 ), 0.88 (t, 3H, CH3) Elemental Analysis: Calculated for C21H42N2O2 (354.56); C, 71.14; H, 11.94; N, 7.90. Found: C, 70.86; H, 11.85; N, 7.78 CG: higher * of 98% The following examples were presented to illustrate
also ophthalmic compositions which may contain one or more of the compounds of the formula (T):
EXAMPLE 16
The following formulation could serve as a vehicle for an ophthalmic drug. The formulation would contain one or more compounds of the formula (I) as a preservative.
Ingredient Quantity (% by weight) Sodium chloride 0.5% Mannitol 2.5% HEPE 0.119% NaOH / CHl pH 7.0 Purified water CBP 100
EXAMPLE 17
The following formulation can be used as a contact lens disinfection solution. The formulation may contain one or more compounds of the formula I co or a disinfectant.
Ingredient Quantity (% by weight) Mannitol 0.64% (w / v) Boric acid 0.225% Sodium borate 0.08% Sodium citrate 0.46% Citric acid 0.016% Sodium chloride 0.48% Sodium disodium 0.05% NaOH / CHL pH 7 0 A ua Purificada CBP 100
EXAMPLE 18 The following formulation, which could contain one or more of the compounds of the formula (I) ee, could be used as a contact lens disinfection solution, and would also assist in the cleaning of the lenses.
Ingredient Quantity (% by weight) Boric acid 0.58% Sodium borate 0.18% Sodium chloride 0.49% Disodium edetate 0.05% PoloxarnmaTM 0. IX Polyquate pn num-1 0.001% NaOH / CHl pH 7 0 Water Pup fied CBP 100
Claims (24)
1. - A preserved pharmaceutical composition comprising an aqueous ophthalmic composition and 0.0001 to 0.05% by weight of a compound of the following formula for preserving said ophthalmic composition against microbial contamination: Rl- (0CH2CH2) mX - (CH2) n "Y (I) where: 0 0 And it is- -N (R3) 2 or -N Z Z is oxygen or NR4; R1 is alkyl, the saturated or saturated alkoxyac or saturated Ce-Cis; m is zero to 16; n is 2 to 16; R2, R31 and R4 < independently of hydrogen, alkyl or hydroxyalkyl saturated or unsaturated Ci-C, or a pharmaceutically acceptable salt thereof, provided that when: 0 R2 is H, Y is ~ -N (R3) 2, and R3 is different from hydrogen, rn can not be * zero.
2. A composition according to claim 1, further characterized in that n is 2 to 4, and is 0 to 5.
3. A composition according to claim 2, further characterized in that R2 is hydrogen or methyl, and R3 is methyl or ethyl.
4. A composition according to claim 1, further characterized in that Rl is heptadec-ñ-enyl, undecyl, undecenyl, dodecyl, tridecyl, tetradecyl, pentadecyl or heptadecyl, R2 is hydrogen or methyl, R3 is methyl or ethyl and R * is hydrogen, methyl or hydroxyethyl.
5. An axis composition conformed with claim 1, further characterized in that * is tpdecyl, m is 0, n is 3, Y is (R3) 2 and R3 is methyl.
6. - An ophthalmic composition for disinfection of contact lenses, comprising axis 0.0001 to 0.05% by weight of a compound of the following formula: Rl ~ (0CH2CH2) ffl-X ~ (CH2) n -Y (I) where : 0 0 And the T; -N (R3) 2 or -N Z Z is oxygen or NR4; R1 is alkyl, alkylamino or saturated alkoxyap or Cs-Cis saturated; rn is zero to 16; n is 2 to 16; R2, R3; and R 4 is independently hydrogen, alkyl or hydroxyalkyl, which is saturated or unsaturated, or a pharmaceutically acceptable salt thereof, provided that when: OR R2 is H, Y is --N (R3) 2, and R3 is different from hydrogen, it can not be zero.
7. A composition according to claim 1, further characterized in that n is 2 to 4, and rn is 0 to 5.
8. A composition according to claim 7, characterized aejemás because R2 is hydrogen or methyl, and R3 is methyl or ethyl.
9. A composition according to claim 6, further characterized in that Rl is heptadec-8-enyl, undecyl, undecenyl, dodecyl, tridecyl, tetradecyl, pentadecyl or heptadecyl, R 2 is hydrogen or methyl, R 3 is methyl or ethyl, and R * is hydrogen, methyl or hydroxyethio.
10. A composition according to claim 6, further characterized in that R1 is tridecyl, rn is 0, n is 3, Y is N (R) 2 and R3 is methyl.
11. A composition according to claim 6, further characterized in that it comprises from 0.0005 to 0.01% by weight of polyquatern? Um-1.
12. A method for disinfecting a contact lens comprising immersing the lens in an anti-microbial composition for a sufficient time to disinfect the lens, said composition comprising 0.0005 to 0.01% in weight of a compound of the following formula: R1- (0CH2CH2) m ~ X- (CH2) n -Y (I) in which: And it is- -N (R3) 2 or -N Z Z is oxygen or NR4; R 1 is alkyl, alkylamino or saturated alkoxapella or more saturated of C 6 ~ Ci 87 rn is zero to 16; n is 2 to 16; R, R3, and R4 are independently hydrogen, alkyl or hydroxyalkyl saturated or unsaturated Ci-C, or a pharmaceutically acceptable salt thereof, provided that when: 0 R2 is H, Y is ~ -N (R3) 2, and R3 is the hydrogen, in can not be zero. 13.- A method of compliance with the claim 12, further characterized in that n is 2 to 4, and rn is 0 to 5. 14. A method of compliance with the claim 13, further characterized in that R2 is hydrogen or methyl, and R3 is methyl or ethyl. 15. A method of confopnielad with claim 12, further characterized in that Rl is heptadec-8-en? it, undecyl, unececem, dodecyl, tridecy, tetradecyl, pentadecyl or heptadecyl, R2 is hydrogen or methyl, R3 is methyl or ethyl and R 4 is hydrogen, methyl or hydroxyethyl. 16. A method according to claim L2, further characterized in that R * is tpdecyl, rn is 0, n is 3, Y is N (R3) 2 and R3 is methyl. 17. A method according to claim 12, further characterized in that it comprises from 0.0005 to 0.01% by weight of polyquaterna urn-1. 18.- A method for preserving an ophthalmic composition which comprises including in the composition from 0.0001 to 0.05% by weight of a compound of the following formula for maintaining said ophthalmic composition against microbial contamination: R1- (0CH2CH2) m ~ X- (CH2) nY (I) wherein: 0 Z is oxygen or NR4; I is alkyl, alkylamino or saturated alkoxyap or C-Ciß axis; w is zero to 16; n is 2 to 10; R, R3, and R4 are independently hydrogen, alkyl or hydroxyalkyl, the saturated or unsaturated Ci-C, or a pharmaceutically acceptable salt thereof, provided that when: 0 X TÍ -C ~ -NR2 or R2 is H, Y is --N (R3) 2, and R3 is different from hydrogen, m can not be zero. 19. A method according to claim 18, further characterized in that n is 2 to 4, and m is 0 to 5. 20. A method according to claim 18, further characterized in that R 2 is hydrogen or methyl, and R 3 is methyl or ethyl. 21. A method according to the claim 10, further characterized in that Rl is heptadec-8 ~ enyl, undecyl, undecenyl, dodecyl, tridecyl, tetradecyl, pentadecyl or heptadecyl, R 2 is hydrogen or methyl, R 3 is methyl or ethyl and R 4 is hydrogen, methyl or hydroxyethyl. 22. A method according to claim 18, further characterized in that R1 is tpdecyl, m is 0, n is 3, Y is N (R3) 2 and R3 is methyl. 23. An axis method according to claim 12, further characterized in that it comprises 0.0005 to 0.01% by weight of polyquaterniu-1. 24. A method according to claim 23, further characterized in that said composition comprises also an effective amount of an ophthalmically effective surfactant.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08395017 | 1995-02-27 | ||
US08/395,017 US5573726A (en) | 1993-09-22 | 1995-02-27 | Use of amidoamines in ophthalmic compositions |
PCT/US1996/002588 WO1996026747A2 (en) | 1995-02-27 | 1996-02-26 | Use of amidoamines in ophthalmic compositions |
Publications (2)
Publication Number | Publication Date |
---|---|
MX9605188A MX9605188A (en) | 1997-09-30 |
MXPA96005188A true MXPA96005188A (en) | 1998-07-03 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2187034C (en) | Use of amidoamines in ophthalmic compositions | |
US5631005A (en) | Use of amidoamines in ophthalmic compositions | |
US4029817A (en) | Soft contact lens preserving solutions | |
CA1259542A (en) | Disinfecting and preserving solutions for contact lenses and methods of use | |
EP1042007B1 (en) | Aminobiguanides and the use thereof to disinfect contact lenses and preserve pharmaceutical compositions | |
AU636942B2 (en) | Contact lens disinfecting system | |
NZ541289A (en) | Use of multifunctional surface active agents such as lauroylethylenediaminetriacetate (LED3A) to clean contact lenses | |
AU691836B2 (en) | Use of amidoamines in ophthalmic compositions | |
AU725665B2 (en) | Method for providing rapid disinfection of contact lenses | |
US5627214A (en) | Use of diamines in ophthalmic compositions | |
US5900213A (en) | Use of diamines to disinfect and clean contact lenses and preserve ophthalmic compositions | |
MXPA96005188A (en) | Use of amidoamines in oftalmi compositions | |
WO2002049627A2 (en) | Antifungal compositions containing an antibiotic and one or more amidoamines | |
JPH0622542B2 (en) | Improved method for sterilizing and storing contact lenses | |
MXPA00006038A (en) | Aminobiguanides and the use thereof to disinfect contact lenses and preserve pharmaceutical compositions |