MXPA99005568A - Multi-purpose compositions and methods of use in contact lens cleaning and disinfecting systems - Google Patents
Multi-purpose compositions and methods of use in contact lens cleaning and disinfecting systemsInfo
- Publication number
- MXPA99005568A MXPA99005568A MXPA/A/1999/005568A MX9905568A MXPA99005568A MX PA99005568 A MXPA99005568 A MX PA99005568A MX 9905568 A MX9905568 A MX 9905568A MX PA99005568 A MXPA99005568 A MX PA99005568A
- Authority
- MX
- Mexico
- Prior art keywords
- composition
- enzyme
- bottle
- approximately
- container
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 227
- 238000004140 cleaning Methods 0.000 title claims abstract description 52
- 230000000249 desinfective Effects 0.000 title claims abstract description 30
- 102000004190 Enzymes Human genes 0.000 claims abstract description 122
- 108090000790 Enzymes Proteins 0.000 claims abstract description 122
- 229940088598 Enzyme Drugs 0.000 claims description 81
- 230000002255 enzymatic Effects 0.000 claims description 58
- 239000004599 antimicrobial Substances 0.000 claims description 36
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 22
- 108090000787 Subtilisin Proteins 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 239000012528 membrane Substances 0.000 claims description 18
- KGBXLFKZBHKPEV-UHFFFAOYSA-N Boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 15
- 239000004327 boric acid Substances 0.000 claims description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000011780 sodium chloride Substances 0.000 claims description 14
- 108090000631 Trypsin Proteins 0.000 claims description 12
- 102000004142 Trypsin Human genes 0.000 claims description 12
- 229960001322 trypsin Drugs 0.000 claims description 12
- 239000012588 trypsin Substances 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 10
- CBTVGIZVANVGBH-UHFFFAOYSA-N Aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 claims description 8
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 7
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 7
- 229920002362 Tetronic® 1304 Polymers 0.000 claims description 7
- 239000000600 sorbitol Substances 0.000 claims description 7
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 5
- 238000002791 soaking Methods 0.000 claims description 5
- 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 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L cacl2 Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 4
- 239000001110 calcium chloride Substances 0.000 claims description 4
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 4
- 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 claims description 4
- 239000001509 sodium citrate Substances 0.000 claims description 4
- 239000011778 trisodium citrate Substances 0.000 claims description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 15
- 101700013721 ADAL Proteins 0.000 claims 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims 3
- 229940037001 sodium edetate Drugs 0.000 claims 3
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 claims 3
- 239000002965 rope Substances 0.000 claims 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 230000000712 assembly Effects 0.000 abstract description 2
- 229940110715 ENZYMES FOR TREATMENT OF WOUNDS AND ULCERS Drugs 0.000 description 40
- 229940020899 hematological Enzymes Drugs 0.000 description 40
- 239000007788 liquid Substances 0.000 description 26
- 239000000243 solution Substances 0.000 description 21
- 239000003826 tablet Substances 0.000 description 21
- -1 polyethylene Polymers 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 13
- 102000035443 Peptidases Human genes 0.000 description 11
- 108091005771 Peptidases Proteins 0.000 description 11
- 238000004659 sterilization and disinfection Methods 0.000 description 11
- 229940024999 Proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- 239000004094 surface-active agent Substances 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 9
- 239000003085 diluting agent Substances 0.000 description 9
- 239000004615 ingredient Substances 0.000 description 9
- 230000002797 proteolythic Effects 0.000 description 9
- 230000000845 anti-microbial Effects 0.000 description 8
- 238000003860 storage Methods 0.000 description 8
- 229940055695 Pancreatin Drugs 0.000 description 7
- 108010019160 Pancreatin Proteins 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 230000001954 sterilising Effects 0.000 description 7
- 235000010338 boric acid Nutrition 0.000 description 6
- 238000007865 diluting Methods 0.000 description 6
- 235000019161 pantothenic acid Nutrition 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 229940027983 antiseptics and disinfectants Quaternary ammonium compounds Drugs 0.000 description 5
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 5
- 239000005018 casein Substances 0.000 description 5
- 235000021240 caseins Nutrition 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 229920005862 polyol Polymers 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 241000193830 Bacillus <bacterium> Species 0.000 description 4
- 206010015946 Eye irritation Diseases 0.000 description 4
- 229960004063 Propylene glycol Drugs 0.000 description 4
- 229940058933 biguanide antimalarials Drugs 0.000 description 4
- 229940090145 biguanide blood glucose lower drugs Drugs 0.000 description 4
- 150000004283 biguanides Chemical class 0.000 description 4
- 231100000013 eye irritation Toxicity 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000006011 modification reaction Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 235000013772 propylene glycol Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 229960003260 Chlorhexidine Drugs 0.000 description 3
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Exidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000002738 chelating agent Substances 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
- 238000004090 dissolution Methods 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000001105 regulatory Effects 0.000 description 3
- 235000010339 sodium tetraborate Nutrition 0.000 description 3
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-Propanediol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 239000004367 Lipase Substances 0.000 description 2
- 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 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 229920001090 Polyaminopropyl biguanide Polymers 0.000 description 2
- 239000004698 Polyethylene (PE) Substances 0.000 description 2
- 229920002413 Polyhexanide Polymers 0.000 description 2
- 108010056079 Subtilisins Proteins 0.000 description 2
- 102000005158 Subtilisins Human genes 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 230000024881 catalytic activity Effects 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 239000000645 desinfectant Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 230000002708 enhancing Effects 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 150000002334 glycols Chemical class 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 102000004882 lipase Human genes 0.000 description 2
- 108090001060 lipase Proteins 0.000 description 2
- 235000019421 lipase Nutrition 0.000 description 2
- 230000002366 lipolytic Effects 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000000813 microbial Effects 0.000 description 2
- 230000001264 neutralization Effects 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 150000002978 peroxides Chemical class 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000007916 tablet composition Substances 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
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (-)-propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- 229940058020 2-amino-2-methyl-1-propanol Drugs 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- JWRLKLYWXKMAFL-UHFFFAOYSA-N 4-[4-(4-aminophenoxy)-3-phenylphenoxy]aniline Chemical compound C1=CC(N)=CC=C1OC(C=C1C=2C=CC=CC=2)=CC=C1OC1=CC=C(N)C=C1 JWRLKLYWXKMAFL-UHFFFAOYSA-N 0.000 description 1
- 101710010860 Acp70A Proteins 0.000 description 1
- XECAHXYUAAWDEL-UHFFFAOYSA-N Acrylonitrile butadiene styrene Chemical compound C=CC=C.C=CC#N.C=CC1=CC=CC=C1 XECAHXYUAAWDEL-UHFFFAOYSA-N 0.000 description 1
- 229920000122 Acrylonitrile butadiene styrene Polymers 0.000 description 1
- 102000004400 Aminopeptidases Human genes 0.000 description 1
- 108090000915 Aminopeptidases Proteins 0.000 description 1
- 229940025131 Amylases Drugs 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 108091005650 Basic proteases Proteins 0.000 description 1
- 229960000686 Benzalkonium Chloride Drugs 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 108010004032 Bromelains Proteins 0.000 description 1
- 241000208199 Buxus sempervirens Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010057248 Cell death Diseases 0.000 description 1
- 102000020504 Collagenase family Human genes 0.000 description 1
- 108060005980 Collagenase family Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 101700012270 GLI3 Proteins 0.000 description 1
- 102100010303 GLI3 Human genes 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 101710013115 HAL Proteins 0.000 description 1
- 125000003798 L-tyrosyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C([H])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 description 1
- IFYDWYVPVAMGRO-UHFFFAOYSA-N N-[3-(dimethylamino)propyl]tetradecanamide Chemical compound CCCCCCCCCCCCCC(=O)NCCCN(C)C IFYDWYVPVAMGRO-UHFFFAOYSA-N 0.000 description 1
- 206010061137 Ocular toxicity Diseases 0.000 description 1
- 241001644482 Onyx Species 0.000 description 1
- 210000000496 Pancreas Anatomy 0.000 description 1
- 108010067372 Pancreatic Elastase Proteins 0.000 description 1
- 102000016387 Pancreatic Elastase Human genes 0.000 description 1
- 229920002057 Pluronic® P 103 Polymers 0.000 description 1
- 229920002594 Polyethylene Glycol 8000 Polymers 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 229920000289 Polyquaternium Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 108010059712 Pronase Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 210000000614 Ribs Anatomy 0.000 description 1
- 210000002966 Serum Anatomy 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 229940033663 Thimerosal Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L Thiomersal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229960004319 Trichloroacetic Acid Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N Trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Tris Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- 239000004676 acrylonitrile butadiene styrene Substances 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 230000001365 aminolytic Effects 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000003466 anti-cipated Effects 0.000 description 1
- 101700024251 apr Proteins 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000018867 autolysis Effects 0.000 description 1
- 229960001716 benzalkonium Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 235000019835 bromelain Nutrition 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 108010089934 carbohydrase Proteins 0.000 description 1
- 125000004432 carbon atoms Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000012459 cleaning agent Substances 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N diguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000001747 exhibiting Effects 0.000 description 1
- 239000010200 folin Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- ISGUIIHZEJGUGQ-UHFFFAOYSA-N heptacosaethylene glycol monomethyl ether Chemical compound COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO ISGUIIHZEJGUGQ-UHFFFAOYSA-N 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 108010059345 keratinase Proteins 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000327 ocular toxicity Toxicity 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000001590 oxidative Effects 0.000 description 1
- 229940112041 peripherally acting muscle relaxants Other quaternary ammonium compounds in ATC Drugs 0.000 description 1
- 229940093424 polyaminopropyl biguanide Drugs 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010079 rubber tapping Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 230000028043 self proteolysis Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000004328 sodium tetraborate Chemical class 0.000 description 1
- 230000003381 solubilizing Effects 0.000 description 1
- 230000000087 stabilizing Effects 0.000 description 1
- 101710018965 subC Proteins 0.000 description 1
- 125000002730 succinyl group Chemical group C(CCC(=O)*)(=O)* 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
Abstract
Two-compartment bottle assemblies useful in preparing multi-purpose compositions containing an ophthalmically acceptable enzyme and disinfectant, methods of preparing these compositions and methods involving the use of these compositions are disclosed for cleaning and disinfecting of contact lenses.
Description
COMPOSITIONS AND METHODS WITH MULTIPLE USEFUL PURPOSES
IN SYSTEMS OF CLEANING AND DISINFECTION OF LENSES
CONTACT
BACKGROUND OF THE INVENTION
The present invention relates to the field of cleaning and disinfecting contact lenses. In particular, this invention is directed to the provision of compositions and methods with multiple purposes for the preparation of these compositions. The invention is also directed to methods for simultaneously cleaning and disinfecting contact lenses using the multi-purpose compositions containing enzymes and disinfectants of the present invention. Various compositions and methods for cleaning contact lenses have been described in the patent and scientific literature. Some of these methods have employed compositions containing surfactants or enzymes to facilitate lens cleaning. The first discussion of the use of proteolytic enzymes to clean contact lenses was in an article by Lo and others in the Journal of the American Optimetric Associaton. volume 40, pages. 1106-1109 (1969). Methods for removing protein deposits from contact lenses by means of proteolytic enzymes have been described in many publications since the initial article of Lo et al., Including U.S. Patent No. 3,910,296 (Karageozian et al.).
Numerous compositions and methods for disinfecting contact lenses have also been described. Those methods can be characterized generally because they involve the use of heat and / or chemical agents. Representative chemical agents for this purpose include organic antimicrobials such as benzalkonium chloride and chlorhexidine, and inorganic antimicrobials such as hydrogen peroxide and peroxide generating compounds. U.S. Patent Nos. 4,407,791 and 4,525,346 (Stark) describe the use of polymeric quaternary ammonium compounds for disinfecting contact lenses and for preserving contact lens care products. U.S. Patent Nos. 4,758,595 and 4836,986 (Ogunbiyi) describe the use of polymeric biguanides for the same purpose. Various methods have been proposed for enzymatically cleaning and disinfecting contact lenses at the same time. In U.S. Patent No. Re 32,672 (Huth et al), methods are described that involve the combined use of proteolytic enzymes and peroxides to simultaneously clean and disinfect contact lenses. In the Japanese patent application 57-24526 (Boghosian et al.), A representative method for simultaneously cleaning and disinfecting contact lenses is described, which involves the use of proteolytic enzymes and quaternary ammonium compounds. In Canadian Patent No. 1,150,907 (Ludwig et al.), The combined use of a biguanide (ie, chlorhexidine) and liquid enzymatic compositions for simultaneously cleaning and disinfecting contact lenses is described. In U.S. Patent No. 4,614,549 (Ogunbiyi), methods are described that involve the combined use of dissolved proteolytic enzymes for cleaning and heat for disinfecting. The combined use of proteolytic enzymes and polymeric biguanides or polymeric quaternary ammonium compounds is disclosed in the commonly assigned U.S. patent application, in progress, serial number 08 / 156,043, and in the corresponding European patent application publication No. 0 456 467 A2 (Rosenthal et al.), As well as U.S. Patent No. 5,096,607 (Mowrey-McKee et al.). The commercial viability of most of the above enzymatic cleansing products has depended on the use of stable enzyme tablets, more specifically, the use of solid enzymatic cleansing compositions has been necessary to ensure the stability of the enzymes before use. In order to use such compositions, a separate package containing a tablet should be opened, the tablet should be placed in a separate vial containing a solution and the tablet should be placed in order to release the enzyme and the solution. This practice is usually done only once a week due to the annoying and tedious procedure and the potential for irritation and toxicity. The use of concentrated liquid enzymatic compositions in combination with a diluent for cleaning contact lenses has been attempted, in an effort to avoid the annoying use of enzyme tablets. Those attempts have been hindered, however, by the fact that concentrated aqueous liquid enzyme compositions are inherently unstable. When a proteolytic enzyme is placed in an aqueous solution for a prolonged period (ie, several months or more), the enzyme can lose all or a substantial portion of its proteolytic activity. Measures can be taken to stabilize the compositions. For example, stabilizing agents can protect enzymes against problems of chemical instability during their storage in an aqueous liquid, by putting the enzymes in a physical latent conformation. However, the use of liquid enzymatic compositions, as well as the use of enzyme tablet compositions described above, still requires a separate additional mixing step each time the lens is to be simultaneously cleaned and disinfected. In addition, since the amount of liquid enzymatic composition put into a diluent composition is purchased by the user, the user's error may result in too much or too little concentrate being given to the diluting solution. Reference may be made to the following patents for further background concerning previous attempts to stabilize the concentrated liquid enzymatic formulations: U.S. Patent Nos. 4,462,922 (Boskamp); 4,537,706 (Severson); and 5,089,163 (Aronson). These patents describe detergent compositions containing enzymes. U.S. Patent No. 5,281,277 (Nakagawa) and Japanese patent applications Nos. 92-370197; 92-143718 and 92-243215 describe liquid enzyme compositions for treating contact lenses.
A number of multi-purpose compositions for cleaning, disinfecting and storing contact lenses is commercially obtainable. The main cleaning ingredients of these products generally comprise surfactants. Soft contact lenses get dirty by collecting various debris and also deposition of accumulated protein on the surface of the lenses. Failing to remove protein deposits results in lens opacification and lens deterioration. Although surfactants are used to eliminate lens debris, they are not very effective at removing protein deposits. Proteolytic agents, in contrast, are very effective at removing protein deposits that form on the lens over time. Thus, cleaning regimes using multi-purpose compositions comprising surfactants still require the additional step of employing a proteolytic agent to remove protein deposits. The use of a single multi-purpose solution containing enzymes for cleaning and disinfecting contact lenses has been proposed in U.S. Patent No. 5,409,546 (Nakagawa et al.) And European Patent Application No. 0 646,641. (Nakayawa and others). These patents set forth compositions in which the enzyme is in a diluted concentration and the compositions do not require, therefore, any dilution step before use. These compositions provide, however, the limited stability of the enzyme (one or two months at room temperature).
This limited storage period of these compositions does not generally allow their commercialization.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a perspective view of a preferred embodiment of the invention. Figure 2 is a vertical view of a preferred embodiment of the invention, Figure 3 is an exploded vertical view of a preferred embodiment of the invention. Figure 4 is an exploded cross-sectional view of a preferred embodiment of the invention about line 4-4 of Figure 3. Figure 5 is a cross-sectional view around Figure 5-5 of the Figure 2 of a preferred embodiment of the invention. Figure 6 is a cross-sectional view about line 5-5 of Figure 2 of a preferred embodiment of the invention, illustrating the downward rotation of a cap / plunger assembly, the rupture of a membrane and the exit of an enzymatic composition. Figure 7 is a top plan view of a housing of the invention.
Figure 8 is a bottom plan view of a cap and collar of the invention.
BRIEF DESCRIPTION OF THE INVENTION
The present invention is directed to two-part systems which provide for the generation of multi-purpose compositions useful in the simultaneous cleaning and disinfection of contact lenses. The present invention is also directed to methods for simultaneously cleaning and disinfecting contact lenses using the two-part system. The two-part system comprises an enzymatic cleansing composition, an aqueous position and one or more antimicrobial agents. The enzyme composition provides a concentrated amount of an enzyme. The aqueous composition provides a diluting solution. The antimicrobial agent is contained either in the enzyme composition or in the aqueous composition. The two-part system is started for use by mixing the enzyme composition with the aqueous composition. The two-part system uses a two compartment device capable of keeping an enzyme composition and a diluent composition separate before its initial use. A feature of this device is that it combines the separate components into a single bottle assembly. This feature has an advantage over prior art systems that have required the more difficult, tedious and annoying use of separate containers. Related to this feature, is the fact that it adds the enzyme only once to the disinfectant composition and the resulting composition can then be used for multiple purposes, often over a period of several months. With most systems of the prior art, the enzyme must be added to the disinfectant composition each time the user cleans their lenses. An additional advantage of this feature is that the two compositions are mixed aseptically. This is due to the fact that the bottle assembly containing the compositions is aseptically assembled with an airtight seal; sterile mixing is then performed within the closed sterile system of the bottle assembly. Another advantage of this feature is that it eliminates the possible error of the user resulting from the addition of inappropriate quantities of an enzymatic composition to the diluting solution. This is important because inappropriate amounts of enzymes or excipients (eg, salts) in the resulting multi-purpose solution can result in ineffective cleaning and disinfection of the lens and / or ocular toxicity. In this way, it is perfected in compliance with the user with the cleaning regime, with the present invention, allowing the realization of maximum cleaning benefits and avoiding unnecessary eye irritation / toxicity. Another feature of the present invention is that the enzyme component is kept separate from the diluting solution before its initial use. This feature minimizes the size of enzymatic activity, which occurs naturally with time in aqueous environments, minimizing the time that the enzyme is solubilized before its initial use. This feature allows delivery at room temperature and long storage life without significant loss of enzyme activity. When the user is ready to use the system, the two components are combined and mixed aseptically, forming the composition for multiple purposes. The composition can then be used for multiple purposes over a period of about 1-3 months. The cleaning and disinfecting compositions of the present invention may utilize ingredients similar to those of known cleaning or disinfecting formulations. Several modifications can be made, however, to enhance the antimicrobial efficacy of the composition for multiple purposes. Other additional components may also be added to increase the storage duration of the mixed components, such as the use of enzyme stabilizers. The compositions and methods with multiple purposes of the present invention provide greater ease of use. This ease of use makes it possible for contact lens wearers to clean their lenses daily, thus achieving maximum proteolytic cleaning of their lenses. It has been found that the daily use of the liquid enzymatic compositions in the multi-purpose compositions of the present invention results in extraordinarily better cleaning, as compared to the enzyme cleaning regimes once a week that are currently being used.DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to the use of a sterile two-part system for the preparation of multi-purpose compositions useful for cleaning and disinfecting contact lenses. The present invention is also directed to methods for cleaning and disinfecting contact lenses using a two-part system of the present invention. The first part ("Part I") is a solid composition (powder or tablets) or sterile liquid containing enzyme and the second part ("Part II") is a sterile diluent composition. An antimicrobial agent is furthermore required and may be included in any of the compositions. The present invention requires the use of a two-compartment device for storing and mixing the sterile two-part system and dispensing the resulting sterile composition for multiple purposes. Various devices may be employed, but the central features of the device is that it provides separate storage of the components, a means for aseptically adding one component to the other component, a mixing chamber and a spout, all in a single bottle assembly. Figure 1 illustrates a preferred two-part bottle assembly for use with the two-part and multi-purpose compositions of the present invention. The preferred two-part bottle assembly, and the bottle assembly 1, generally comprises the bottle 2 and the container 4. As illustrated in Figures 2-4, the bottle 2 comprises the neck 13, the opening 10, the rings external 12 and inner rings 43. The neck 13 is formed in such a way that the rings 12 protrude from the neck 13. The bottle 12 is generally made of molded polyethylene, although other materials such as polyethylene-methyllate (PET) and polypropylene ( P / P). As best seen in Figures 3 and 4, the container 4 comprises the housing 5, the plunger 6, the cover 8 and the collar 28. The housing 5 comprises the hollow cylinder 14 and the lid 16. The cylinder 14 has the two external threads 36 which protrude annularly near the upper end 15 and a membrane disc 18 which covers the lower end 17. The stops 23 are arranged annularly around the exterior 38 of the cylinder 14 (figure 7) the membrane 18 has a thin thickness 49 in cross section around its circumference. The cover 16 has the internal protruding rings 20 and the cylinder 14 is arranged coaxially inside the cover 16 in such a way that the upper end 15 and the lower end 14 protrude from the layer 16. The plunger 6 comprises the hollow cylinder 24, the open end 22, the spout end 25 and the ribs 34. The open end 22 has the tooth 39 and is thinner than the thickness in cross section than the thickness of the recess 24, thus forming the sharp point 41 of the tooth 39. cover 8 comprises the pin 33, the hollow cone 32, the internal cords 30 and the stops 21. As best seen in figure 8, the collar 28 has the appendix 29, the spokes 19 and the perforation 27 the which forms the ends 31. The components of the container 4 are generally made of molded high density polyethylene or polycarbonate, but other materials and methods of manufacture such as P / P, PET, polystyrene and acrylonitrile-butadiene-styrene (A BS). As illustrated in Figure 4, the container 4 is prepared by first adding the enzymatic cleaning composition 7 to the hollow cylinder 14 of the housing 5, causing the collar 28 to be surrounded by cylinder 14, inserting the plunger 6 into the cylinder 14 in such a way that the rings 34 of the plunger 6 press against the inside of the cylinder 14 and screwing the cover 8 onto the plunger 6, splicing the pin 33 of the cover 8 with the notch 26 of the plunger 6, screwing the internal threads 30 into the threads 36 of the 5. In this configuration, the spokes 19 of the collar 28 are interposed between both stops 21 of the cover 8 and the stops 23 of the housing 5. The cover 8 in this configuration (see figures 2 and 5) is only partially screwed in of the threads 36 of the housing 5 due to the impediment of the further downward rotation of the cover 8 for the collar 28. The aqueous composition 9 is added to the bottle 2, the container 4 is then placed on the neck 13, and the lid 16 is forced down on the neck 13 in such a way that the rings 20 make radial pressure against the neck 13, and the outer rings 12 press against the interior 47 of the lid 16, forming a hermetic seal to the air.
In operation, the collar 28 of the container 4 is first removed by screwing the cover 8 downwardly on the housing 5. When the cover 8 is rotated, the stops 21 butt-up and pull the spokes 19, while the stops 23 keep the spokes stationary 19. The resulting stress causes the collar 28 to split in the bore 27. The collar 28 can then be removed by pulling on the tab 29. The cover 8 is then screwed down on the housing 5. With the rotation of the cover 8, the plunger 6 is pushed simultaneously downwards causing the plunger 6 to descend down the cylinder 14. When the plunger 6 reaches the membrane 18 of the housing 5, the sharp tip 41 to give the thin circumference 49 of the membrane 18. The rotation further of the lid 8 causes the open end 22 of the plunger 6 to lower further, by tapping the membrane 18 around its circumference from the housing 5, similarly in the operation of a die press dora At this point, the enzymatic cleansing composition contained in the housing 5 is exposed to the interior 11 of the bottle 2 and falls into the aqueous diluent composition 9 of the bottle 2. It can be inverted and then agitated the bottle 2, thus affecting the mixing of the enzymatic composition and the aqueous diluent. When the membrane 18 of the housing 5 is cut, a channel is formed extending from the bottle 2 behind the now open housing 5, the plunger 6 and the spout end 25. With the removal of the cover 8, the resulting composition for purposes Multiple can now be dispensed through this channel into an appropriate container for cleaning, disinfecting, rinsing and storing contact lenses.
Other embodiments of two compartment bottle assemblies may be employed in the present invention. For example, a blister pouch and a perforating means such as the enzyme compartment and the rupture membrane component, respectively, of a bottle assembly can be used. As stated above, the present invention is comprised of two separate compositions which are then combined before initial use. Part I comprises an enzyme and part II comprises an aqueous diluent solution. The resulting multi-purpose composition may contain several other agents, but must contain: 1) an antimicrobial agent, 2) an enzyme, 3) a pH regulating agent, 4) a tonicity agent and 5) water. The multi-purpose compositions of the present invention are intended to function as storage, rinsing, cleaning and disinfecting solutions. Therefore, compositions with multiple purposes will be physiologically compatible with the eye. The sterile enzymatic composition of part I of the present invention is generally composed of one or more enzymes and several carriers. The enzyme composition can be formulated as a powder, tablet or liquid. Dry powder compositions or tablets may be preferred when the enzymatic compositions of part I need to be stable for longer periods than those of liquids. The excipients constituting the powdered enzyme compositions are known in the art. Generally, the powdered enzyme composition will include fillers to bring the relatively small volume of enzyme to the diluent solution. Such fillers typically include polyols (eg, mannitol or sorbitol), polyethylene glycols (molecular weights greater than 1000) and sugars. Other excipients may include salts such as NaCl, chelating agents such as EDTA, and pH regulating agents such as Tris. Other additives may include surfactants to facilitate dispersion and dissolution of the powder in the water. Preferred powdered enzyme compositions comprise mannitol and polyethylene glycol-5000 (PEG-5000). Enzymatic tablet compositions and manufacturing methods are known in the art. Enzymatic tablets require the use of fillers and binding agents. Additionally, the tablets may contain effervescent agents such as bicarbonate to facilitate the dissolution of the tablet to the diluting solution. Other excipients known in the art can be added to provide greater consistency and easier manufacture of the tablets. Preferred enzyme compositions in tablets include sodium bicarbonate, citric acid, PEG-8000, carboxymethylcellulose and lactose. Liquid enzymatic compositions are the preferred part I compositions of the present invention due to their ease of preparation, sterilization and assortment within the enzyme container of a bottle assembly. Liquid enzymatic compositions and manufacturing methods are known in the art. The enzymes contained in the liquid compositions of part I can be solubilized in aqueous compositions or dispersed in non-aqueous compositions. Aqueous enzymatic compositions are generally preferred because of their ease of preparation and sterilization. The aqueous enzyme compositions comprise one or more polyols and a borate or boric acid compound. Preferred aqueous enzyme compositions of the present invention comprise a polycarbon of 2-3 carbons and a compound of borate or boric acid. As used herein, the term "2-3 carbon polyol" refers to a compound having two to three carbon atoms and at least two hydroxy groups. Examples of 2-3 carbon polyols are 1,2-propane diol ("propylene glycol"), 1,3-propanediol and ethylene glycol. Glycerol is the 2-3 carbon polyol that is most preferred. The borate or boric acid compounds that can be used in the liquid enzyme compositions of the present invention include alkali metal salts of borate, boric acid and borax. Other excipients that may be included in the aqueous enzyme compositions in part I include divalent ions such as calcium, organic acids stabilizing enzymes such as benzoic acid and surfactants such as alkyl ethoxylates. The non-aqueous enzymatic compositions employed in the compositions of part I of the present invention generally comprise a crystalline enzyme uniformly dispersed in an organic liquid soluble in water. Typical organic liquids include polyoxyethylenes (e.g., PEG-400) and alkoxypolyoxyethylenes such as methoxypolyethylene glycols. In this composition, the enzyme is in a latent state and, following dissolution in the composition of part II of the present invention, the enzyme is stabilized and activated. Preferred non-aqueous enzymatic compositions comprise an enzyme in PEG-400. As stated above, the antimicrobial agents of the present invention can be included in any of the enzyme compositions described herein. The actual amount of the antimicrobial agent will vary, but will provide effective contact lens disinfection, as described below. The enzymatic compositions of part I that are described above are generally treated aseptically by the sterile state of the liquids, or the lyophilization, the aseptic treatment and the terminal gamma irradiation of the solids. These and other methods of sterilizing liquids and solid compositions are well known in the art. Enzymes that can be used in the compositions and methods of the present invention including enzymes that: 1) are useful for removing contact lens deposits; 2) they cause, at best, only mild eye irritation in case a small amount of enzyme comes in contact with the eye; 3) are relatively chemically stable and effective in dilute salt solutions; and 4) do not adversely affect the physical or chemical properties of the lens being treated. The proteolytic enzymes used herein must have at least a partial ability to hydrolyze peptide-amide bonds in order to reduce the protein material found in the lens deposits to smaller water soluble subunits. Additionally, such enzymes may exhibit certain lipolytic, aminolytic or related activities, associated with proteolytic activity and may be neutral, acidic or alkaline. In addition, separate lipases or carbohydrases can be used in combination with the proteolytic enzymes. For the purposes of the present specification, reference is made to enzymes that satisfy the foregoing requirements as "ophthalmically acceptable". Some examples of ophthalmically acceptable proteolytic enzymes that can be used in the present invention include, but are not limited to: pancreatin, trypsin, subtilisin, collagenase, keratinase, carboxypeptide, bromelain, aminopeptidase, elastase, Aspergill peptidase, pronase E (from Si griseus), dispasa (from Bacillus polimixa) and mixtures thereof. Microbically derived enzymes, such as those derived from the microorganisms Bacillus, Streptomyces, and Aspergillus, represent a preferred type of enzyme that can be used in the present invention. Of this group of enzymes, the most preferred are the neutral or slightly alkaline proteases derived from Bacillus, generically called "subtilisin".
The identification, separation and purification of enzymes are known in the art. There are many identification and isolation techniques in the general scientific literature for the isolation of enzymes, including those enzymes that have proteolytic activity and mixed proteolytic / lipolytic / aminolithic activity. The enzymes contemplated by this invention can be easily obtained by known techniques from plant, animal or microbial sources. With the arrival of DNA techniques to the combiner, it is anticipated that new sources and types of entable proteolytic enzymes will become available. It should be considered that such enzymes fall within the scope of the invention as long as they satisfy the criteria set forth herein. Preferred genetically modified enzymes include variants of the BPN subtilisin such as those described in PCT / US94 / 10020 (Procter and Gamble), WIPO publication WO 95/3001 (Procter and Gamble) and the patent of USA No. 4,990,452 (Genex Corp.). Subtilisins and variants referred to in specific include subtilisin Carlsberg, subtilisin PB92, sublislysin 309, subtilisin147, subtilein 168, subtilisin DY and truncations, modifications and variants thereof. Other enzymes modified from their natural structure can also be used in the present invention. Such modifications include "begilation" that is, the covalent linkage of polyoxyethylene glycol derivatives to the enzymes, as well as monomeric covalent additions to enzymes with small organic compounds (eg, methyl, ethyl, succinyl groups, etc.). they will generally prevent the enzymes from being ionically bound to the contact lens, especially in the case of negatively charged hydrophilic soft lenses. In bond to the contact lens it can expose unnecessarily high amounts of the enzyme to the eye. With some enzymes, this exposure can cause undesirable inflammatory responses. These modifications can also improve the stability of the enzymes in aqueous environments such as the compositions of part I with their multiple purposes of the present invention. It is believed that the alkylation of hydrolytically sensitive enzymes limits the autolysis of the enzyme. Subtilisin and trypsin are more preferred enzymes for use in the present invention. Subtilisin is derived from Bacillus bacteria and is commercially available from several commercial sources including Novo Industries (Bagsvaerd, Denmark), Fluka Biochemika (Buchs, Switzerland) and Boehringer Mannheim (Indianapolis, Indiana, E.U.A.). The trypsinal is purified from various animal sources and is commercially available from Sigma Chemical Co. and Boehringer Mannheim. Subtilisin BPN variants as described above, its genetically modified subtilisins which have been described in 4,990,452 (Genex Cop.), PCT / ES94 / 10020 (Procter and Gamble) and WIPO Publication WO 95/30011 ( Procter and Gamble). Enzymes can be chosen by the methods described in these publications.
Pancreatin is extracted from mammalian pancreas and is commercially available from several sources, including Scientific Protein Laboratories (Wisconsin, USA), Novo Insustries (Bagsvaerd, Denmark), Sigma Chemical Co. (St. Louis, Missouri, USA), and Boehringer Mannheim (Indianapolis, Idiana, USA). Pancreatin USP is a mixture of poteases, lipases and amylases, and is defined by the United States Pharmacopoeia ("USP"). Pancreatin 9X is the most preferred form of pancreatin. As used herein, the term "Pancreatin 9X" means a filtered pancreatin (0.2 micros) that contains nine times the unitary professed USP content. The concentration of above part I will depend on several factors, such as: the enzyme or the combination of enzymes selected; the amount of enzymatic composition to be added to the aqueous composition of Part II, the purity, specificity and efficacy of the selected enzymes; the volume of the aqueous composition of part II; the type of lenses to be cleaned; and the desired duration of each cleaning. During storage, part of the activity of the enzyme may be lost, depending on the storage duration and the temperature conditions. In this manner, the enzymatic compositions of part I and the present invention can be prepared with initial amounts of enzymes exceeding an amount necessary to achieve the final intervals than with the multi-purpose enzyme situation described herein. In general, the enzyme compositions of the present invention will preferably contain one or more enzymes in an amount of about 100-1000,000 PAU / g or 100-100,000 PAU / ml. The compositions of part I, however, will contain an effective amount of one or more enzymes sufficient to substantially eliminate or significantly reduce deposits of proteins, lipids, mucopolysaccharides and other materials typically found on contact lenses worn by humans when mixed. a relatively small amount of an enzymatic composition of part I with an aqueous diluent conversion of part II. As used herein, reference is made to an enzyme concentration at the end of the resulting composition with multiple purposes as the "effective amount for cleaning the lens". However, the cleaning methods of the present invention will generally employ an amount of the enzymatic compositions described above, sufficient to provide an ultimate enzymatic concentration in the multi-purpose composition of about 1/100 PAU / mL of solution, followed by the dispersion of an enzymatic composition of part I in a composition of part II. A final concentration of about 5-25 PAU / mL is preferred. For compounds of that specification, a "unit of proteolytic activity" or "PAU" is defined as the amount of enzymatic activity necessary to generalize one microgram (mcg) of tyrosine per minute ("mcg Tyr / min"), as determined by means of the colorimetric test of the casein decision, which is described below.
Casein Digestion Test A portion of 5.0 ml of casein substrate (casein at 0.65% w / v) is equilibrated for 10 minutes (min) ± 5 seconds (sec) and 37 ° C. An enzymatic solution is prepared from the enzymatic composition of part I by solubilizing and diluting the composition of part I in pH PBS buffer. A 1.0 ml portion of this enzyme solution (0.2 mg / ml) is then added to the casein substrate and the mixture is vortexed, then incubated for 10 min ± 5 sec and 37 ° C. After incubation, 5.0 ml of the 14% trichloracetic acid portion are added and the resulting mixture is immediately vortexed. A mixture is incubated for at least another 30 min, then vortexed and centrifuged for 15-20 min (approximately 200 rpm). The supernatant of the centrifuged sample is filtered to a serum filter sample taker and 2.0 ml of aliquot is removed. To the 2.0 ml sample is added 5.0 ml of Na2CO3. The sample is vortexed, 1.0 ml of Folin's phenol is added at 0.67 N and the sample is immediately vortexed again, then incubated for 60 min at 37 ° C. The sample is then read on a light spectrophotometer visible at 660 nanometers (nm) relative to purified water as a reference. The sample concentration is then determined by comparison with a conventional tyrosine curve. The concentration of part I is then calculated taking into account the dilution ratio. The aqueous compositions of part II provide the volume of distilled water necessary for the multi-purpose compositions of the present invention. In general, the composition of part II may also contain sodium chloride and other excipients which together provide an ophthalmically compatible solution. However, as noted above, the compositions of part I may contain a percentage of all or all of these ingredients, and the compositions of part II may provide only a percentage of these ingredients or none of them. As will be appreciated by those skilled in the art, the compositions of part II used in the present invention may contain various other components such as suitable pH regulators, chelating agents and / or sequestrants and tonicity adjusting agents. The compositions of part II may also contain surfactants. As stated above, antimicrobial agents may also be included in the compositions in part II. In general, the compositions of part II will contain one or more antimicrobial agents (e.g., PHMB or polyquatemium-1), a pH regulator (e.g., borate), citrates, tonicity agents (e.g., NaCl, sugars) , a chelating agent (e.g. EDTA), and surfactants (e.g., block copolymers). Other agents that enhance the antimicrobin efficacy of the compositions, such as aminoalcohols and alkylamines, can also be added. The compositions of part II comprise polyquarteam-1, sodium borate, boric acid, propylene glycol and Pluronic P-103. Compositions of part II that are not preferred include boric acid, sobitol 2-amino-2-methyl-1-propanol 95% ("AMP-95"), sodium citrate, sodium chloride, disodium edetate, polyquaternium -1, Tetronic 1304 and Myristamidopropyldimethylamine ("" APDA "). The multi-purpose compositions are intended to be used with various types of contact lenses including rigid lenses (" RGP ") and soft lenses. Depending on the type of lens to be cleaned, the compositions can be optimized for multiple purposes to effect maximum cleaning benefits while minimizing the potential for eye irritation / toxicity. For example, since soft contact lenses are electronegatively charged, they tend to bind enzymes with high isoelectric points (i.e., more positively charged at the pH of a multi-purpose composition). This increased exposure of the enzyme to the eye, through a lens loaded with enzyme, can lead to eye irritation / toxicity. Thus, the use of natural or modified enzymes having lower isollectric points (eg, subtilisin BPN 'variants) is preferable, and therefore less tendency to interact with soft lenses. Less consideration of the choice of the enzyme is necessary when treating RGP lenses, due to the potential for binding with generally lower enzymes of the RGP lenses. The cleaning obtained with the liquid enzymatic compositions of the present invention is a function of time. The soaking times used will generally vary from about 1 hour to the course of the night. However, if the longer soaking periods were to be extended (eg, 24 hours), lower concentrations described above may be used. The cleaning methods of the present invention involve the use of a small amount of the enzymatic compositions described above to facilitate the removal of proteins and other deposits from contact lenses. The amount of enzymatic composition used in the particular embodiments of the present invention may vary, depending on the enzyme concentration, as described above, as well as several other factors, such as the purity of the enzyme, the proposed duration of the exposure of the enzyme. the lenses to the compositions, the nature of the lens care regime (for example, the frequency of disinfection and cleaning of the lenses), the type of lens being treated and the use of auxiliary cleaning agents (e.g. surfactants). In general, approximately one gram of powder, one tablet or 1 milliliter of the composition of part I will be added to approximately 120 milliliters of a composition of part II, although larger or smaller amounts of the present invention are contemplated. The enzymatic compositions of the present invention demonstrated the effectiveness of effective cleaning while exhibiting minimal adverse effects or, more preferably, increased effects on antimicrobial activity of the antimicrobial agents. The antimicrobial activity of the disinfecting agents, particularly quaternary ammonium polymeric compounds such as polyquaternium-1, is adversely affected by high concentrations of sodium chloride other ionic solutes. More specifically, the polymeric quaternary ammonium compounds and particularly those of the formula of (I), then, lose the antimicrobial activity when the concentration of the ionic solutes in the multi-purpose compositions is too high. Generally, the multi-purpose compositions of the present invention will have tonicities / osmolalities in the range of hypotonic to isotonic and more preferably in the range of 150 to 350 milliosmoles per kilogram (mOs / kg). A range of 200 to 300 mOs / kg is particularly preferred and an osmolality of approximately 220 mOs / kg is most preferred. The cleaning and disinfecting methods of the present invention utilize a multi-purpose composition of the present invention that contains an antimicrobial agent. The antimicrobial agents are generally given non-oxidizing polymeric antimicrobial agents that derive their antimicrobial activity through a chemical or physicochemical alteration with the organisms. As used in the present specification, the term "polymeric antimicrobial agent" refers to any polymer or copolymer containing nitrogen which has antimicrobial activity. Preferred polymeric antimicrobial agents include: polyquaternium-1, which is a polymeric quaternary ammonium compound; and polyhexamethylbiguanide ("PHMB") or polyaminopropylbiguanide ("PAPB"), which are polymeric biguanides. These preferred antimicrobial agents are described in U.S. Patent Nos. 4,407,791 and 4,525,346 issued to Stark, and 4,758,595 and 4,836,986 Ogunbiyi, respectively. The entire contents of the foregoing publications are hereby incorporated into the present specification by reference. Other antimicrobial agents suitable for the methods of the present invention include: other quaternary ammonium compounds, such as benzalkonium halides and other biguanides, such as chlorhexidine. The antimicrobial agents used herein are preferably employed in the absence of mercury-containing compounds such as thimerosal. The most preferred antimicrobial agents are the polymeric quaternary ammonium compounds of the structure:
wherein: Ri and R2 may be the same or different and are selected from: N + (CH2CH2OH) 3X ", N (CH3) 2 or OH; X" is a pharmaceutically acceptable anion, preferably chloride; and n = integer from 1 to 50.
The most preferred structure compound is polyquaternium-1, which is also known as Onamer M ™ (registered trademark of Onyx Chemical Corporation) or as Polyquad® (registered trademark of Alcon Laboratories, Inc.). Polyquaternium-1 is a mixture of the compounds referred to above, wherein X "is chloride and Ri, R 2 and n are defined above.The antimicrobial agents described above are used in the methods of the present invention in an amount effective to substantially eliminate or significantly reduce the number of viable microorganisms found in contact lenses, in accordance with the requirements of governmental regulatory agencies, such as the Food and Drug Administration of the United States For the purposes of this specification, refers to that amount as "an effective amount to disinfect" or "an antimicrobially effective amount." The amount of microbial agent used will vary, depending on factors such as the type of lens care regimen in which the method is being used. For example, the use of an effective daily cleanser in the regimen of Lens care can substantially reduce the amount of material deposited on the lenses, including microorganisms and thus decrease the amount of antimicrobial agent required to disinfect the lenses. The type of lens being treated (for example, "hard" versus "soft" lenses) can also be a factor. In general, a concentration in the range of about 0.00001% to about 0.1% by weight of one or more of the above-described antimicrobial agents will be employed. The most preferred concentration of the quaternary ammonium polymer compounds of the formula I is about 0.001% by weight. The methods of the present invention will typically involve adding about 2-10 ml of a multi-purpose composition of the present invention to a lens case, putting the dirty lens into the multi-purpose composition that is dispensed and soaking the lens for a period of time. effective to clean and disinfect the lens. Optionally, contact lenses are first rubbed with a multi-purpose composition of the present invention or a surfactant-based cleanser before immersion in the composition for multiple purposes. The lens will typically be soaked in the course of the night, but shorter or longer durations are contemplated in the methods of the present invention. A soaking time of 4 to 8 hours is preferred. The methods of the present invention allow the above described regimen to be performed daily. The following examples are presented to further illustrate various aspects of the present invention, but are not intended to limit the scope of the invention in any respect.
EXAMPLE 1
A preferred enzymatic composition of part I and a preferred aqueous composition of part II containing an antimicrobial agent for use in a two-component, multi-use bottle assembly composition of the present invention are described below:
A. Liquid trypsin composition of part I The following liquid enzymatic composition represents a preferred enzyme composition of the present invention:
The calcium chloride and boric acid are dispersed in 30% of the volume of purified water. PEG and glycerol are then added. The pH of the solution is adjusted and the enzyme is then dissolved in the solution, followed by a final volume adjustment with purified water. The composition is filtered for sterilization using a 0.2 μm filter.
The aqueous composition of part II The following formulation represents a preferred aqueous composition:
The ingredients are dissolved with 90% of the volume of purified water, the pH is adjusted and the volume is raised to 100% of the volume. The sterile composition is then filtered for sterilization using a 0.2 μm membrane filter. Several volumes of the above enzymatic and aqueous compositions can be employed in a two-compartment bottle assembly of the present invention. Preferred amounts include 1 ml of the enzyme composition and 120 ml of the aqueous composition.
EXAMPLE 2
The following is an example of a liquid enzymatic composition of the present invention:
The above formulation is prepared by first mixing sequentially with propylene glycol, purified water, hydrochloric acid and sodium borate. The required amount of trypsin (approximately 0.3 w / v) is then dissolved in the above mixture, the pH is adjusted and the solution is increased to 100% volume. The enzymatic compositions are then filtered for sterilization (0.2 μm filter). The optimum pH of the previous formulation is the range of 5-7; a pH of 6 is more preferred.
EXAMPLE 3
The following are examples of the preferred solid enzyme compositions of part I of the present invention.
I. Composition in tablets of trypsin from part I.
Composition of subtilisin tablets from part I.
The tablets are generally prepared by first mixing the appropriate amounts of one of the ingredients and passing a mixture through an oscillating granulator equipped with a 20 mesh hard screen. The sieved ingredients are then added to a mixer of suitable size and mixed for 30 minutes. An appropriate amount of PEG and enzyme was then passed through a 20 mesh hard screen and this mixture is added to the mixer. The sifted ingredients combined for an additional 15 minutes. Using a tableting press equipped with a 4 mm tool, the mixed ingredients are then compressed into tablets having a designated weight of 50/80 mg and a hardness of 8 SCU. The tablets are then stabilized by the gamma sterilization method.
Powdered composition of part trypsin
Dissolve the enzyme and lactose in water (1 gram of enzyme / lactose per 1 mL of water) and filter to sterilize using a 0.2 μm filter. The sterile enzymatic solution is then asexylized.
EXAMPLE 4
The following are examples of the aqueous compositions of part II of the present invention:
Aqueous composition of the part
Sustaining composition.
The compositions of Part II are prepared in a manner similar to those of Example 1 above. The compositions of part I and II described in the above examples will be combined, stored and mixed in a single bottle assembly in various amounts, in general, the preferred amounts will be: Part I: 1g powder or 1 tablet of an enzymatic composition solid, or 1 ml of liquid enzymatic compositions. Part II: approximately 120 ml. (Similarly, 2 g of powder, 2 tablets or 2 ml of liquid would be combined with approximately 240 ml of part II).
The preferred enzyme activity in the final multi-purpose solution will be about 5-25 PAU / ml.
Claims (9)
1. A two-compartment, multi-purpose, sterile composition generator bottle assembly for use in cleaning, disinfecting, rinsing and storing contact lenses, comprising: a) a bottle containing an aqueous composition; b) a sealed container comprising a peelable membrane and containing an enzyme composition containing an enzyme; and c) an antimicrobial agent in an amount effective to disinfect the lens; wherein the antimicrobial agent is included in either the aqueous composition or the enzymatic composition, the container is secured and partially inside the bottle, forming an internally sterile two-compartment bottle assembly, and the release of the membrane allows the exit sterile of the enzymatic composition to the aqueous composition of the bottle, wherein the composition can be formed for multiple purposes by keeping an amount of the enzyme effective to clean the lens and an amount of the antimicrobial agent effective to disinfect the lens.
2. A bottle assembly in accordance with the claim 1, further characterized in that: the container further comprises a housing, a plunger, a removable lid and a collar; the housing comprises a hollow cylinder containing the enzymatic composition, an insulating means, external cords and the membrane covers one end of the housing cylinder; the plunger comprises a hollow cylinder, a dispensing end and a bevelled opposite end; the lid comprises internal cords; and the bottle also comprises an open end, a neck and a receiving means for receiving and securing the container; wherein the plunger is received within the hollow cylinder of the housing, the cover covers the plunger jet end and the inner cords of the lid are interlocked with the outer cords of the housing and the container is received and secured on the open end and the neck of the bottle, forming an air-tight bottle assembly.
3. A bottle assembly according to claim 1, further characterized in that the enzyme is trypsin, subtilisin or a variant of subtilisin BPN '
4. A bottle assembly according to claim 1, further characterized by the antimicrobial agent is policuarternio-1.
5. A bottle assembly in accordance with the claim 1, further characterized in that the aqueous composition comprises polyquaternium-1, boric acid, sorbitol, sodium chloride, citrate, Tetronic 1304, disodium edetate, AMP-95, MAPDA, sodium hydroxide, hydrochloric acid and water; and the enzymatic composition comprises boric acid, glycerol, PEG-400, calcium chloride, water and an enzyme selected from the group consisting of trypsin, subtilisin and a variant of subtilisin BPN '.
6. - A bottle assembly according to claim 5, further characterized in that the aqueous composition comprises: about 0.001% w / v of polyquatemium-1; about 0.6% w / v of boric acid; about 1.2% w / v of sorbitol; approximately 0.65% w / v sodium citrate; approximately 0.1% w / v sodium chloride; approximately 0.05% p / v of Tetronic 1304; approximately 0.05% w / v of sodium edetate; approximately 0.45% p / v of AMP-95; approximately 0.0005% p / v of MAPDA; and water; wherein the composition is adjusted to pH 7-8 with sodium hydroxide and hydrochloric acid.
7. A method for preparing a sterile multi-purpose composition comprising: employing a two-compartment bottle assembly, said bottle assembly comprising: a) a bottle containing an aqueous composition; b) a sealed container comprising a peelable membrane and containing an enzyme composition containing an enzyme; and c) an antimicrobial agent; wherein the antimicrobial agent is included in either the aqueous composition or the enzymatic composition, and the container is insured and partially inside the bottle, forming a two-compartment, internally sterile bottle assembly; detach the membrane and allow the enzyme composition of the container to leave the aqueous composition; mixing the enzymatic composition and the aqueous composition with each other; and forming a multi-purpose composition containing an enzyme in an amount effective to clean the lens and an antimicrobial agent in an amount effective to disinfect the lens.
8. A method according to claim 7, further characterized in that: the container further comprises a housing, a plunger, a removable lid and a collar; the housing comprises a hollow cylinder containing the enzymatic composition, an insulating means, external ropes and the membrane covers one end of the housing cylinder; the plunger comprises a hollow cylinder, a dispensing end and a bevelled opposite end; the lid comprises internal cords; and the bottle also comprises an open end, a neck and a receiving means for receiving and securing the container; wherein the plunger is received within the hollow cylinder of the housing, the cover covers the plunger jet end and the inner cords of the lid are interlocked with the outer cords of the housing and the container is received and secured on the open end and the neck of the bottle, forming an air-tight bottle assembly.
9. A method according to claim 7, further characterized in that the enzyme is trypsin, subtilisin or a variant of subtilisin BPN '10. A method according to claim 7, further characterized in that the antimicrobial agent is polyquartem-1. . 1 - A method according to claim 7, further characterized in that the aqueous composition comprises polyquaternium-1, boric acid, sorbitol, sodium chloride, citrate, Tetronic 1304, disodium edetate, AMP-95, MAPDA, hydroxide of sodium, hydrochloric acid and water; and the enzymatic composition comprises boric acid, glycerol, PEG-400, calcium chloride, water and an enzyme selected from the group consisting of trypsin, subtilisin and a variant of subtilisin BPN '. 12. A method according to claim 11, further characterized in that the aqueous composition comprises: about 0.001% w / v polyquaternium-1; about 0.6% w / v of boric acid; about 1.2% w / v of sorbitol; approximately 0.65% w / v sodium citrate; approximately 0.1% w / v sodium chloride; approximately 0.05% p / v of Tetronic 1304; approximately 0.05% w / v of sodium edetate; approximately 0.45% p / v of AMP-95; approximately 0.0005% p / v of MAPDA; and water; wherein the composition is adjusted to pH 7-8 with sodium hydroxide and hydrochloric acid. 13. A method for preparing a sterile multi-purpose composition comprising: preparing a sterile multi-purpose composition employing a two-compartment bottle assembly, said bottle assembly comprising: a) a bottle containing an aqueous composition; b) a sealed container comprising a peelable membrane and containing an enzyme composition containing an enzyme; and c) an antimicrobial agent; wherein the antimicrobial agent is included in either the aqueous composition or the enzymatic composition, and the container is insured and partially within the bottle, forming an internally sterile, two-compartment bottle assembly; detach the membrane and allow the enzyme composition of the container to leave the aqueous composition; mixing the enzymatic composition and the aqueous composition with each other; and forming a multi-purpose composition containing an enzyme in an amount effective to clean the lens and an antimicrobial agent in an amount effective to disinfect the lens; stock composition for multiple purposes to recipient; Soaking the lens in the composition for multiple purposes of the receptacle for a sufficient time to clean and disinfect the lens. 14. A method according to claim 13, further characterized in that: the container further comprises a housing, a plunger, a removable lid and a collar; the housing comprises a hollow cylinder containing the enzymatic composition, an insulating means, external ropes and the membrane covers one end of the housing cylinder; the plunger comprises a hollow cylinder, a dispensing end and a bevelled opposite end; the lid comprises internal cords; and the bottle also comprises an open end, a neck and a receiving means for receiving and securing the container; wherein the plunger is received within the hollow cylinder of the housing, the cover covers the plunger jet end and the inner cords of the lid are interlocked with the outer cords of the housing and the container is received and secured on the open end and the neck of the bottle, forming an air-tight bottle assembly. 15. A method according to claim 13, further characterized in that the enzyme is trypsin, subtilisin or a variant of subtilisin BPN '16. - A method according to claim 13, further characterized in that the antimicrobial agent is policuarternio-1 . 17. A method according to claim 13, further characterized in that the aqueous composition comprises polyquaternium-1, boric acid, sorbitol, sodium chloride, citrate, Tetronic 1304, , disodium edetate, AMP-95, MAPDA, sodium hydroxide, hydrochloric acid and water; and the enzymatic composition comprises boric acid, glycerol, PEG-400, calcium chloride, water and an enzyme selected from the group consisting of trypsin, subtilisin and a variant of BPN 'subtylein. 18. A method according to claim 17, further characterized in that the aqueous composition comprises: about 0.001% w / v of polyquatemium-1; about 0.6% w / v of boric acid; about 1.2% w / v of sorbitol; approximately 0.65% w / v sodium citrate; approximately 0.1% w / v sodium chloride; approximately 0.05% p / v of Tetronic 1304; approximately 0.05% w / v of sodium edetate; approximately the
0. 45% p / v of AMP-95; approximately 0.0005% p / v of MAPDA; and water; wherein the composition is adjusted to pH 7-8 with sodium hydroxide and hydrochloric acid.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/032839 | 1996-12-13 | ||
US032839 | 1996-12-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA99005568A true MXPA99005568A (en) | 2000-01-21 |
Family
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