WO2024042550A1 - Ophthalmic combination composition - Google Patents
Ophthalmic combination composition Download PDFInfo
- Publication number
- WO2024042550A1 WO2024042550A1 PCT/IN2023/050801 IN2023050801W WO2024042550A1 WO 2024042550 A1 WO2024042550 A1 WO 2024042550A1 IN 2023050801 W IN2023050801 W IN 2023050801W WO 2024042550 A1 WO2024042550 A1 WO 2024042550A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- acid
- sodium
- combinations
- group
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 124
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims abstract description 41
- 108010036949 Cyclosporine Proteins 0.000 claims abstract description 41
- 229960001265 ciclosporin Drugs 0.000 claims abstract description 41
- 229930182912 cyclosporin Natural products 0.000 claims abstract description 41
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 claims abstract description 39
- 229960005381 lifitegrast Drugs 0.000 claims abstract description 38
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims abstract description 22
- 206010013774 Dry eye Diseases 0.000 claims abstract description 16
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 12
- 239000000243 solution Substances 0.000 claims description 97
- -1 perborates Chemical compound 0.000 claims description 45
- 235000002639 sodium chloride Nutrition 0.000 claims description 44
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 33
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 239000008215 water for injection Substances 0.000 claims description 21
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- 229920001223 polyethylene glycol Polymers 0.000 claims description 17
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 16
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 16
- 239000003755 preservative agent Substances 0.000 claims description 16
- 230000002335 preservative effect Effects 0.000 claims description 16
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 15
- 229920002678 cellulose Polymers 0.000 claims description 15
- 239000001913 cellulose Substances 0.000 claims description 15
- 235000010980 cellulose Nutrition 0.000 claims description 15
- 235000011187 glycerol Nutrition 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 13
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 12
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 claims description 12
- 239000003963 antioxidant agent Substances 0.000 claims description 12
- 230000003078 antioxidant effect Effects 0.000 claims description 12
- 235000006708 antioxidants Nutrition 0.000 claims description 12
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 11
- 239000002202 Polyethylene glycol Substances 0.000 claims description 11
- 239000000839 emulsion Substances 0.000 claims description 11
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 229930195725 Mannitol Natural products 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 229920002125 Sokalan® Polymers 0.000 claims description 9
- 239000002738 chelating agent Substances 0.000 claims description 9
- 229960001484 edetic acid Drugs 0.000 claims description 9
- 239000000594 mannitol Substances 0.000 claims description 9
- 235000010355 mannitol Nutrition 0.000 claims description 9
- 229960004063 propylene glycol Drugs 0.000 claims description 9
- 239000006172 buffering agent Substances 0.000 claims description 8
- 239000003906 humectant Substances 0.000 claims description 8
- 239000003961 penetration enhancing agent Substances 0.000 claims description 8
- 229920000642 polymer Polymers 0.000 claims description 8
- 229920005862 polyol Polymers 0.000 claims description 8
- 150000003077 polyols Chemical class 0.000 claims description 8
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 8
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 claims description 8
- 239000004094 surface-active agent Substances 0.000 claims description 8
- 239000002562 thickening agent Substances 0.000 claims description 8
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 7
- 235000001014 amino acid Nutrition 0.000 claims description 7
- 150000001413 amino acids Chemical class 0.000 claims description 7
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 7
- 239000004327 boric acid Substances 0.000 claims description 7
- 239000004359 castor oil Substances 0.000 claims description 7
- 235000019438 castor oil Nutrition 0.000 claims description 7
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 7
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 7
- 239000003002 pH adjusting agent Substances 0.000 claims description 7
- 239000000725 suspension Substances 0.000 claims description 7
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 7
- VAZJLPXFVQHDFB-UHFFFAOYSA-N 1-(diaminomethylidene)-2-hexylguanidine Polymers CCCCCCN=C(N)N=C(N)N VAZJLPXFVQHDFB-UHFFFAOYSA-N 0.000 claims description 6
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 claims description 6
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims description 6
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 claims description 6
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 claims description 6
- 239000004322 Butylated hydroxytoluene Substances 0.000 claims description 6
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 6
- 229920001287 Chondroitin sulfate Polymers 0.000 claims description 6
- 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 6
- 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 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 229920002413 Polyhexanide Polymers 0.000 claims description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 235000010323 ascorbic acid Nutrition 0.000 claims description 6
- 239000011668 ascorbic acid Substances 0.000 claims description 6
- 229960005070 ascorbic acid Drugs 0.000 claims description 6
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 6
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 6
- 229940095259 butylated hydroxytoluene Drugs 0.000 claims description 6
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 6
- 229940059329 chondroitin sulfate Drugs 0.000 claims description 6
- 239000008121 dextrose Substances 0.000 claims description 6
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 6
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 claims description 6
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 6
- 229920001282 polysaccharide Polymers 0.000 claims description 6
- 239000005017 polysaccharide Substances 0.000 claims description 6
- 150000004804 polysaccharides Chemical class 0.000 claims description 6
- 229960003471 retinol Drugs 0.000 claims description 6
- 239000011607 retinol Substances 0.000 claims description 6
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 6
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 claims description 6
- 239000000600 sorbitol Substances 0.000 claims description 6
- 235000010356 sorbitol Nutrition 0.000 claims description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 6
- 229960000281 trometamol Drugs 0.000 claims description 6
- 229920002554 vinyl polymer Polymers 0.000 claims description 6
- 229920001285 xanthan gum Polymers 0.000 claims description 6
- 235000010493 xanthan gum Nutrition 0.000 claims description 6
- 239000000230 xanthan gum Substances 0.000 claims description 6
- 229940082509 xanthan gum Drugs 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 235000013772 propylene glycol Nutrition 0.000 claims description 5
- 229930003427 Vitamin E Natural products 0.000 claims description 4
- 150000001642 boronic acid derivatives Chemical class 0.000 claims description 4
- 239000006185 dispersion Substances 0.000 claims description 4
- 239000006196 drop Substances 0.000 claims description 4
- 239000003974 emollient agent Substances 0.000 claims description 4
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 4
- 239000003349 gelling agent Substances 0.000 claims description 4
- 239000007943 implant Substances 0.000 claims description 4
- 239000012535 impurity Substances 0.000 claims description 4
- 239000002674 ointment Substances 0.000 claims description 4
- 239000003981 vehicle Substances 0.000 claims description 4
- 239000004034 viscosity adjusting agent Substances 0.000 claims description 4
- 235000019165 vitamin E Nutrition 0.000 claims description 4
- 229940046009 vitamin E Drugs 0.000 claims description 4
- 239000011709 vitamin E Substances 0.000 claims description 4
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 3
- WCDDVEOXEIYWFB-VXORFPGASA-N (2s,3s,4r,5r,6r)-3-[(2s,3r,5s,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O)[C@H](O)[C@H]1O WCDDVEOXEIYWFB-VXORFPGASA-N 0.000 claims description 3
- JCIIKRHCWVHVFF-UHFFFAOYSA-N 1,2,4-thiadiazol-5-amine;hydrochloride Chemical compound Cl.NC1=NC=NS1 JCIIKRHCWVHVFF-UHFFFAOYSA-N 0.000 claims description 3
- SERLAGPUMNYUCK-DCUALPFSSA-N 1-O-alpha-D-glucopyranosyl-D-mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-DCUALPFSSA-N 0.000 claims description 3
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 claims description 3
- CTPDSKVQLSDPLC-UHFFFAOYSA-N 2-(oxolan-2-ylmethoxy)ethanol Chemical compound OCCOCC1CCCO1 CTPDSKVQLSDPLC-UHFFFAOYSA-N 0.000 claims description 3
- 229930000083 3-dehydroretinol Natural products 0.000 claims description 3
- 239000004475 Arginine Substances 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine 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 claims description 3
- 229920000858 Cyclodextrin Polymers 0.000 claims description 3
- 229920002307 Dextran Polymers 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- 239000004386 Erythritol Substances 0.000 claims description 3
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims description 3
- 229920002148 Gellan gum Polymers 0.000 claims description 3
- 102000006587 Glutathione peroxidase Human genes 0.000 claims description 3
- 108700016172 Glutathione peroxidases Proteins 0.000 claims description 3
- 229920002683 Glycosaminoglycan Polymers 0.000 claims description 3
- 229920002907 Guar gum Polymers 0.000 claims description 3
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 3
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 claims description 3
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 claims description 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 3
- 229920000161 Locust bean gum Polymers 0.000 claims description 3
- UPYKUZBSLRQECL-UKMVMLAPSA-N Lycopene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1C(=C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=C)CCCC2(C)C UPYKUZBSLRQECL-UKMVMLAPSA-N 0.000 claims description 3
- JEVVKJMRZMXFBT-XWDZUXABSA-N Lycophyll Natural products OC/C(=C/CC/C(=C\C=C\C(=C/C=C/C(=C\C=C\C=C(/C=C/C=C(\C=C\C=C(/CC/C=C(/CO)\C)\C)/C)\C)/C)\C)/C)/C JEVVKJMRZMXFBT-XWDZUXABSA-N 0.000 claims description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004472 Lysine Substances 0.000 claims description 3
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- 229920001090 Polyaminopropyl biguanide Polymers 0.000 claims description 3
- 229920000148 Polycarbophil calcium Polymers 0.000 claims description 3
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 3
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 3
- 239000004283 Sodium sorbate Substances 0.000 claims description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- 102000019197 Superoxide Dismutase Human genes 0.000 claims description 3
- 108010012715 Superoxide dismutase Proteins 0.000 claims description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 239000007983 Tris buffer Substances 0.000 claims description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 claims description 3
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 claims description 3
- XWCYDHJOKKGVHC-UHFFFAOYSA-N Vitamin A2 Chemical compound OCC=C(C)C=CC=C(C)C=CC1=C(C)C=CCC1(C)C XWCYDHJOKKGVHC-UHFFFAOYSA-N 0.000 claims description 3
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 3
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 235000010443 alginic acid Nutrition 0.000 claims description 3
- 239000000783 alginic acid Substances 0.000 claims description 3
- 229920000615 alginic acid Polymers 0.000 claims description 3
- 229960001126 alginic acid Drugs 0.000 claims description 3
- 150000004781 alginic acids Chemical class 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 229910001514 alkali metal chloride Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 229910001617 alkaline earth metal chloride Inorganic materials 0.000 claims description 3
- 150000005215 alkyl ethers Chemical class 0.000 claims description 3
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims description 3
- 235000019169 all-trans-retinol Nutrition 0.000 claims description 3
- 239000011717 all-trans-retinol Substances 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 3
- 235000010385 ascorbyl palmitate Nutrition 0.000 claims description 3
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 3
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 3
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 3
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 claims description 3
- 229960001950 benzethonium chloride Drugs 0.000 claims description 3
- JBIROUFYLSSYDX-UHFFFAOYSA-M benzododecinium chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 JBIROUFYLSSYDX-UHFFFAOYSA-M 0.000 claims description 3
- 229960004074 benzododecinium chloride Drugs 0.000 claims description 3
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 3
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 claims description 3
- 239000003833 bile salt Substances 0.000 claims description 3
- 229940093761 bile salts Drugs 0.000 claims description 3
- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
- 235000011148 calcium chloride Nutrition 0.000 claims description 3
- MCFVRESNTICQSJ-RJNTXXOISA-L calcium sorbate Chemical compound [Ca+2].C\C=C\C=C\C([O-])=O.C\C=C\C=C\C([O-])=O MCFVRESNTICQSJ-RJNTXXOISA-L 0.000 claims description 3
- 235000010244 calcium sorbate Nutrition 0.000 claims description 3
- 239000004303 calcium sorbate Substances 0.000 claims description 3
- 229940031663 carbomer-974p Drugs 0.000 claims description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
- 229920001525 carrageenan Polymers 0.000 claims description 3
- 229960003260 chlorhexidine Drugs 0.000 claims description 3
- 229960004926 chlorobutanol Drugs 0.000 claims description 3
- 229960002242 chlorocresol Drugs 0.000 claims description 3
- 239000002812 cholic acid derivative Substances 0.000 claims description 3
- 150000001860 citric acid derivatives Chemical class 0.000 claims description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 3
- 235000018417 cysteine Nutrition 0.000 claims description 3
- 229960002433 cysteine Drugs 0.000 claims description 3
- 229960002086 dextran Drugs 0.000 claims description 3
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 3
- 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 description 3
- 229940124274 edetate disodium Drugs 0.000 claims description 3
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims description 3
- 235000019414 erythritol Nutrition 0.000 claims description 3
- 229940009714 erythritol Drugs 0.000 claims description 3
- 239000000194 fatty acid Substances 0.000 claims description 3
- 229930195729 fatty acid Natural products 0.000 claims description 3
- 229940074391 gallic acid Drugs 0.000 claims description 3
- 235000004515 gallic acid Nutrition 0.000 claims description 3
- 235000010492 gellan gum Nutrition 0.000 claims description 3
- 239000000216 gellan gum Substances 0.000 claims description 3
- 229960005219 gentisic acid Drugs 0.000 claims description 3
- 229960002442 glucosamine Drugs 0.000 claims description 3
- 229960005150 glycerol Drugs 0.000 claims description 3
- 150000002334 glycols Chemical class 0.000 claims description 3
- 229920000578 graft copolymer Polymers 0.000 claims description 3
- 229940094952 green tea extract Drugs 0.000 claims description 3
- 235000020688 green tea extract Nutrition 0.000 claims description 3
- 235000010417 guar gum Nutrition 0.000 claims description 3
- 239000000665 guar gum Substances 0.000 claims description 3
- 229960002154 guar gum Drugs 0.000 claims description 3
- 229940005740 hexametaphosphate Drugs 0.000 claims description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 3
- 229920002674 hyaluronan Polymers 0.000 claims description 3
- 229940014041 hyaluronate Drugs 0.000 claims description 3
- 229960003160 hyaluronic acid Drugs 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 235000010439 isomalt Nutrition 0.000 claims description 3
- 239000000905 isomalt Substances 0.000 claims description 3
- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Natural products CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 0.000 claims description 3
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims description 3
- 239000000832 lactitol Substances 0.000 claims description 3
- 235000010448 lactitol Nutrition 0.000 claims description 3
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 claims description 3
- 229960003451 lactitol Drugs 0.000 claims description 3
- AGBQKNBQESQNJD-UHFFFAOYSA-M lipoate Chemical compound [O-]C(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-M 0.000 claims description 3
- 235000019136 lipoic acid Nutrition 0.000 claims description 3
- 235000010420 locust bean gum Nutrition 0.000 claims description 3
- 239000000711 locust bean gum Substances 0.000 claims description 3
- 235000012661 lycopene Nutrition 0.000 claims description 3
- 229960004999 lycopene Drugs 0.000 claims description 3
- OAIJSZIZWZSQBC-GYZMGTAESA-N lycopene Chemical compound CC(C)=CCC\C(C)=C\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C=C(/C)CCC=C(C)C OAIJSZIZWZSQBC-GYZMGTAESA-N 0.000 claims description 3
- 239000001751 lycopene Substances 0.000 claims description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- 235000011147 magnesium chloride Nutrition 0.000 claims description 3
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 3
- 235000010449 maltitol Nutrition 0.000 claims description 3
- 239000000845 maltitol Substances 0.000 claims description 3
- 229940035436 maltitol Drugs 0.000 claims description 3
- 229960001855 mannitol Drugs 0.000 claims description 3
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 3
- 229910021645 metal ion Inorganic materials 0.000 claims description 3
- 229920005615 natural polymer Polymers 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 125000002347 octyl 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])[H] 0.000 claims description 3
- 125000005430 oxychloro group Chemical group 0.000 claims description 3
- 229960003330 pentetic acid Drugs 0.000 claims description 3
- 150000002978 peroxides Chemical class 0.000 claims description 3
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 3
- 229940096826 phenylmercuric acetate Drugs 0.000 claims description 3
- PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 claims description 3
- 235000021317 phosphate Nutrition 0.000 claims description 3
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 3
- 229920001467 poly(styrenesulfonates) Polymers 0.000 claims description 3
- 239000004584 polyacrylic acid Substances 0.000 claims description 3
- 229940093424 polyaminopropyl biguanide Drugs 0.000 claims description 3
- 229950005134 polycarbophil Drugs 0.000 claims description 3
- 229920001451 polypropylene glycol Polymers 0.000 claims description 3
- 229920000136 polysorbate Polymers 0.000 claims description 3
- 229950008882 polysorbate Drugs 0.000 claims description 3
- 229960002796 polystyrene sulfonate Drugs 0.000 claims description 3
- 239000011970 polystyrene sulfonate Substances 0.000 claims description 3
- 239000001103 potassium chloride Substances 0.000 claims description 3
- 235000011164 potassium chloride Nutrition 0.000 claims description 3
- 235000010241 potassium sorbate Nutrition 0.000 claims description 3
- 239000004302 potassium sorbate Substances 0.000 claims description 3
- 229940069338 potassium sorbate Drugs 0.000 claims description 3
- 229940069328 povidone Drugs 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 229940076788 pyruvate Drugs 0.000 claims description 3
- 150000004728 pyruvic acid derivatives Chemical class 0.000 claims description 3
- 229930002330 retinoic acid Natural products 0.000 claims description 3
- 235000020944 retinol Nutrition 0.000 claims description 3
- 229930182490 saponin Natural products 0.000 claims description 3
- 150000007949 saponins Chemical class 0.000 claims description 3
- 235000017709 saponins Nutrition 0.000 claims description 3
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 3
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 3
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 3
- 229960005055 sodium ascorbate Drugs 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 3
- 239000001509 sodium citrate Substances 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 3
- OABYVIYXWMZFFJ-ZUHYDKSRSA-M sodium glycocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 OABYVIYXWMZFFJ-ZUHYDKSRSA-M 0.000 claims description 3
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 3
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 3
- 235000010344 sodium nitrate Nutrition 0.000 claims description 3
- 239000004317 sodium nitrate Substances 0.000 claims description 3
- 239000001488 sodium phosphate Substances 0.000 claims description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 3
- 235000011008 sodium phosphates Nutrition 0.000 claims description 3
- LROWVYNUWKVTCU-STWYSWDKSA-M sodium sorbate Chemical compound [Na+].C\C=C\C=C\C([O-])=O LROWVYNUWKVTCU-STWYSWDKSA-M 0.000 claims description 3
- 235000019250 sodium sorbate Nutrition 0.000 claims description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 3
- 235000011152 sodium sulphate Nutrition 0.000 claims description 3
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 3
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 3
- WSWCOQWTEOXDQX-MQQKCMAXSA-N sorbic acid group Chemical class C(\C=C\C=C\C)(=O)O WSWCOQWTEOXDQX-MQQKCMAXSA-N 0.000 claims description 3
- 229960002920 sorbitol Drugs 0.000 claims description 3
- 150000003890 succinate salts Chemical class 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- 229920001059 synthetic polymer Polymers 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- 150000003892 tartrate salts Chemical class 0.000 claims description 3
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 claims description 3
- 229940033663 thimerosal Drugs 0.000 claims description 3
- 229960002663 thioctic acid Drugs 0.000 claims description 3
- 239000012929 tonicity agent Substances 0.000 claims description 3
- ZCIHMQAPACOQHT-ZGMPDRQDSA-N trans-isorenieratene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/c1c(C)ccc(C)c1C)C=CC=C(/C)C=Cc2c(C)ccc(C)c2C ZCIHMQAPACOQHT-ZGMPDRQDSA-N 0.000 claims description 3
- 229960001727 tretinoin Drugs 0.000 claims description 3
- 229920000428 triblock copolymer Polymers 0.000 claims description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 3
- 229920001664 tyloxapol Polymers 0.000 claims description 3
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 claims description 3
- 229960004224 tyloxapol Drugs 0.000 claims description 3
- 229940116269 uric acid Drugs 0.000 claims description 3
- 150000002266 vitamin A derivatives Chemical class 0.000 claims description 3
- 235000010447 xylitol Nutrition 0.000 claims description 3
- 239000000811 xylitol Substances 0.000 claims description 3
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 3
- 229960002675 xylitol Drugs 0.000 claims description 3
- 229960001790 sodium citrate Drugs 0.000 claims description 2
- 150000003712 vitamin E derivatives Chemical class 0.000 claims description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 9
- 238000003756 stirring Methods 0.000 description 38
- 238000009097 single-agent therapy Methods 0.000 description 9
- 230000001954 sterilising effect Effects 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 108010064548 Lymphocyte Function-Associated Antigen-1 Proteins 0.000 description 5
- 238000011049 filling Methods 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 102000015271 Intercellular Adhesion Molecule-1 Human genes 0.000 description 3
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 3
- 229920001983 poloxamer Polymers 0.000 description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229940068968 polysorbate 80 Drugs 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- PBKADZMAZVCJMR-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid;dihydrate Chemical compound O.O.OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O PBKADZMAZVCJMR-UHFFFAOYSA-N 0.000 description 2
- 208000009319 Keratoconjunctivitis Sicca Diseases 0.000 description 2
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 description 2
- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 229940057850 carbomer copolymer type a Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003246 corticosteroid Substances 0.000 description 2
- 229960001334 corticosteroids Drugs 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- 238000003801 milling Methods 0.000 description 2
- 229920004914 octoxynol-40 Polymers 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- QGNJRVVDBSJHIZ-QHLGVNSISA-N retinyl acetate Chemical compound CC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C QGNJRVVDBSJHIZ-QHLGVNSISA-N 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- VBJGJHBYWREJQD-UHFFFAOYSA-M sodium;dihydrogen phosphate;dihydrate Chemical compound O.O.[Na+].OP(O)([O-])=O VBJGJHBYWREJQD-UHFFFAOYSA-M 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 1
- 239000001606 7-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5-hydroxy-2-(4-hydroxyphenyl)chroman-4-one Substances 0.000 description 1
- JMGZEFIQIZZSBH-UHFFFAOYSA-N Bioquercetin Natural products CC1OC(OCC(O)C2OC(OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5)C(O)C2O)C(O)C(O)C1O JMGZEFIQIZZSBH-UHFFFAOYSA-N 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 229940122739 Calcineurin inhibitor Drugs 0.000 description 1
- 102100024123 Calcineurin-binding protein cabin-1 Human genes 0.000 description 1
- 101710192106 Calcineurin-binding protein cabin-1 Proteins 0.000 description 1
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 1
- 206010011017 Corneal graft rejection Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 208000001344 Macular Edema Diseases 0.000 description 1
- 206010025415 Macular oedema Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920002675 Polyoxyl Polymers 0.000 description 1
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 description 1
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229930002945 all-trans-retinaldehyde Natural products 0.000 description 1
- 208000002205 allergic conjunctivitis Diseases 0.000 description 1
- 229940124326 anaesthetic agent Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 150000001510 aspartic acids Chemical class 0.000 description 1
- 206010069664 atopic keratoconjunctivitis Diseases 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- PMATZTZNYRCHOR-UHFFFAOYSA-N cyclosporine a Chemical group CCC1NC(=O)C(C(O)C(C)CC=CC)N(C)C(=O)C(C(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(CC(C)C)N(C)C(=O)C(C)NC(=O)C(C)NC(=O)C(CC(C)C)N(C)C(=O)C(C(C)C)NC(=O)C(CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-UHFFFAOYSA-N 0.000 description 1
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000010894 electron beam technology Methods 0.000 description 1
- 206010014801 endophthalmitis Diseases 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- IVTMALDHFAHOGL-UHFFFAOYSA-N eriodictyol 7-O-rutinoside Natural products OC1C(O)C(O)C(C)OC1OCC1C(O)C(O)C(O)C(OC=2C=C3C(C(C(O)=C(O3)C=3C=C(O)C(O)=CC=3)=O)=C(O)C=2)O1 IVTMALDHFAHOGL-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- FOYKKGHVWRFIBD-UHFFFAOYSA-N gamma-tocopherol acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 FOYKKGHVWRFIBD-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 150000002307 glutamic acids Chemical class 0.000 description 1
- AIONOLUJZLIMTK-AWEZNQCLSA-N hesperetin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O)=CC(O)=C2C(=O)C1 AIONOLUJZLIMTK-AWEZNQCLSA-N 0.000 description 1
- 229960001587 hesperetin Drugs 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 229940028885 interleukin-4 Drugs 0.000 description 1
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 201000010230 macular retinal edema Diseases 0.000 description 1
- 229940057917 medium chain triglycerides Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000005875 quercetin Nutrition 0.000 description 1
- 229960001285 quercetin Drugs 0.000 description 1
- FDRQPMVGJOQVTL-UHFFFAOYSA-N quercetin rutinoside Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 FDRQPMVGJOQVTL-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000011604 retinal Substances 0.000 description 1
- 235000020945 retinal Nutrition 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- NCYCYZXNIZJOKI-OVSJKPMPSA-N retinal group Chemical group C\C(=C/C=O)\C=C\C=C(\C=C\C1=C(CCCC1(C)C)C)/C NCYCYZXNIZJOKI-OVSJKPMPSA-N 0.000 description 1
- 229960000342 retinol acetate Drugs 0.000 description 1
- 235000019173 retinyl acetate Nutrition 0.000 description 1
- 239000011770 retinyl acetate Substances 0.000 description 1
- 229940108325 retinyl palmitate Drugs 0.000 description 1
- 235000019172 retinyl palmitate Nutrition 0.000 description 1
- 239000011769 retinyl palmitate Substances 0.000 description 1
- 235000005493 rutin Nutrition 0.000 description 1
- IKGXIBQEEMLURG-BKUODXTLSA-N rutin Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@@H]1OC[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 IKGXIBQEEMLURG-BKUODXTLSA-N 0.000 description 1
- ALABRVAAKCSLSC-UHFFFAOYSA-N rutin Natural products CC1OC(OCC2OC(O)C(O)C(O)C2O)C(O)C(O)C1OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5 ALABRVAAKCSLSC-UHFFFAOYSA-N 0.000 description 1
- 229960004555 rutoside Drugs 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000005549 size reduction Methods 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000004488 tear evaporation Effects 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 125000002640 tocopherol group Chemical class 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 201000005539 vernal conjunctivitis Diseases 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical class OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
Definitions
- the present invention is related to an ophthalmic combination composition
- an ophthalmic combination composition comprising of lifitegrast or its salt thereof and cyclosporine or its salt thereof.
- the said composition is useful for treatment of dry eye syndrome.
- Dry Eye Disease is a common condition that occurs when your tears are not able to provide adequate lubrication for your eyes.
- the medical term for this condition is keratoconjunctivitis sicca.
- Tear film has three layers: fatty oils, aqueous fluid, and mucus. This combination normally keeps the surface of eyes lubricated, smooth and clear. Problems with any of these layers can cause dry eyes. For example, dry eyes may occur if you do not produce enough tears or there is increased tear evaporation. This tear instability leads to inflammation and damage of the eye's surface. It is accompanied by increased osmolality of the tear film. Dry eye symptoms affect activities of daily living and can lead to despair, depression, decreased productivity, and adversely impact tasks such as driving and our daily routine works. If left untreated, the chronic nature of DED can progress to corneal scarring, ulcers and ultimately vision loss.
- Commonly prescribed drugs for dry eye includes immune-suppressing medication (XiidraTM, RestasisTM, CequaTM, IkervisTM) or corticosteroids (e.g., FluoromethoIone, FMLTM, FlarexTM) which can help relieve inflammation in the cornea.
- Corticosteroids are not ideal for long-term use due to possible side effects.
- RestasisTM (Cyclosporine) ophthalmic emulsion is administered twice a day in each eye approximately 12 hours apart. Cyclosporine works by reducing the inflammation in eyes and tear ducts. This action helps to improve body's natural ability to make tears, which moistens your eyes and reduces dry eye symptoms.
- XiidraTM (Lifitegrast) is also administered twice daily (approximately 12 hours apart) into each eye.
- Lifitegrast is a lymphocyte function-associated antigen- 1 (LFA-1) antagonist.
- LFA-1 is ubiquitously expressed on large granular lymphocytes, B lymphocytes, and T lymphocytes.
- Lifitegrast binds to LFA-1 and inhibits it from interacting with its ligand, intercellular adhesion molecule 1 (ICAM-1), an immunoglobulin superfamily cellular adhesion molecule.
- ICAM-1 is expressed by endothelial cells when inflammation or an infection is present but may be overexpressed in corneal and conjunctival tissues in individuals with DED.
- cytokine secretion e.g., interferon gamma, interleukin 4
- cell destruction e.g., cell destruction, and self-amplification of the inflammatory immune response that further aggravates symptoms of DED.
- RestasisTM and XiidraTM normally take a period of time to take effect. These medications are available as monotherapies.
- the inventors of the present invention have formulated the ophthalmic composition comprising combination of lifitegrast and cyclosporine, which has stability, safety, efficacy and leads to increased patient compliance.
- the present invention provides an ophthalmic composition comprising combination of lifitegrast and cyclosporine.
- the present invention provides an ophthalmic combination composition comprising of lifitegrast or a salt thereof and cyclosporine or a salt thereof.
- the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition contains one or more pharmaceutically acceptable excipients.
- the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the pharmaceutically acceptable excipients are selected from the group comprising buffering agent, preservative, antioxidant, chelating agent, pH-adjusting agent, tonicity-adjusting agent, surfactant/solubilizer, penetration enhancer, thickener/viscosity modifier/gelling agent, demulcents/humectant, polyol, polymers, solvent/vehicle and/or combinations thereof.
- the present invention provides an ophthalmic composition
- ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is in the form of solution, suspension, emulsion, nanomicellar, gel, gel forming solution, drops, implant, insert, ointment or dispersion thereof.
- the present invention provides an ophthalmic composition
- ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is in the form of solution.
- the present invention provides an ophthalmic composition
- an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is free of preservative.
- the present invention provides an ophthalmic composition
- an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is free of antioxidant and/or preservative.
- the present invention provides an ophthalmic composition
- ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is administered twice daily.
- the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition contains total impurities not more than 3.0% when stored at a temperature of about 40°C for a period of at least 1 month.
- the present invention provides a method of treating dry eye by administering a combination composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof.
- Lifitegrast is (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro- 1,2,3, 4-tetrahydroisoquinoline-6- carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid.
- the molecular formula of lifitegrast is C29H24CI2N2O7S and its molecular weight is 615.5 g/mol.
- the present invention contains lifitegrast in an amount of about 0.1% w/v to about 50% w/v of the composition. Preferably, about 1.0% w/v to about 10% w/v of the composition.
- Cyclosporine is a calcineurin inhibitor immunosuppressant with anti-inflammatory effects.
- Cyclosporine’s chemical name is Cyclo[[(E)-(2S,3R,4R)-3-hydroxy-4-methyl-2-(methylamino)- 6-octenoyl]-L-2-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valylN-methyl-L-leucyl-L- alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl].
- the molecular formula of cyclosporine is C62H111N11O12 and its molecular weight is 1202.6 g/mol.
- the present invention contains cyclosporine in an amount of about 0.01% w/v to about 10.0 % w/v of the composition.
- composition of the present invention may comprises the amorphous form of active ingredient or any of its crystalline form, or a combination thereof.
- the present invention provides an ophthalmic composition
- ophthalmic composition comprising lifitegrast and cyclosporine, wherein the weight ratio of lifitegrast and cyclosporine is in the range of 1 :50 to 50: 1 by weight of the composition.
- the ophthalmic composition according to the present invention may also contain one or more pharmaceutically acceptable excipients selected from the group comprising buffering agent, preservative, antioxidant, chelating agent, pH-adjusting agent, tonicity-adjusting agent, surfactant, penetration enhancer, thickener/viscosity modifier/gelling agent, demulcents/humectant, polyol, polymers, solvent/vehicle and/or combinations thereof.
- one or more pharmaceutically acceptable excipients selected from the group comprising buffering agent, preservative, antioxidant, chelating agent, pH-adjusting agent, tonicity-adjusting agent, surfactant, penetration enhancer, thickener/viscosity modifier/gelling agent, demulcents/humectant, polyol, polymers, solvent/vehicle and/or combinations thereof.
- Suitable buffering agent is selected from the group comprising phosphates (sodium phosphate monobasic/dibasic), bicarbonates, acetates, citrates, borates, boric acid, tartrates, succinates, amino acids, tromethamine (TRIS, 2-amino-2-hydroxymethyl- 1,3 -propanediol) and/or combinations thereof. Buffering agent is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
- Suitable preservative is selected from the group comprising benzalkonium chloride, benzethonium chloride, benzododecinium chloride, chlorobutanol, chlorhexidine, parabens, stabilized oxychloro compounds, purite, benzyl alcohol, chlorocresol, perborates, phenylmercuric acetate, phenylmercuric nitrate, thimerosal, sorbic acid salts such as potassium sorbate, calcium sorbate, sodium sorbate, polyaminopropyl biguanide, pyruvates, polyquaternium- 1 , polyhexamethylene biguanide (PHMB), PVP -Iodine complex, metal ions, peroxides, amino acids and/or combinations thereof.
- Preservative is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
- Suitable antioxidant is selected from the group comprising ascorbic acid, salts of ascorbic acid such as ascorbyl palmitate and sodium ascorbate, ascorbyl glucosamine, gentisic acid, sodium thiosulfate pentahydrate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E (i.e., Tocopherols Such as a-tocopherol) derivatives of vitamin E (e.g., toco pheryl acetate), retinoids such as retinoic acid, retinol, trans retinol, cis-retinol, 3 -dehydroretinol and derivatives of vitamin A (e.g., retinyl acetate, retinal and retinyl palmitate, also known as tetinyl palmitate), sodium citrate, trisodium citrate dihydrate, sodium bisulfite, sodium metabisulfite lycop
- Suitable chelating agent is selected from the group comprising edetate disodium, ethylenediamine tetracetic acid, edetic acid, disodium edetate dihydrate, diethylenetriamine pentaacetic acid, citric acid, alkali metal hexametaphosphate and/or combinations thereof.
- Other acceptable chelating agents such as amino acids like glutamic and aspartic acids and borates may be used.
- Chelating agent is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
- Suitable pH adjusting agent is selected from the group comprising hydrochloric acid, phosphoric acid, acetic acid, boric acid, citric acid, tartaric acid, nitric acid, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, sodium hydrogen carbonate, tromethamine, arginine, lysine, histidine, guanine or salts thereof and/or combinations thereof.
- Suitable tonicity adjusting agent is selected from the group comprising alkali metal chlorides and alkaline earth metal chlorides, such as sodium chloride, potassium chloride, calcium chloride and magnesium chloride, sodium nitrate, sodium sulfate, sodium bromide, sodium phosphate, glycerol, propylene glycol, polyethylene glycols (PEG), mannitol, sucrose, dextrose and/or combinations thereof.
- Tonicity agent is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
- Suitable surfactant/solubilizer is selected from the group comprising tyloxapol, polysorbate, polyoxyethylene hydrogenated castor oil, poly (ethyleneoxide) /poly (propyleneoxide) triblock copolymers (Pluronics® / Poloxamers®), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, polyoxyethylene fatty acid esters, ethoxylated alkyl phenol (e.g., Octoxynol-40), polyoxyethylene alkylphenyl ethers, and polyoxyethylene alkyl ethers and/or combinations thereof.
- Surfactant is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
- Suitable penetration enhancer is selected from the group comprising cyclodextrin, dimethylsulphoxide (DMSO), ethylenediaminetetraacetic acid (EDTA), sodium glycocholate & related cholates, saponins, bile salts and /or combinations thereof.
- DMSO dimethylsulphoxide
- EDTA ethylenediaminetetraacetic acid
- the present invention contains penetration enhancer in an amount of about 0.01% w/v to about 10.0 % w/v of the composition.
- Suitable thickening agent is selected from the group comprising hydroxyalkylated cellulose, alkylated cellulose, sodium carboxymethyl cellulose, chondroitin sulfate, polyacrylic acid, polyvinyl alcohol, polyethylene glycol, polysaccharides, polyvinylpyrrolidone, hyaluronic acid, carboxyvinyl polymer (Carbomer 974 P), xanthan gum, gellan gum, alginic acid, carageenans and/or combinations thereof.
- the hydroxyalkylated cellulose may be hydroxypropylcellulose, hydroxymenthyl cellulose, hydroxyethylcellulose or hydroxypropylmethylcellulose.
- the alkylated cellulose may be methylcellulose or ethylcellulose.
- the present invention contains thickening agent in an amount of about 0.1% w/v to about 50.0 % w/v of the composition.
- Suitable humectant is selected from the group comprising polyvinyl alcohol, polyvinyl pyrrolidone, cellulose derivatives, glycerin, sorbitol, mannitol polyethylene glycol and/or combinations thereof. Humectant is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
- Suitable polyol is selected from the group comprising mannitol, sorbitol, propylene glycol, glycerin, maltitol, lactitol, xylitol, isomalt, erythritol, dextrose and/or combinations thereof. Polyol is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
- Suitable polymers include, but are not limited to, natural and synthetic polymers, polysaccharides, polyaminoglycosides, cellulose derivatives, guar gum, xanthan gum, geltrite, dextran, hyaluronate, chondroitin sulfate, locust bean gum, polyvinyl alcohol, polyvinyl pyrrolidone, carbopol, polycarbophil, polystyrene sulfonate and/or combinations thereof.
- the present invention contains polymer in an amount of about 0.1% w/v to about 50.0 % w/v by weight of the composition.
- the ophthalmic composition according to the present invention may contain oils such as the medium chain triglycerides, mineral oil, vegetable oil such as castor oil.
- Suitable solvents may be selected from a group comprising water for injection, normal saline solution, Ringer’s solution, alcohols, such as ethanol, and glycols such as ethylene glycol, propylene glycol, polyethylene glycol, glycofurol, glycerin, polyvinyl alcohol, povidone, glycosaminoglycans such as sodium hyaluronate and/or combinations thereof.
- alcohols such as ethanol
- glycols such as ethylene glycol, propylene glycol, polyethylene glycol, glycofurol, glycerin, polyvinyl alcohol, povidone, glycosaminoglycans such as sodium hyaluronate and/or combinations thereof.
- composition as per the present invention is in the form of solution, suspension, emulsion, nanomicellar, gel, gel forming solution, drops, implant, insert, ointment or dispersion thereof.
- composition as per the present invention is in the form of solution or drops.
- the present invention provides an ophthalmic composition
- ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is administered once to thrice daily, more preferably twice daily or once daily.
- the pharmaceutical composition of the invention may be administered one to four drops per time, preferably one to two drops, more preferably one to two drops, and most preferably one drop per day.
- the present invention provides an ophthalmic composition
- ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof along with one or more pharmaceutically acceptable excipients, wherein the composition is free of antioxidant and/or preservative.
- the present invention provides an ophthalmic composition
- ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof along with one or more pharmaceutically acceptable excipients, wherein the composition is free of preservative.
- the ophthalmic composition according to the present invention is provided/supplied in a single dose container or a multi-dose container.
- single-dose container refers to those containers which contain composition which is intended for a single use such as vials, ampoules, bottles, UNIMS, pre-filled syringes, cartridges, bags, BFS, etc.
- multi-dose container refers to those containers which are designed for removal of portions of composition multiple times such as multi-dose vials or bottles.
- the ophthalmic composition according to the present invention has pH in the range of about 5.0 to about 8.0, preferably in the range of about 6.5 to about 8.0.
- the ophthalmic composition according to the present invention is therapeutically as effective as compared to individual monotherapy products when administered separately.
- the ophthalmic composition according to the present invention provides synergistic effect as compared to individual monotherapy products when administered separately.
- the ophthalmic composition according to the present invention provides favourable safety profile as compared to individual monotherapy products when administered separately.
- the ophthalmic composition according to the present invention leads to reduced side effects as compared to individual monotherapy products when administered separately.
- the ophthalmic composition according to the present invention leads to increased patient compliance as compared to individual monotherapy products when administered separately.
- the ophthalmic composition according to the present invention provides reduction in total dose of active ingredients administered per day as compared to individual monotherapy products when administered separately.
- the ophthalmic composition according to the present invention provides early onset of action as compared to individual monotherapy products when administered separately.
- the ophthalmic composition according to the present invention is meant for topical ocular application.
- the pharmaceutical composition as per the present invention can be sterilized using any of the known methods of sterilization, such as filtration, moist heat, dry heat, gas sterilization or irradiation (gamma and electron beam).
- the pharmaceutical composition prepared according to present invention is stable when subject to stability testing conditions.
- composition according to present invention contains total impurities not more than 3.0% when stored at a temperature of about 40 °C for a period of at least 1 month.
- the particle size of the active ingredient i.e., D90 of cyclosporine in the present composition is in the range of about 1 pm to 30 pm.
- Milling/Size reduction of active ingredient can be performed using high pressure homogenizer, bead mill, ball mill etc.
- the ophthalmic composition of the present invention may be required to be isotonic with respect to the ophthalmic fluids present in the human eye.
- the composition of the present invention is having an osmolality of about 250 mOsm/kg to about 500 mOsm/kg.
- the ophthalmic composition according to the present invention has a viscosity between 5 and 100 cP.
- the present composition optionally further comprises one or more therapeutic agents.
- additional therapeutic agent for conjoint administration or inclusion in a pharmaceutical composition with a compound of this invention may be an anti-inflammatory, analgesic or anaesthetic agent, steroid, antibiotic or the like.
- the present invention provides a pharmaceutical composition which is useful in treating any such conditions, preferably are ophthalmic or ocular conditions that is relating to or having to do with one or more parts of an eye of a human or animal. Included among such conditions are, without limitation, dry eye syndrome, phacoanaphylactic endophthalmitis, uveitis, macular edema, vernal conjunctivitis, atopic keratoconjunctivitis, corneal graft rejection and the like conditions.
- the present invention is particularly effective in treating dry eye syndrome also known as keratoconjunctivitis sicca.
- composition of the present invention can also be provided as kit.
- the main embodiment of the present invention provides a composition comprising, a) lifitegrast or its pharmaceutically acceptable salt thereof, b) cyclosporine or its pharmaceutically acceptable salt thereof, wherein the composition optionally comprises one or more pharmaceutically acceptable excipients.
- lifitegrast is present in an amount of about 0.1% w/v to about 50% w/v of the composition.
- cyclosporine is present in an amount of about 0.01% w/v to about 10.0 % w/v of the composition.
- the ratio of lifitegrast to cyclosporine is in the range of 1:50 to 50:1 by weight of the composition.
- the pharmaceutically acceptable excipients are selected from the group comprising buffering agent, preservative, antioxidant, chelating agent, pH- adjusting agent, tonicity- adjusting agent, surfactant/solubilizer, penetration enhancer, thickener/viscosity modifier/gelling agent, demulcents/humectant, polyol, polymers, solvent/vehicle and/or combinations thereof.
- the buffering agent is selected from the group comprising phosphates (sodium phosphate monobasic/dibasic), bicarbonates, acetates, citrates, borates, boric acid, tartrates, succinates, amino acids, tromethamine (TRIS, 2-amino-2- hydroxymethyl-l,3-propanediol) and/or combinations thereof.
- phosphates sodium phosphate monobasic/dibasic
- bicarbonates acetates, citrates, borates, boric acid, tartrates, succinates, amino acids, tromethamine (TRIS, 2-amino-2- hydroxymethyl-l,3-propanediol) and/or combinations thereof.
- the preservative is selected from the group comprising benzalkonium chloride, benzethonium chloride, benzododecinium chloride, chlorobutanol, chlorhexidine, parabens, stabilized oxychloro compounds, purite, benzyl alcohol, chlorocresol, perborates, phenylmercuric acetate, phenylmercuric nitrate, thimerosal, sorbic acid salts such as potassium sorbate, calcium sorbate, sodium sorbate, polyaminopropyl biguanide, pyruvates, polyquaternium- 1 , polyhexamethylene biguanide (PHMB), PVP -Iodine complex, metal ions, peroxides, amino acids and/or combinations thereof.
- benzalkonium chloride benzethonium chloride
- benzododecinium chloride chlorobutanol
- chlorhexidine parabens
- parabens stabilized oxy
- the antioxidant is selected from the group comprising ascorbic acid, salts of ascorbic acid such as ascorbyl palmitate and sodium ascorbate, ascorbyl glucosamine, gentisic acid, sodium thiosulfate pentahydrate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, derivatives of vitamin E, retinoids such as retinoic acid, retinol, trans-retinol, cis-retinol, 3 -dehydroretinol and derivatives of vitamin A, sodium citrate, trisodium citrate dihydrate, sodium bisulfite, sodium metabisulfite lycopene, thiourea, anthocyanids, bioflavinoids, superoxide dismutase, glutathione peroxidase, lipoic acid or its derivatives, propyl, octyl and dodecyl
- the chelating agent is selected from the group comprising edetate disodium, ethylenediamine tetracetic acid, edetic acid, disodium edetate dihydrate, diethylenetriamine pentaacetic acid, citric acid, alkali metal hexametaphosphate and/or combinations thereof.
- the pH adjusting agent is selected from the group comprising hydrochloric acid, phosphoric acid, acetic acid, boric acid, citric acid, tartaric acid, nitric acid, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, sodium hydrogen carbonate, tromethamine, arginine, lysine, histidine, guanine or salts thereof and/or combinations thereof.
- the tonicity agent is selected from the group comprising alkali metal chlorides and alkaline earth metal chlorides, such as sodium chloride, potassium chloride, calcium chloride and magnesium chloride, sodium nitrate, sodium sulfate, sodium bromide, sodium phosphate, glycerol, propylene glycol, polyethylene glycols (PEG), mannitol, sucrose, dextrose and/or combinations thereof.
- alkali metal chlorides and alkaline earth metal chlorides such as sodium chloride, potassium chloride, calcium chloride and magnesium chloride, sodium nitrate, sodium sulfate, sodium bromide, sodium phosphate, glycerol, propylene glycol, polyethylene glycols (PEG), mannitol, sucrose, dextrose and/or combinations thereof.
- the surfactant/solubilizer is selected from the group comprising tyloxapol, polysorbate, polyoxyethylene hydrogenated castor oil, poly (ethyleneoxide) /poly (propyleneoxide) triblock copolymers, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, polyoxyethylene fatty acid esters, ethoxylated alkyl phenol, polyoxyethylene alkylphenyl ethers, and polyoxyethylene alkyl ethers and/or combinations thereof.
- the penetration enhancer is selected from the group comprising cyclodextrin, dimethylsulphoxide (DMSO), ethylenediaminetetraacetic acid (EDTA), sodium glycocholate & related cholates, saponins, bile salts and /or combinations thereof.
- the thickening agent is selected from the group comprising hydroxyalkylated cellulose, alkylated cellulose, sodium carboxymethyl cellulose, chondroitin sulfate, polyacrylic acid, polyvinyl alcohol, polyethylene glycol, polysaccharides, polyvinylpyrrolidone, hyaluronic acid, carboxyvinyl polymer (Carbomer 974 P), xanthan gum, gellan gum, alginic acid, carageenans and/or combinations thereof.
- the humectant is selected from the group comprising polyvinyl alcohol, polyvinyl pyrrolidone, cellulose derivatives, glycerin, sorbitol, mannitol polyethylene glycol and/or combinations thereof.
- the polyol is selected from the group comprising mannitol, sorbitol, propylene glycol, glycerin, maltitol, lactitol, xylitol, isomalt, erythritol, dextrose and/or combinations thereof.
- the polymer is selected from the group comprising natural and synthetic polymers, polysaccharides, polyaminoglycosides, cellulose derivatives, guar gum, xanthan gum, geltrite, dextran, hyaluronate, chondroitin sulfate, locust bean gum, polyvinyl alcohol, polyvinyl pyrrolidone, carbopol, polycarbophil, polystyrene sulfonate and/or combinations thereof.
- the solvent is selected from a group comprising water for injection, normal saline solution, Ringer’s solution, alcohols, such as ethanol, and glycols such as ethylene glycol, propylene glycol, polyethylene glycol, glycofurol, glycerin, polyvinyl alcohol, povidone, glycosaminoglycans such as sodium hyaluronate and/or combinations thereof.
- alcohols such as ethanol
- glycols such as ethylene glycol, propylene glycol, polyethylene glycol, glycofurol, glycerin, polyvinyl alcohol, povidone, glycosaminoglycans such as sodium hyaluronate and/or combinations thereof.
- the pharmaceutically acceptable excipients are present in an amount of 0.001% w/v to 50.0% w/v of the composition.
- the composition is in the form of solution, suspension, emulsion, nanomicellar, gel, gel forming solution, drops, implant, insert, ointment or dispersion thereof.
- the composition is in the form of solution.
- the composition is free of preservative.
- the composition is free of antioxidant and/or preservative.
- the composition is administered once or twice daily, preferable once daily.
- the composition contains total impurities not more than 3.0% when stored at a temperature of about 40°C for a period of at least 1 month.
- the composition is used for treating dry eye syndrome.
- step 2 Slowly adding polyoxyl hydrogenated castor oil into the water of injection of step 1 under continuous stirring to get a clear solution.
- step 3 Adding octoxynol-40 and polyvinylpyrrolidone into the above solution of step 2 to form clear solution. 4. Adding sodium chloride to the solution of step 3 under continuous stirring.
- step 5 Adding the dispensed quantity of sodium phosphate monobasic dihydrate to solution of step 4 under continuous stirring till it dissolves completely.
- step 6 Adding the dispensed quantity of sodium phosphate dibasic anhydrous to above solution of step 5 under continuous stirring to form clear solution.
- step 6 7. Adding cyclosporine to above solution of step 6 under continuous stirring till it dissolves completely.
- step 8 9. Adding the dispensed quantity of lifitegrast to above solution of step 8 under continuous stirring to obtain clear solution.
- step 9 Checking the pH of solution of step 9 and adjusting it up to 7.0-8.0 with freshly prepared, IN Sodium hydroxide solution/ IN Hydrochloric acid solution.
- step 11 Filtering the solution of step 11 through 0.2 pm sterilizing grade filter.
- step 4 5. Adding sodium chloride to the water for injection of step 4 under continuous stirring.
- step 6 Adding the dispensed quantity of sodium phosphate monobasic dihydrate to solution of step 5 under continuous stirring till it dissolves completely.
- step 7 Adding the dispensed quantity of sodium phosphate dibasic anhydrous to above solution of step 6 under continuous stirring to form clear solution.
- step 8 9. Adding the dispensed quantity of lifitegrast to above solution of step 8 under continuous stirring to obtain clear solution.
- step 11 Checking the pH of solution of step 10 and adjusting it up to 7.0-8.0 with freshly prepared, IN Sodium hydroxide solution/ IN Hydrochloric acid solution.
- step 13 Filtering the solution of step 12 through 0.2pm sterilizing grade filter.
- step 2 2. Adding Brij 35 into the water of injection of step 1 under continuous stirring to get a clear solution.
- step 6 Adding EDTA dihydrate to the water for injection of step 5 under continuous stirring.
- step 7 Adding the dispensed quantity of glycerin to solution of step 6 under continuous stirring till it dissolves completely.
- step 10 Adding the dispensed quantity of lifitegrast to above solution of step 9 under continuous stirring to obtain clear solution.
- step 11 Checking the pH of solution of step 11 and adjusting it up to 7.0-8.0 with freshly prepared, IN Sodium hydroxide solution/ IN Hydrochloric acid solution.
- step 14 Filtering the solution of step 13 through 0.2 pm sterilizing grade filter.
- step 2 2. Adding EDTA dihydrate into the water of injection of step 1 under continuous stirring to get a clear solution.
- step 3 Adding carbomer copolymer type A into the solution of step 2 under continuous stirring to get a clear solution.
- step 4 Adjusting the pH of step 4 solution with sodium hydroxide solution and making up the volume up to 50% of the actual batch size with water for injection.
- step 5 Autoclaving the step 5 solution at 121 °C for 30 minutes and cooling the solution.
- step 8 Adding the dispensed quantity of sodium phosphate dibasic anhydrous to solution of step 8 under continuous stirring till it dissolves completely.
- step 11 Adding the dispensed quantity of lifitegrast to above solution of step 10 under continuous stirring to obtain clear solution. 12. Filtering the step 11 solution through 0.2pm sterilizing grade filter and adding cyclosporine into it under continuous stirring.
- step 12 Milling the step 12 cyclosporine slurry with high pressure homogenizer to get desired particle size.
- step 13 Transferring the step 13 homogenized slurry to step 6 solution under stirring to form suspension.
- step 14 Making up the volume of suspension obtained in step 14 up to 100% with water for injection.
- step 16 Filling the final suspension obtained in step 15 in suitable container.
- step 2 2. Adding carbomer copolymer type A into the water of injection of step 2 under continuous stirring to get a clear solution.
- step 6 Adding cyclosporine into step 5 mixture under stirring and maintaining the temperature up to 60°C until it dissolves completely. Taking 10% hot WFI in a separate container and adding glycerin into it under stirring. Adding step 6 solution into step 7 glycerin solution under high shear mixture for 60 minutes to achieve desire globule size. Adjusting the pH of the step 8 emulsion with sodium hydroxide solution. Filtering the step 9 emulsion through 0.2pm sterilizing grade filter and transferring it to step 3 solution under stirring to obtain emulsion. Taking 35 % WFI of the actual batch size in a container and adding sodium phosphate dibasic anhydrous into it under continuous stirring.
- step 11 Adding the dispensed quantity of sodium thiosulfate pentahydrate to above solution of step 11 under continuous stirring to form clear solution. Adding the dispensed quantity of lifitegrast to above solution of step 12 under continuous stirring to obtain clear solution. Filtering the step 13 solution through 0.2pm sterilizing grade filter and adding it into emulsion of step 10 under stirring. Making up the volume of emulsion obtained in step 14 up to 100% with water for injection. Filling the final emulsion obtained in step 15 in suitable container.
Abstract
The present invention provides an ophthalmic combination composition comprising of lifitegrast or its salt thereof and cyclosporine or its salt thereof, along with one or more pharmaceutically acceptable excipients. It further provides the process of preparing such composition and its use for treatment of dry eye syndrome.
Description
“OPHTHALMIC COMBINATION COMPOSITION”
FIELD OF THE INVENTION
The present invention is related to an ophthalmic combination composition comprising of lifitegrast or its salt thereof and cyclosporine or its salt thereof. The said composition is useful for treatment of dry eye syndrome.
BACKGROUND OF THE INVENTION
Dry Eye Disease (DED) is a common condition that occurs when your tears are not able to provide adequate lubrication for your eyes. The medical term for this condition is keratoconjunctivitis sicca. Tear film has three layers: fatty oils, aqueous fluid, and mucus. This combination normally keeps the surface of eyes lubricated, smooth and clear. Problems with any of these layers can cause dry eyes. For example, dry eyes may occur if you do not produce enough tears or there is increased tear evaporation. This tear instability leads to inflammation and damage of the eye's surface. It is accompanied by increased osmolality of the tear film. Dry eye symptoms affect activities of daily living and can lead to despair, depression, decreased productivity, and adversely impact tasks such as driving and our daily routine works. If left untreated, the chronic nature of DED can progress to corneal scarring, ulcers and ultimately vision loss.
Commonly prescribed drugs for dry eye includes immune-suppressing medication (Xiidra™, Restasis™, Cequa™, Ikervis™) or corticosteroids (e.g., FluoromethoIone, FML™, Flarex™) which can help relieve inflammation in the cornea. Corticosteroids are not ideal for long-term use due to possible side effects.
Restasis™ (Cyclosporine) ophthalmic emulsion is administered twice a day in each eye approximately 12 hours apart. Cyclosporine works by reducing the inflammation in eyes and tear ducts. This action helps to improve body's natural ability to make tears, which moistens your eyes and reduces dry eye symptoms.
Xiidra™ (Lifitegrast) is also administered twice daily (approximately 12 hours apart) into each eye. Lifitegrast is a lymphocyte function-associated antigen- 1 (LFA-1) antagonist. LFA-1 is ubiquitously expressed on large granular lymphocytes, B lymphocytes, and T lymphocytes. Lifitegrast binds to LFA-1 and inhibits it from interacting with its ligand, intercellular adhesion
molecule 1 (ICAM-1), an immunoglobulin superfamily cellular adhesion molecule. ICAM-1 is expressed by endothelial cells when inflammation or an infection is present but may be overexpressed in corneal and conjunctival tissues in individuals with DED. By competitively binding to the LFA-1, lifitegrast prevents the adhesion, activation, migration, and proliferation of lymphocytes, which ultimately lead to cytokine secretion (e.g., interferon gamma, interleukin 4), cell destruction, and self-amplification of the inflammatory immune response that further aggravates symptoms of DED. Restasis™ and Xiidra™ normally take a period of time to take effect. These medications are available as monotherapies.
However, to treat the large population of dry eye patients, physicians advise moving in a stepwise fashion, trying one method at a time and then supplementing with others in cases of unimproved symptoms by monotherapies or due to higher severity of disease. Further, there are concerns and expressed reservations in the ophthalmic community about patient compliance when the patient is required to administer separate medications to treat a single disease or condition such as dry eye. Therefore, there exists a long felt need for an effective and safe topical ophthalmic pharmaceutical composition which is capable of simultaneously treating more than one of the underlying DED pathologies and which could potentially improve the treatment efficacy. Unexpectedly, it has been discovered that cyclosporine in combination with lifitegrast meets these criteria.
The inventors of the present invention have formulated the ophthalmic composition comprising combination of lifitegrast and cyclosporine, which has stability, safety, efficacy and leads to increased patient compliance.
SUMMARY OF THE INVENTION
The present invention provides an ophthalmic composition comprising combination of lifitegrast and cyclosporine.
According to one aspect, the present invention provides an ophthalmic combination composition comprising of lifitegrast or a salt thereof and cyclosporine or a salt thereof.
According to one embodiment, the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition contains one or more pharmaceutically acceptable excipients.
According to another embodiment, the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the pharmaceutically acceptable excipients are selected from the group comprising buffering agent, preservative, antioxidant, chelating agent, pH-adjusting agent, tonicity-adjusting agent, surfactant/solubilizer, penetration enhancer, thickener/viscosity modifier/gelling agent, demulcents/humectant, polyol, polymers, solvent/vehicle and/or combinations thereof.
According to another embodiment, the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is in the form of solution, suspension, emulsion, nanomicellar, gel, gel forming solution, drops, implant, insert, ointment or dispersion thereof.
According to another embodiment, the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is in the form of solution.
According to another embodiment, the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is free of preservative.
According to another embodiment, the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is free of antioxidant and/or preservative.
According to another embodiment, the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is administered twice daily.
According to another embodiment, the present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition contains total impurities not more than 3.0% when stored at a temperature of about 40°C for a period of at least 1 month.
According to another aspect, the present invention provides a method of treating dry eye by administering a combination composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. For the values provided herein, the term “about” indicates a given number may vary by at least ±10%.
Lifitegrast is (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro- 1,2,3, 4-tetrahydroisoquinoline-6- carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid. The molecular formula of lifitegrast is C29H24CI2N2O7S and its molecular weight is 615.5 g/mol. The present invention contains lifitegrast in an amount of about 0.1% w/v to about 50% w/v of the composition. Preferably, about 1.0% w/v to about 10% w/v of the composition.
Cyclosporine is a calcineurin inhibitor immunosuppressant with anti-inflammatory effects. Cyclosporine’s chemical name is Cyclo[[(E)-(2S,3R,4R)-3-hydroxy-4-methyl-2-(methylamino)- 6-octenoyl]-L-2-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valylN-methyl-L-leucyl-L- alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]. The molecular formula of cyclosporine is C62H111N11O12 and its molecular weight is 1202.6 g/mol. The present invention contains cyclosporine in an amount of about 0.01% w/v to about 10.0 % w/v of the composition.
The composition of the present invention may comprises the amorphous form of active ingredient or any of its crystalline form, or a combination thereof.
The present invention provides an ophthalmic composition comprising lifitegrast and cyclosporine, wherein the weight ratio of lifitegrast and cyclosporine is in the range of 1 :50 to 50: 1 by weight of the composition.
The ophthalmic composition according to the present invention may also contain one or more pharmaceutically acceptable excipients selected from the group comprising buffering agent, preservative, antioxidant, chelating agent, pH-adjusting agent, tonicity-adjusting agent, surfactant,
penetration enhancer, thickener/viscosity modifier/gelling agent, demulcents/humectant, polyol, polymers, solvent/vehicle and/or combinations thereof.
Suitable buffering agent is selected from the group comprising phosphates (sodium phosphate monobasic/dibasic), bicarbonates, acetates, citrates, borates, boric acid, tartrates, succinates, amino acids, tromethamine (TRIS, 2-amino-2-hydroxymethyl- 1,3 -propanediol) and/or combinations thereof. Buffering agent is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
Suitable preservative is selected from the group comprising benzalkonium chloride, benzethonium chloride, benzododecinium chloride, chlorobutanol, chlorhexidine, parabens, stabilized oxychloro compounds, purite, benzyl alcohol, chlorocresol, perborates, phenylmercuric acetate, phenylmercuric nitrate, thimerosal, sorbic acid salts such as potassium sorbate, calcium sorbate, sodium sorbate, polyaminopropyl biguanide, pyruvates, polyquaternium- 1 , polyhexamethylene biguanide (PHMB), PVP -Iodine complex, metal ions, peroxides, amino acids and/or combinations thereof. Preservative is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
Suitable antioxidant is selected from the group comprising ascorbic acid, salts of ascorbic acid such as ascorbyl palmitate and sodium ascorbate, ascorbyl glucosamine, gentisic acid, sodium thiosulfate pentahydrate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E (i.e., Tocopherols Such as a-tocopherol) derivatives of vitamin E (e.g., toco pheryl acetate), retinoids such as retinoic acid, retinol, trans retinol, cis-retinol, 3 -dehydroretinol and derivatives of vitamin A (e.g., retinyl acetate, retinal and retinyl palmitate, also known as tetinyl palmitate), sodium citrate, trisodium citrate dihydrate, sodium bisulfite, sodium metabisulfite lycopene, thiourea, anthocyanids, bioflavinoids (e.g., hesperitin, naringen, rutin and quercetin), superoxide dismutase, glutathione peroxidase, lipoic acid or its derivatives, propyl, octyl and dodecyl esters of gallic acid, green tea extract, uric acid, cysteine, pyruvate, and/or combinations thereof. The Antioxidant is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
Suitable chelating agent is selected from the group comprising edetate disodium, ethylenediamine tetracetic acid, edetic acid, disodium edetate dihydrate, diethylenetriamine pentaacetic acid, citric acid, alkali metal hexametaphosphate and/or combinations thereof. Other acceptable chelating
agents such as amino acids like glutamic and aspartic acids and borates may be used. Chelating agent is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
Suitable pH adjusting agent is selected from the group comprising hydrochloric acid, phosphoric acid, acetic acid, boric acid, citric acid, tartaric acid, nitric acid, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, sodium hydrogen carbonate, tromethamine, arginine, lysine, histidine, guanine or salts thereof and/or combinations thereof.
Suitable tonicity adjusting agent is selected from the group comprising alkali metal chlorides and alkaline earth metal chlorides, such as sodium chloride, potassium chloride, calcium chloride and magnesium chloride, sodium nitrate, sodium sulfate, sodium bromide, sodium phosphate, glycerol, propylene glycol, polyethylene glycols (PEG), mannitol, sucrose, dextrose and/or combinations thereof. Tonicity agent is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
Suitable surfactant/solubilizer is selected from the group comprising tyloxapol, polysorbate, polyoxyethylene hydrogenated castor oil, poly (ethyleneoxide) /poly (propyleneoxide) triblock copolymers (Pluronics® / Poloxamers®), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, polyoxyethylene fatty acid esters, ethoxylated alkyl phenol (e.g., Octoxynol-40), polyoxyethylene alkylphenyl ethers, and polyoxyethylene alkyl ethers and/or combinations thereof. Surfactant is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
Suitable penetration enhancer is selected from the group comprising cyclodextrin, dimethylsulphoxide (DMSO), ethylenediaminetetraacetic acid (EDTA), sodium glycocholate & related cholates, saponins, bile salts and /or combinations thereof. The present invention contains penetration enhancer in an amount of about 0.01% w/v to about 10.0 % w/v of the composition.
Suitable thickening agent is selected from the group comprising hydroxyalkylated cellulose, alkylated cellulose, sodium carboxymethyl cellulose, chondroitin sulfate, polyacrylic acid, polyvinyl alcohol, polyethylene glycol, polysaccharides, polyvinylpyrrolidone, hyaluronic acid, carboxyvinyl polymer (Carbomer 974 P), xanthan gum, gellan gum, alginic acid, carageenans and/or combinations thereof. The hydroxyalkylated cellulose may be hydroxypropylcellulose, hydroxymenthyl cellulose, hydroxyethylcellulose or hydroxypropylmethylcellulose. The
alkylated cellulose may be methylcellulose or ethylcellulose. The present invention contains thickening agent in an amount of about 0.1% w/v to about 50.0 % w/v of the composition.
Suitable humectant is selected from the group comprising polyvinyl alcohol, polyvinyl pyrrolidone, cellulose derivatives, glycerin, sorbitol, mannitol polyethylene glycol and/or combinations thereof. Humectant is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
Suitable polyol is selected from the group comprising mannitol, sorbitol, propylene glycol, glycerin, maltitol, lactitol, xylitol, isomalt, erythritol, dextrose and/or combinations thereof. Polyol is present in an amount of about 0.001% w/v to about 10.0 % w/v of the composition.
Suitable polymers, include, but are not limited to, natural and synthetic polymers, polysaccharides, polyaminoglycosides, cellulose derivatives, guar gum, xanthan gum, geltrite, dextran, hyaluronate, chondroitin sulfate, locust bean gum, polyvinyl alcohol, polyvinyl pyrrolidone, carbopol, polycarbophil, polystyrene sulfonate and/or combinations thereof. The present invention contains polymer in an amount of about 0.1% w/v to about 50.0 % w/v by weight of the composition.
The ophthalmic composition according to the present invention may contain oils such as the medium chain triglycerides, mineral oil, vegetable oil such as castor oil.
Suitable solvents may be selected from a group comprising water for injection, normal saline solution, Ringer’s solution, alcohols, such as ethanol, and glycols such as ethylene glycol, propylene glycol, polyethylene glycol, glycofurol, glycerin, polyvinyl alcohol, povidone, glycosaminoglycans such as sodium hyaluronate and/or combinations thereof.
The composition as per the present invention is in the form of solution, suspension, emulsion, nanomicellar, gel, gel forming solution, drops, implant, insert, ointment or dispersion thereof.
The composition as per the present invention is in the form of solution or drops.
The present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof, wherein the composition is administered once to thrice daily, more preferably twice daily or once daily. The pharmaceutical composition of the invention may
be administered one to four drops per time, preferably one to two drops, more preferably one to two drops, and most preferably one drop per day.
The present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof along with one or more pharmaceutically acceptable excipients, wherein the composition is free of antioxidant and/or preservative.
The present invention provides an ophthalmic composition comprising lifitegrast or a salt thereof and cyclosporine or a salt thereof along with one or more pharmaceutically acceptable excipients, wherein the composition is free of preservative.
The ophthalmic composition according to the present invention is provided/supplied in a single dose container or a multi-dose container.
The term “single-dose container” as used herein refers to those containers which contain composition which is intended for a single use such as vials, ampoules, bottles, UNIMS, pre-filled syringes, cartridges, bags, BFS, etc.
The term “multi-dose container” as used herein refers to those containers which are designed for removal of portions of composition multiple times such as multi-dose vials or bottles.
The ophthalmic composition according to the present invention has pH in the range of about 5.0 to about 8.0, preferably in the range of about 6.5 to about 8.0.
The ophthalmic composition according to the present invention is therapeutically as effective as compared to individual monotherapy products when administered separately.
The ophthalmic composition according to the present invention provides synergistic effect as compared to individual monotherapy products when administered separately.
The ophthalmic composition according to the present invention provides favourable safety profile as compared to individual monotherapy products when administered separately.
The ophthalmic composition according to the present invention leads to reduced side effects as compared to individual monotherapy products when administered separately.
The ophthalmic composition according to the present invention leads to increased patient compliance as compared to individual monotherapy products when administered separately.
The ophthalmic composition according to the present invention provides reduction in total dose of active ingredients administered per day as compared to individual monotherapy products when administered separately.
The ophthalmic composition according to the present invention provides early onset of action as compared to individual monotherapy products when administered separately.
The ophthalmic composition according to the present invention is meant for topical ocular application.
The pharmaceutical composition as per the present invention can be sterilized using any of the known methods of sterilization, such as filtration, moist heat, dry heat, gas sterilization or irradiation (gamma and electron beam).
The pharmaceutical composition prepared according to present invention is stable when subject to stability testing conditions.
In another preferred embodiment the composition according to present invention contains total impurities not more than 3.0% when stored at a temperature of about 40 °C for a period of at least 1 month.
The particle size of the active ingredient i.e., D90 of cyclosporine in the present composition is in the range of about 1 pm to 30 pm.
Milling/Size reduction of active ingredient can be performed using high pressure homogenizer, bead mill, ball mill etc.
The ophthalmic composition of the present invention may be required to be isotonic with respect to the ophthalmic fluids present in the human eye. The composition of the present invention is having an osmolality of about 250 mOsm/kg to about 500 mOsm/kg.
The ophthalmic composition according to the present invention has a viscosity between 5 and 100 cP.
The present composition optionally further comprises one or more therapeutic agents. For example, additional therapeutic agent for conjoint administration or inclusion in a pharmaceutical
composition with a compound of this invention may be an anti-inflammatory, analgesic or anaesthetic agent, steroid, antibiotic or the like.
The present invention provides a pharmaceutical composition which is useful in treating any such conditions, preferably are ophthalmic or ocular conditions that is relating to or having to do with one or more parts of an eye of a human or animal. Included among such conditions are, without limitation, dry eye syndrome, phacoanaphylactic endophthalmitis, uveitis, macular edema, vernal conjunctivitis, atopic keratoconjunctivitis, corneal graft rejection and the like conditions. The present invention is particularly effective in treating dry eye syndrome also known as keratoconjunctivitis sicca.
The composition of the present invention can also be provided as kit.
The main embodiment of the present invention provides a composition comprising, a) lifitegrast or its pharmaceutically acceptable salt thereof, b) cyclosporine or its pharmaceutically acceptable salt thereof, wherein the composition optionally comprises one or more pharmaceutically acceptable excipients.
In another embodiment of the present invention, lifitegrast is present in an amount of about 0.1% w/v to about 50% w/v of the composition.
In another embodiment of the present invention, cyclosporine is present in an amount of about 0.01% w/v to about 10.0 % w/v of the composition.
In another embodiment of the present invention, the ratio of lifitegrast to cyclosporine is in the range of 1:50 to 50:1 by weight of the composition.
In another embodiment of the present invention, the pharmaceutically acceptable excipients are selected from the group comprising buffering agent, preservative, antioxidant, chelating agent, pH- adjusting agent, tonicity- adjusting agent, surfactant/solubilizer, penetration enhancer, thickener/viscosity modifier/gelling agent, demulcents/humectant, polyol, polymers, solvent/vehicle and/or combinations thereof.
In another embodiment of the present invention, the buffering agent is selected from the group comprising phosphates (sodium phosphate monobasic/dibasic), bicarbonates, acetates, citrates, borates, boric acid, tartrates, succinates, amino acids, tromethamine (TRIS, 2-amino-2- hydroxymethyl-l,3-propanediol) and/or combinations thereof.
In another embodiment of the present invention, the preservative is selected from the group comprising benzalkonium chloride, benzethonium chloride, benzododecinium chloride, chlorobutanol, chlorhexidine, parabens, stabilized oxychloro compounds, purite, benzyl alcohol, chlorocresol, perborates, phenylmercuric acetate, phenylmercuric nitrate, thimerosal, sorbic acid salts such as potassium sorbate, calcium sorbate, sodium sorbate, polyaminopropyl biguanide, pyruvates, polyquaternium- 1 , polyhexamethylene biguanide (PHMB), PVP -Iodine complex, metal ions, peroxides, amino acids and/or combinations thereof.
In another embodiment of the present invention, the antioxidant is selected from the group comprising ascorbic acid, salts of ascorbic acid such as ascorbyl palmitate and sodium ascorbate, ascorbyl glucosamine, gentisic acid, sodium thiosulfate pentahydrate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, derivatives of vitamin E, retinoids such as retinoic acid, retinol, trans-retinol, cis-retinol, 3 -dehydroretinol and derivatives of vitamin A, sodium citrate, trisodium citrate dihydrate, sodium bisulfite, sodium metabisulfite lycopene, thiourea, anthocyanids, bioflavinoids, superoxide dismutase, glutathione peroxidase, lipoic acid or its derivatives, propyl, octyl and dodecyl esters of gallic acid, green tea extract, uric acid, cysteine, pyruvate, and/or combinations thereof.
In another embodiment of the present invention, the chelating agent is selected from the group comprising edetate disodium, ethylenediamine tetracetic acid, edetic acid, disodium edetate dihydrate, diethylenetriamine pentaacetic acid, citric acid, alkali metal hexametaphosphate and/or combinations thereof.
In another embodiment of the present invention, the pH adjusting agent is selected from the group comprising hydrochloric acid, phosphoric acid, acetic acid, boric acid, citric acid, tartaric acid, nitric acid, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, sodium
hydrogen carbonate, tromethamine, arginine, lysine, histidine, guanine or salts thereof and/or combinations thereof.
In another embodiment of the present invention, the tonicity agent is selected from the group comprising alkali metal chlorides and alkaline earth metal chlorides, such as sodium chloride, potassium chloride, calcium chloride and magnesium chloride, sodium nitrate, sodium sulfate, sodium bromide, sodium phosphate, glycerol, propylene glycol, polyethylene glycols (PEG), mannitol, sucrose, dextrose and/or combinations thereof.
In another embodiment of the present invention, the surfactant/solubilizer is selected from the group comprising tyloxapol, polysorbate, polyoxyethylene hydrogenated castor oil, poly (ethyleneoxide) /poly (propyleneoxide) triblock copolymers, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, polyoxyethylene fatty acid esters, ethoxylated alkyl phenol, polyoxyethylene alkylphenyl ethers, and polyoxyethylene alkyl ethers and/or combinations thereof.
In another embodiment of the present invention, the penetration enhancer is selected from the group comprising cyclodextrin, dimethylsulphoxide (DMSO), ethylenediaminetetraacetic acid (EDTA), sodium glycocholate & related cholates, saponins, bile salts and /or combinations thereof.
In another embodiment of the present invention, the thickening agent is selected from the group comprising hydroxyalkylated cellulose, alkylated cellulose, sodium carboxymethyl cellulose, chondroitin sulfate, polyacrylic acid, polyvinyl alcohol, polyethylene glycol, polysaccharides, polyvinylpyrrolidone, hyaluronic acid, carboxyvinyl polymer (Carbomer 974 P), xanthan gum, gellan gum, alginic acid, carageenans and/or combinations thereof.
In another embodiment of the present invention, the humectant is selected from the group comprising polyvinyl alcohol, polyvinyl pyrrolidone, cellulose derivatives, glycerin, sorbitol, mannitol polyethylene glycol and/or combinations thereof.
In another embodiment of the present invention, the polyol is selected from the group comprising mannitol, sorbitol, propylene glycol, glycerin, maltitol, lactitol, xylitol, isomalt, erythritol, dextrose and/or combinations thereof.
In another embodiment of the present invention, the polymer is selected from the group comprising natural and synthetic polymers, polysaccharides, polyaminoglycosides, cellulose derivatives, guar gum, xanthan gum, geltrite, dextran, hyaluronate, chondroitin sulfate, locust bean gum, polyvinyl alcohol, polyvinyl pyrrolidone, carbopol, polycarbophil, polystyrene sulfonate and/or combinations thereof.
In another embodiment of the present invention, the solvent is selected from a group comprising water for injection, normal saline solution, Ringer’s solution, alcohols, such as ethanol, and glycols such as ethylene glycol, propylene glycol, polyethylene glycol, glycofurol, glycerin, polyvinyl alcohol, povidone, glycosaminoglycans such as sodium hyaluronate and/or combinations thereof.
In another embodiment of the present invention, the pharmaceutically acceptable excipients are present in an amount of 0.001% w/v to 50.0% w/v of the composition.
In another embodiment of the present invention, the composition is in the form of solution, suspension, emulsion, nanomicellar, gel, gel forming solution, drops, implant, insert, ointment or dispersion thereof.
In another embodiment of the present invention, the composition is in the form of solution.
In another embodiment of the present invention, the composition is free of preservative.
In another embodiment of the present invention, the composition is free of antioxidant and/or preservative.
In another embodiment of the present invention, the composition is administered once or twice daily, preferable once daily.
In another embodiment of the present invention, the composition contains total impurities not more than 3.0% when stored at a temperature of about 40°C for a period of at least 1 month.
In another embodiment of the present invention, the composition is used for treating dry eye syndrome.
EXAMPLES
While the present invention is disclosed generally above, additional aspects are further discussed and illustrated with reference to the examples below. However, the examples are presented merely to illustrate the invention and should not be considered as limitations thereto.
Example 1:
Method of Preparation:
1. Taking 70 % (of actual batch size) of water for injection in a container.
2. Slowly adding polyoxyl hydrogenated castor oil into the water of injection of step 1 under continuous stirring to get a clear solution.
3. Adding octoxynol-40 and polyvinylpyrrolidone into the above solution of step 2 to form clear solution.
4. Adding sodium chloride to the solution of step 3 under continuous stirring.
5. Adding the dispensed quantity of sodium phosphate monobasic dihydrate to solution of step 4 under continuous stirring till it dissolves completely.
6. Adding the dispensed quantity of sodium phosphate dibasic anhydrous to above solution of step 5 under continuous stirring to form clear solution.
7. Adding cyclosporine to above solution of step 6 under continuous stirring till it dissolves completely.
8. Adding the dispensed quantity of sodium thiosulfate pentahydrate to above solution of step 7 under continuous stirring.
9. Adding the dispensed quantity of lifitegrast to above solution of step 8 under continuous stirring to obtain clear solution.
10. Checking the pH of solution of step 9 and adjusting it up to 7.0-8.0 with freshly prepared, IN Sodium hydroxide solution/ IN Hydrochloric acid solution.
11. Making up the volume up to 100% with water for injection.
12. Filtering the solution of step 11 through 0.2 pm sterilizing grade filter.
13. Filling the final solution in suitable container.
Example 2:
Method of Preparation:
1. Taking 30 % (of actual batch size) of water for injection in a container.
2. Slowly adding Kolliphor Pl 88 into the water of injection of step 1 under continuous stirring to get a clear solution.
3. Adding cyclosporine into the above solution of step 2 to form clear solution.
4. Taking 40 % (of actual batch size) of water for injection in a container.
5. Adding sodium chloride to the water for injection of step 4 under continuous stirring.
6. Adding the dispensed quantity of sodium phosphate monobasic dihydrate to solution of step 5 under continuous stirring till it dissolves completely.
7. Adding the dispensed quantity of sodium phosphate dibasic anhydrous to above solution of step 6 under continuous stirring to form clear solution.
8. Adding the dispensed quantity of sodium thiosulfate pentahydrate to above solution of step 7 under continuous stirring.
9. Adding the dispensed quantity of lifitegrast to above solution of step 8 under continuous stirring to obtain clear solution.
10. Adding the solution of cyclosporine of step 3 into the solution of step 9 under continuous stirring.
11. Checking the pH of solution of step 10 and adjusting it up to 7.0-8.0 with freshly prepared, IN Sodium hydroxide solution/ IN Hydrochloric acid solution.
12. Making up the volume up to 100% with water for injection.
13. Filtering the solution of step 12 through 0.2pm sterilizing grade filter.
14. Filling the final solution in suitable container.
Example 3:
Method of Preparation:
1. Taking 30 % (of actual batch size) of water for injection in a container.
2. Adding Brij 35 into the water of injection of step 1 under continuous stirring to get a clear solution.
3. Adding polysorbate 80 into the solution of step 2 under continuous stirring to get a clear solution.
4. Adding cyclosporine into the above solution of step 3 to form clear solution.
5. Taking 40 % (of actual batch size) of water for injection in a container.
6. Adding EDTA dihydrate to the water for injection of step 5 under continuous stirring.
7. Adding the dispensed quantity of glycerin to solution of step 6 under continuous stirring till it dissolves completely.
8. Adding the dispensed quantity of boric acid to above solution of step 7 under continuous stirring to form clear solution.
9. Adding the dispensed quantity of sodium thiosulfate pentahydrate to above solution of step 8 under continuous stirring.
10. Adding the dispensed quantity of lifitegrast to above solution of step 9 under continuous stirring to obtain clear solution.
11. Adding the solution of cyclosporine of step 3 into the solution of step 10 under stirring.
12. Checking the pH of solution of step 11 and adjusting it up to 7.0-8.0 with freshly prepared, IN Sodium hydroxide solution/ IN Hydrochloric acid solution.
13. Making up the volume up to 100% with water for injection.
14. Filtering the solution of step 13 through 0.2 pm sterilizing grade filter.
15. Filling the final solution in suitable container.
Example 4:
Method of Preparation:
1. Taking 30 % (of actual batch size) of water for injection in a container.
2. Adding EDTA dihydrate into the water of injection of step 1 under continuous stirring to get a clear solution.
3. Adding carbomer copolymer type A into the solution of step 2 under continuous stirring to get a clear solution.
4. Adding sodium chloride into the above solution of step 3 to form clear solution.
5. Adjusting the pH of step 4 solution with sodium hydroxide solution and making up the volume up to 50% of the actual batch size with water for injection.
6. Autoclaving the step 5 solution at 121 °C for 30 minutes and cooling the solution.
7. Taking 40 % (of actual batch size) of water for injection in a container.
8. Adding polysorbate 80 to the solution of step 7 under continuous stirring.
9. Adding the dispensed quantity of sodium phosphate dibasic anhydrous to solution of step 8 under continuous stirring till it dissolves completely.
10. Adding the dispensed quantity of sodium thiosulfate pentahydrate to above solution of step 9 under continuous stirring to form clear solution.
11. Adding the dispensed quantity of lifitegrast to above solution of step 10 under continuous stirring to obtain clear solution.
12. Filtering the step 11 solution through 0.2pm sterilizing grade filter and adding cyclosporine into it under continuous stirring.
13. Milling the step 12 cyclosporine slurry with high pressure homogenizer to get desired particle size.
14. Transferring the step 13 homogenized slurry to step 6 solution under stirring to form suspension.
15. Making up the volume of suspension obtained in step 14 up to 100% with water for injection.
16. Filling the final suspension obtained in step 15 in suitable container.
Example 5:
Method of Preparation:
1. Taking 20 % (of actual batch size) of water for injection in a container.
2. Adding carbomer copolymer type A into the water of injection of step 2 under continuous stirring to get a clear solution.
3. Autoclaving the step 2 solution at 121 °C for 30 minutes and cooling the solution.
4. Taking castor oil in a container and heating it up to 70°C.
5. Adding polysorbate 80 half quantity into castor oil of step 4 while heating and mixing well.
6. Adding cyclosporine into step 5 mixture under stirring and maintaining the temperature up to 60°C until it dissolves completely.
Taking 10% hot WFI in a separate container and adding glycerin into it under stirring. Adding step 6 solution into step 7 glycerin solution under high shear mixture for 60 minutes to achieve desire globule size. Adjusting the pH of the step 8 emulsion with sodium hydroxide solution. Filtering the step 9 emulsion through 0.2pm sterilizing grade filter and transferring it to step 3 solution under stirring to obtain emulsion. Taking 35 % WFI of the actual batch size in a container and adding sodium phosphate dibasic anhydrous into it under continuous stirring. Adding the dispensed quantity of sodium thiosulfate pentahydrate to above solution of step 11 under continuous stirring to form clear solution. Adding the dispensed quantity of lifitegrast to above solution of step 12 under continuous stirring to obtain clear solution. Filtering the step 13 solution through 0.2pm sterilizing grade filter and adding it into emulsion of step 10 under stirring. Making up the volume of emulsion obtained in step 14 up to 100% with water for injection. Filling the final emulsion obtained in step 15 in suitable container.
Claims
THE CLAIMS: A composition comprising, a) lifitegrast or its pharmaceutically acceptable salt thereof, b) cyclosporine or its pharmaceutically acceptable salt thereof, wherein the composition optionally comprises one or more pharmaceutically acceptable excipients. The composition as claimed in claim 1 wherein lifitegrast is present in an amount of about 0.1% w/v to about 50% w/v of the composition. The composition as claimed in claim 1 wherein cyclosporine is present in an amount of about 0.01% w/v to about 10.0 % w/v of the composition. The composition as claimed in claim 1 wherein ratio of lifitegrast to cyclosporine is in the range of 1:50 to 50: 1 by weight of the composition. The composition as claimed in claim 1 wherein the pharmaceutically acceptable excipients are selected from the group comprising buffering agent, preservative, antioxidant, chelating agent, pH- adjusting agent, tonicity- adjusting agent, surfactant/solubilizer, penetration enhancer, thickener/viscosity modifier/gelling agent, demulcents/humectant, polyol, polymers, solvent/vehicle and/or combinations thereof. The composition as claimed in claim 5 wherein the buffering agent is selected from the group comprising phosphates (sodium phosphate monobasic/dibasic), bicarbonates, acetates, citrates, borates, boric acid, tartrates, succinates, amino acids, tromethamine (TRIS, 2-amino-2- hydroxymethyl-l,3-propanediol) and/or combinations thereof. The composition as claimed in claim 5 wherein the preservative is selected from the group comprising benzalkonium chloride, benzethonium chloride, benzododecinium chloride, chlorobutanol, chlorhexidine, parabens, stabilized oxychloro compounds, purite, benzyl alcohol,
chlorocresol, perborates, phenylmercuric acetate, phenylmercuric nitrate, thimerosal, sorbic acid salts such as potassium sorbate, calcium sorbate, sodium sorbate, polyaminopropyl biguanide, pyruvates, polyquaternium- 1 , polyhexamethylene biguanide (PHMB), PVP -Iodine complex, metal ions, peroxides, amino acids and/or combinations thereof. The composition as claimed in claim 5 wherein the antioxidant is selected from the group comprising ascorbic acid, salts of ascorbic acid such as ascorbyl palmitate and sodium ascorbate, ascorbyl glucosamine, gentisic acid, sodium thiosulfate pentahydrate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, derivatives of vitamin E, retinoids such as retinoic acid, retinol, trans-retinol, cis-retinol, 3 -dehydroretinol and derivatives of vitamin A, sodium citrate, trisodium citrate dihydrate, sodium bisulfite, sodium metabisulfite lycopene, thiourea, anthocyanids, bioflavinoids, superoxide dismutase, glutathione peroxidase, lipoic acid or its derivatives, propyl, octyl and dodecyl esters of gallic acid, green tea extract, uric acid, cysteine, pyruvate, and/or combinations thereof. The composition as claimed in claim 5 wherein the chelating agent is selected from the group comprising edetate disodium, ethylenediamine tetracetic acid, edetic acid, disodium edetate dihydrate, diethylenetriamine pentaacetic acid, citric acid, alkali metal hexametaphosphate and/or combinations thereof. The composition as claimed in claim 5 wherein the pH adjusting agent is selected from the group comprising hydrochloric acid, phosphoric acid, acetic acid, boric acid, citric acid, tartaric acid, nitric acid, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, sodium hydrogen carbonate, tromethamine, arginine, lysine, histidine, guanine or salts thereof and/or combinations thereof. The composition as claimed in claim 5 wherein the tonicity agent is selected from the group comprising alkali metal chlorides and alkaline earth metal chlorides, such as sodium chloride, potassium chloride, calcium chloride and magnesium chloride, sodium nitrate, sodium sulfate, sodium bromide, sodium phosphate, glycerol, propylene glycol, polyethylene glycols (PEG), mannitol, sucrose, dextrose and/or combinations thereof.
The composition as claimed in claim 5 wherein the surfactant/solubilizer is selected from the group comprising tyloxapol, polysorbate, polyoxyethylene hydrogenated castor oil, poly (ethyleneoxide) /poly (propyleneoxide) triblock copolymers, polyvinyl caprolactam-poly vinyl acetatepolyethylene glycol graft co-polymer, polyoxyethylene fatty acid esters, ethoxylated alkyl phenol, polyoxyethylene alkylphenyl ethers, and polyoxyethylene alkyl ethers and/or combinations thereof. The composition as claimed in claim 5 wherein the penetration enhancer is selected from the group comprising cyclodextrin, dimethylsulphoxide (DMSO), ethylenediaminetetraacetic acid (EDTA), sodium glycocholate & related cholates, saponins, bile salts and /or combinations thereof. The composition as claimed in claim 5 wherein the thickening agent is selected from the group comprising hydroxyalkylated cellulose, alkylated cellulose, sodium carboxymethyl cellulose, chondroitin sulfate, polyacrylic acid, polyvinyl alcohol, polyethylene glycol, polysaccharides, polyvinylpyrrolidone, hyaluronic acid, carboxyvinyl polymer (Carbomer 974 P), xanthan gum, gellan gum, alginic acid, carageenans and/or combinations thereof. The composition as claimed in claim 5 wherein the humectant is selected from the group comprising polyvinyl alcohol, polyvinyl pyrrolidone, cellulose derivatives, glycerin, sorbitol, mannitol polyethylene glycol and/or combinations thereof. The composition as claimed in claim 5 wherein the polyol is selected from the group comprising mannitol, sorbitol, propylene glycol, glycerin, maltitol, lactitol, xylitol, isomalt, erythritol, dextrose and/or combinations thereof. The composition as claimed in claim 5 wherein the polymer is selected from the group comprising natural and synthetic polymers, polysaccharides, polyaminoglycosides, cellulose derivatives, guar gum, xanthan gum, geltrite, dextran, hyaluronate, chondroitin sulfate, locust bean gum, polyvinyl alcohol, polyvinyl pyrrolidone, carbopol, polycarbophil, polystyrene sulfonate and/or combinations thereof.
The composition as claimed in claim 5 wherein the solvent is selected from a group comprising water for injection, normal saline solution, Ringer’s solution, alcohols, such as ethanol, and glycols such as ethylene glycol, propylene glycol, polyethylene glycol, glycofurol, glycerin, polyvinyl alcohol, povidone, glycosaminoglycans such as sodium hyaluronate and/or combinations thereof. The composition as claimed in claim 5 wherein pharmaceutically acceptable excipients are present in an amount of 0.001% w/v to 50.0% w/v of the composition. The composition as claimed in claim 1 wherein the composition is in the form of solution, suspension, emulsion, nanomicellar, gel, gel forming solution, drops, implant, insert, ointment or dispersion thereof. The composition as claimed in claim 1 wherein the composition is in the form of solution. The composition as claimed in claim 1 wherein the composition is free of preservative. The composition as claimed in claim 1 wherein the composition is free of antioxidant and/or preservative. The composition as claimed in claim 1 wherein the composition is administered once or twice daily, preferable once daily. The composition as claimed in claim 1 wherein the composition contains total impurities not more than 3.0% when stored at a temperature of about 40°C for a period of at least 1 month. The composition as claimed in claim 1 wherein the composition is used for treating dry eye syndrome.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN202211048424 | 2022-08-25 | ||
| IN202211048424 | 2022-08-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2024042550A1 true WO2024042550A1 (en) | 2024-02-29 |
Family
ID=90012764
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2023/050801 WO2024042550A1 (en) | 2022-08-25 | 2023-08-25 | Ophthalmic combination composition |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2024042550A1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180098937A1 (en) * | 2016-10-12 | 2018-04-12 | Ps Therapies Ltd | Artificial tear, contact lens and drug vehicle compositions and methods of use thereof |
| WO2019171260A1 (en) * | 2018-03-09 | 2019-09-12 | Mankind Pharma Ltd. | Pharmaceutical composition of lifitegrast |
| WO2020047197A1 (en) * | 2018-08-29 | 2020-03-05 | Ocugen, Inc. | Ophthalmic compositions and methods of use |
| US10918694B2 (en) * | 2016-02-29 | 2021-02-16 | Sun Pharma Global Fze | Topical cyclosporine-containing formulations and uses thereof |
-
2023
- 2023-08-25 WO PCT/IN2023/050801 patent/WO2024042550A1/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10918694B2 (en) * | 2016-02-29 | 2021-02-16 | Sun Pharma Global Fze | Topical cyclosporine-containing formulations and uses thereof |
| US20180098937A1 (en) * | 2016-10-12 | 2018-04-12 | Ps Therapies Ltd | Artificial tear, contact lens and drug vehicle compositions and methods of use thereof |
| WO2019171260A1 (en) * | 2018-03-09 | 2019-09-12 | Mankind Pharma Ltd. | Pharmaceutical composition of lifitegrast |
| WO2020047197A1 (en) * | 2018-08-29 | 2020-03-05 | Ocugen, Inc. | Ophthalmic compositions and methods of use |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8969385B2 (en) | Ocular formulations of norketotifen | |
| US20080050335A1 (en) | Ophthalmic Solutions | |
| US10555947B2 (en) | Ophthalmic compositions and methods of use | |
| US7335682B2 (en) | Pharmaceutical compositions and methods for treating immune-response associated diseases of the surface and the anterior segment of the eye | |
| ES2750123T3 (en) | Compositions and methods for non-surgical treatment of ptosis | |
| US20050182039A1 (en) | Use of Loteprednol etabonate for the treatment of dry eye | |
| WO2020018498A1 (en) | Cyclodextrin formulations | |
| AU2008262491A1 (en) | Formulations and methods for treating dry eye | |
| US9114168B2 (en) | Pharmaceutical compositions containing a fluoroquinolone antibiotic drug | |
| US20080039398A1 (en) | Formulations and methods for treating dry eye | |
| WO2017066052A1 (en) | Formulations and methods for treating high intraocular pressure | |
| US20190008920A1 (en) | Ophthalmic compositions and methods of use | |
| EP3860600A1 (en) | Ophthalmic preparations of muscarinic agonist and methods of use | |
| EP1283043B1 (en) | Ophthalmic solution | |
| WO2024042550A1 (en) | Ophthalmic combination composition | |
| US20230338540A1 (en) | Xanthan-based ophthalmic topical formulations with a reduced dosage regimen | |
| WO2019171260A1 (en) | Pharmaceutical composition of lifitegrast | |
| TW201815397A (en) | Ophthalmic agent and ophthalmologic drug | |
| US20210299121A1 (en) | Cetirizine ophthalmic compositions | |
| CA3115664A1 (en) | Ophthalmic compositions and methods of use | |
| TWI809317B (en) | Ophthalmic preparations of-muscarinic agonist and methods of use | |
| US20230158045A1 (en) | Pharmaceutical compositions of mycophenolic acid and/or betamethasone for the treatment of ocular disorders | |
| KR20220089106A (en) | Eye drop composition comprising corzolamide or polysorbate 80 as an active ingredient | |
| WO2023141334A2 (en) | Pharmaceutical compositions of mycophenolic acid and/or betamethasone for the treatment of ocular disorders | |
| WO2023152644A1 (en) | Pharmaceutical composition of lifitegrast and loteprednol etabonate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 23856854 Country of ref document: EP Kind code of ref document: A1 |