CN115671090A - Compositions and methods for treating the eye - Google Patents
Compositions and methods for treating the eye Download PDFInfo
- Publication number
- CN115671090A CN115671090A CN202211161743.8A CN202211161743A CN115671090A CN 115671090 A CN115671090 A CN 115671090A CN 202211161743 A CN202211161743 A CN 202211161743A CN 115671090 A CN115671090 A CN 115671090A
- Authority
- CN
- China
- Prior art keywords
- extract
- carbon atoms
- compound
- optionally
- carbonising
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 145
- 238000000034 method Methods 0.000 title abstract description 59
- 239000000284 extract Substances 0.000 claims abstract description 273
- 150000001875 compounds Chemical class 0.000 claims abstract description 118
- 125000004432 carbon atom Chemical group C* 0.000 claims description 107
- 125000004122 cyclic group Chemical group 0.000 claims description 63
- 229920006395 saturated elastomer Polymers 0.000 claims description 63
- 230000009286 beneficial effect Effects 0.000 claims description 47
- 241000196324 Embryophyta Species 0.000 claims description 37
- -1 C 2 -C 6 Alkenyl radical Chemical class 0.000 claims description 36
- 125000003118 aryl group Chemical group 0.000 claims description 35
- 239000000419 plant extract Substances 0.000 claims description 35
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims description 33
- 206010013774 Dry eye Diseases 0.000 claims description 33
- 238000004519 manufacturing process Methods 0.000 claims description 31
- 241001312519 Trigonella Species 0.000 claims description 29
- 230000001580 bacterial effect Effects 0.000 claims description 26
- 210000004087 cornea Anatomy 0.000 claims description 26
- 238000011282 treatment Methods 0.000 claims description 26
- 230000029142 excretion Effects 0.000 claims description 25
- 241001446247 uncultured actinomycete Species 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 19
- 108090000623 proteins and genes Proteins 0.000 claims description 19
- 102000004169 proteins and genes Human genes 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 241000604865 Licaria Species 0.000 claims description 16
- GWEOLLCXJGXWOD-UHFFFAOYSA-N 3-(4-farnesyloxyphenyl)propionic acid Natural products CC(C)=CCCC(C)=CCCC(C)=CCOC1=CC=C(CCC(O)=O)C=C1 GWEOLLCXJGXWOD-UHFFFAOYSA-N 0.000 claims description 14
- AJBZENLMTKDAEK-UHFFFAOYSA-N 3a,5a,5b,8,8,11a-hexamethyl-1-prop-1-en-2-yl-1,2,3,4,5,6,7,7a,9,10,11,11b,12,13,13a,13b-hexadecahydrocyclopenta[a]chrysene-4,9-diol Chemical compound CC12CCC(O)C(C)(C)C1CCC(C1(C)CC3O)(C)C2CCC1C1C3(C)CCC1C(=C)C AJBZENLMTKDAEK-UHFFFAOYSA-N 0.000 claims description 13
- 235000003880 Calendula Nutrition 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 12
- 239000012530 fluid Substances 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 12
- 241000723347 Cinnamomum Species 0.000 claims description 10
- 125000005907 alkyl ester group Chemical group 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 241000186046 Actinomyces Species 0.000 claims description 8
- 230000035876 healing Effects 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 125000004494 ethyl ester group Chemical group 0.000 claims description 7
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 230000000845 anti-microbial effect Effects 0.000 claims description 5
- ICYDSPQRIZHMSX-UHFFFAOYSA-N 3-[3-hydroxy-4-(3,7,11-trimethyldodeca-2,6,10-trienoxy)phenyl]propanoic acid Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCOC1=CC=C(CCC(O)=O)C=C1O ICYDSPQRIZHMSX-UHFFFAOYSA-N 0.000 claims description 4
- FWKHJRHYKZIANI-UHFFFAOYSA-N 3-[3-methoxy-4-(3,7,11-trimethyldodeca-2,6,10-trienoxy)phenyl]propanoic acid Chemical compound COC1=CC(CCC(O)=O)=CC=C1OCC=C(C)CCC=C(C)CCC=C(C)C FWKHJRHYKZIANI-UHFFFAOYSA-N 0.000 claims description 4
- 230000001737 promoting effect Effects 0.000 claims description 4
- 230000029663 wound healing Effects 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 244000080208 Canella winterana Species 0.000 claims description 3
- 235000008499 Canella winterana Nutrition 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000004030 farnesyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 150000003573 thiols Chemical class 0.000 claims description 3
- 241000933223 Licaria brittoniana Species 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 241000132025 Calendula Species 0.000 claims 5
- 241001081179 Litsea Species 0.000 claims 3
- 235000012854 Litsea cubeba Nutrition 0.000 claims 3
- 241001071917 Lithospermum Species 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 6
- 239000000243 solution Substances 0.000 description 163
- 241000158748 Acronychia Species 0.000 description 71
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 60
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 38
- 239000004615 ingredient Substances 0.000 description 37
- 235000002639 sodium chloride Nutrition 0.000 description 37
- 108010063954 Mucins Proteins 0.000 description 36
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 36
- 102000015728 Mucins Human genes 0.000 description 35
- 240000001432 Calendula officinalis Species 0.000 description 32
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 31
- 235000005979 Citrus limon Nutrition 0.000 description 30
- 244000131522 Citrus pyriformis Species 0.000 description 30
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 30
- 238000009472 formulation Methods 0.000 description 30
- 229920002385 Sodium hyaluronate Polymers 0.000 description 29
- 229940010747 sodium hyaluronate Drugs 0.000 description 29
- 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 description 29
- 239000007864 aqueous solution Substances 0.000 description 28
- 239000008213 purified water Substances 0.000 description 28
- 210000001508 eye Anatomy 0.000 description 25
- 239000000463 material Substances 0.000 description 25
- 235000005881 Calendula officinalis Nutrition 0.000 description 24
- 241000183024 Populus tremula Species 0.000 description 24
- 239000011780 sodium chloride Substances 0.000 description 24
- 229910021538 borax Inorganic materials 0.000 description 22
- 235000010339 sodium tetraborate Nutrition 0.000 description 22
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 229920001213 Polysorbate 20 Polymers 0.000 description 20
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 20
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 20
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 19
- 239000004327 boric acid Substances 0.000 description 19
- 229940068977 polysorbate 20 Drugs 0.000 description 19
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 18
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 18
- 229920000053 polysorbate 80 Polymers 0.000 description 18
- 229940068968 polysorbate 80 Drugs 0.000 description 18
- 239000001103 potassium chloride Substances 0.000 description 18
- 235000011164 potassium chloride Nutrition 0.000 description 18
- 210000001519 tissue Anatomy 0.000 description 18
- 235000018102 proteins Nutrition 0.000 description 17
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 16
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 16
- 241000209502 Pistia Species 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 15
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 15
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 15
- 229960003943 hypromellose Drugs 0.000 description 15
- 229910001629 magnesium chloride Inorganic materials 0.000 description 15
- 230000003204 osmotic effect Effects 0.000 description 15
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 14
- 244000250129 Trigonella foenum graecum Species 0.000 description 14
- 235000001484 Trigonella foenum graecum Nutrition 0.000 description 14
- 235000001019 trigonella foenum-graecum Nutrition 0.000 description 14
- 102100034256 Mucin-1 Human genes 0.000 description 13
- 150000004676 glycans Chemical class 0.000 description 13
- 229920001282 polysaccharide Polymers 0.000 description 13
- 239000005017 polysaccharide Substances 0.000 description 13
- 150000003839 salts Chemical class 0.000 description 13
- 241000596504 Tamarindus Species 0.000 description 12
- 235000004298 Tamarindus indica Nutrition 0.000 description 12
- 235000013399 edible fruits Nutrition 0.000 description 12
- 235000011187 glycerol Nutrition 0.000 description 11
- 125000001424 substituent group Chemical group 0.000 description 11
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 10
- 101000972282 Homo sapiens Mucin-5AC Proteins 0.000 description 10
- 241000720991 Illicium Species 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 238000002156 mixing Methods 0.000 description 10
- 239000001540 sodium lactate Substances 0.000 description 10
- 235000011088 sodium lactate Nutrition 0.000 description 10
- 229940005581 sodium lactate Drugs 0.000 description 10
- BMOKTGMYFSXGFI-UHFFFAOYSA-M sodium;chlorite;dihydrate Chemical compound O.O.[Na+].[O-]Cl=O BMOKTGMYFSXGFI-UHFFFAOYSA-M 0.000 description 10
- 241000894007 species Species 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 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 description 9
- 102100022496 Mucin-5AC Human genes 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 9
- 229910000397 disodium phosphate Inorganic materials 0.000 description 9
- 235000019800 disodium phosphate Nutrition 0.000 description 9
- 239000001488 sodium phosphate Substances 0.000 description 9
- 239000004471 Glycine Substances 0.000 description 8
- 108010008707 Mucin-1 Proteins 0.000 description 8
- 235000010323 ascorbic acid Nutrition 0.000 description 8
- 229960005070 ascorbic acid Drugs 0.000 description 8
- 239000011668 ascorbic acid Substances 0.000 description 8
- LLSDKQJKOVVTOJ-UHFFFAOYSA-L calcium chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Ca+2] LLSDKQJKOVVTOJ-UHFFFAOYSA-L 0.000 description 8
- 229940052299 calcium chloride dihydrate Drugs 0.000 description 8
- 239000008103 glucose Substances 0.000 description 8
- 238000009736 wetting Methods 0.000 description 8
- 239000002023 wood Substances 0.000 description 8
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 7
- 150000001335 aliphatic alkanes Chemical class 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 230000001954 sterilising effect Effects 0.000 description 7
- 238000004659 sterilization and disinfection Methods 0.000 description 7
- 241000660877 Coridius Species 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000001747 exhibiting effect Effects 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 6
- 229960002218 sodium chlorite Drugs 0.000 description 6
- 229960000999 sodium citrate dihydrate Drugs 0.000 description 6
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 6
- 229910019142 PO4 Inorganic materials 0.000 description 5
- 239000000043 antiallergic agent Substances 0.000 description 5
- 239000003974 emollient agent Substances 0.000 description 5
- 210000002919 epithelial cell Anatomy 0.000 description 5
- 210000000981 epithelium Anatomy 0.000 description 5
- 230000014509 gene expression Effects 0.000 description 5
- 229940051875 mucins Drugs 0.000 description 5
- 239000012454 non-polar solvent Substances 0.000 description 5
- 150000007524 organic acids Chemical class 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 229920005862 polyol Polymers 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 4
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 description 4
- 102100022693 Mucin-4 Human genes 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 229920000289 Polyquaternium Polymers 0.000 description 4
- 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 4
- 206010052428 Wound Diseases 0.000 description 4
- 208000027418 Wounds and injury Diseases 0.000 description 4
- 150000005215 alkyl ethers Chemical class 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 229940093915 gynecological organic acid Drugs 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 229930014626 natural product Natural products 0.000 description 4
- 235000005985 organic acids Nutrition 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 235000021317 phosphate Nutrition 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000028327 secretion Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 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 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000555678 Citrus unshiu Species 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 102100023123 Mucin-16 Human genes 0.000 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 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000004599 antimicrobial Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000004359 castor oil Substances 0.000 description 3
- 235000019438 castor oil Nutrition 0.000 description 3
- 239000002738 chelating agent Substances 0.000 description 3
- 150000001924 cycloalkanes Chemical class 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 150000002009 diols Chemical class 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940124274 edetate disodium Drugs 0.000 description 3
- 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 description 3
- 229920002674 hyaluronan Polymers 0.000 description 3
- 229960003160 hyaluronic acid Drugs 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 125000005647 linker group Chemical group 0.000 description 3
- 210000004379 membrane Anatomy 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000003961 penetration enhancing agent Substances 0.000 description 3
- 239000002798 polar solvent Substances 0.000 description 3
- 238000010839 reverse transcription Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 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 description 3
- 239000001509 sodium citrate Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 229940082892 tamarind seed extract Drugs 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 2
- VKZRWSNIWNFCIQ-UHFFFAOYSA-N 2-[2-(1,2-dicarboxyethylamino)ethylamino]butanedioic acid Chemical compound OC(=O)CC(C(O)=O)NCCNC(C(O)=O)CC(O)=O VKZRWSNIWNFCIQ-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 244000256618 Acronychia laurifolia Species 0.000 description 2
- 240000006880 Acronychia pedunculata Species 0.000 description 2
- 241001079133 Acronychia vestita Species 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 239000002028 Biomass Substances 0.000 description 2
- 108010008629 CA-125 Antigen Proteins 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 244000024675 Eruca sativa Species 0.000 description 2
- 235000014755 Eruca sativa Nutrition 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 208000010412 Glaucoma Diseases 0.000 description 2
- 108010007979 Glycocholic Acid Proteins 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 101000623901 Homo sapiens Mucin-16 Proteins 0.000 description 2
- 101000972286 Homo sapiens Mucin-4 Proteins 0.000 description 2
- 101150114927 MUC1 gene Proteins 0.000 description 2
- 101150001976 MUC16 gene Proteins 0.000 description 2
- 101150059949 MUC4 gene Proteins 0.000 description 2
- 108010008699 Mucin-4 Proteins 0.000 description 2
- 102000007270 Mucin-4 Human genes 0.000 description 2
- 101100346932 Mus musculus Muc1 gene Proteins 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 238000011530 RNeasy Mini Kit Methods 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 240000004336 Trigonella corniculata Species 0.000 description 2
- 241000712689 Velutina Species 0.000 description 2
- 240000005592 Veronica officinalis Species 0.000 description 2
- 241000584803 Xanthosia rotundifolia Species 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 239000012911 assay medium Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000004397 blinking Effects 0.000 description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 2
- 150000001642 boronic acid derivatives Chemical class 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 2
- 229960003964 deoxycholic acid Drugs 0.000 description 2
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 229960001484 edetic acid Drugs 0.000 description 2
- 229910001651 emery Inorganic materials 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000003889 eye drop Substances 0.000 description 2
- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical class O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 description 2
- 229960005150 glycerol Drugs 0.000 description 2
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic acid Chemical compound 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 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 description 2
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000013632 homeostatic process Effects 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 239000000401 methanolic extract Substances 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 239000003607 modifier Substances 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 239000003495 polar organic solvent Substances 0.000 description 2
- 239000004584 polyacrylic acid Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 230000002980 postoperative effect Effects 0.000 description 2
- 159000000001 potassium salts Chemical class 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000000899 pressurised-fluid extraction Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 2
- 229940108325 retinyl palmitate Drugs 0.000 description 2
- 235000019172 retinyl palmitate Nutrition 0.000 description 2
- 239000011769 retinyl palmitate Substances 0.000 description 2
- 229930182490 saponin Natural products 0.000 description 2
- 150000007949 saponins Chemical class 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 108010019783 tear proteins Proteins 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 238000011269 treatment regimen Methods 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 238000003809 water extraction Methods 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 1
- BAERPNBPLZWCES-UHFFFAOYSA-N (2-hydroxy-1-phosphonoethyl)phosphonic acid Chemical compound OCC(P(O)(O)=O)P(O)(O)=O BAERPNBPLZWCES-UHFFFAOYSA-N 0.000 description 1
- MDKGKXOCJGEUJW-VIFPVBQESA-N (2s)-2-[4-(thiophene-2-carbonyl)phenyl]propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-VIFPVBQESA-N 0.000 description 1
- AODPIQQILQLWGS-UHFFFAOYSA-N (3alpa,5beta,11beta,17alphaOH)-form-3,11,17,21-Tetrahydroxypregnan-20-one, Natural products C1C(O)CCC2(C)C3C(O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC21 AODPIQQILQLWGS-UHFFFAOYSA-N 0.000 description 1
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- VNQNXQYZMPJLQX-UHFFFAOYSA-N 1,3,5-tris[(3,5-ditert-butyl-4-hydroxyphenyl)methyl]-1,3,5-triazinane-2,4,6-trione Chemical compound CC(C)(C)C1=C(O)C(C(C)(C)C)=CC(CN2C(N(CC=3C=C(C(O)=C(C=3)C(C)(C)C)C(C)(C)C)C(=O)N(CC=3C=C(C(O)=C(C=3)C(C)(C)C)C(C)(C)C)C2=O)=O)=C1 VNQNXQYZMPJLQX-UHFFFAOYSA-N 0.000 description 1
- MQQKTNDBASEZSD-UHFFFAOYSA-N 1-(octadecyldisulfanyl)octadecane Chemical compound CCCCCCCCCCCCCCCCCCSSCCCCCCCCCCCCCCCCCC MQQKTNDBASEZSD-UHFFFAOYSA-N 0.000 description 1
- SXGZJKUKBWWHRA-UHFFFAOYSA-N 2-(N-morpholiniumyl)ethanesulfonate Chemical compound [O-]S(=O)(=O)CC[NH+]1CCOCC1 SXGZJKUKBWWHRA-UHFFFAOYSA-N 0.000 description 1
- KDISOQKLYCBGFY-UHFFFAOYSA-N 3-[bis(2-hydroxyethyl)amino]propane-1,2-diol Chemical compound OCCN(CCO)CC(O)CO KDISOQKLYCBGFY-UHFFFAOYSA-N 0.000 description 1
- VSAWBBYYMBQKIK-UHFFFAOYSA-N 4-[[3,5-bis[(3,5-ditert-butyl-4-hydroxyphenyl)methyl]-2,4,6-trimethylphenyl]methyl]-2,6-ditert-butylphenol Chemical compound CC1=C(CC=2C=C(C(O)=C(C=2)C(C)(C)C)C(C)(C)C)C(C)=C(CC=2C=C(C(O)=C(C=2)C(C)(C)C)C(C)(C)C)C(C)=C1CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 VSAWBBYYMBQKIK-UHFFFAOYSA-N 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241001601680 Acronychia acuminata Species 0.000 description 1
- 244000135330 Acronychia laevis Species 0.000 description 1
- 241001601661 Acronychia littoralis Species 0.000 description 1
- 241000435297 Acronychia oblongifolia Species 0.000 description 1
- 241000227584 Acronychia octandra Species 0.000 description 1
- 241001601671 Acronychia parviflora Species 0.000 description 1
- 241000435377 Acronychia pubescens Species 0.000 description 1
- 241000186361 Actinobacteria <class> Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 238000009020 BCA Protein Assay Kit Methods 0.000 description 1
- 229940122361 Bisphosphonate Drugs 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010006784 Burning sensation Diseases 0.000 description 1
- 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 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 240000009005 Calendula arvensis Species 0.000 description 1
- 235000007864 Calendula arvensis Nutrition 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical class NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- 241000675019 Cinnamomum kotoense Species 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- 241001362614 Crassa Species 0.000 description 1
- 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 description 1
- 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 description 1
- GHKOFFNLGXMVNJ-UHFFFAOYSA-N Didodecyl thiobispropanoate Chemical compound CCCCCCCCCCCCOC(=O)CCSCCC(=O)OCCCCCCCCCCCC GHKOFFNLGXMVNJ-UHFFFAOYSA-N 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- 235000001942 Elaeis Nutrition 0.000 description 1
- 241000512897 Elaeis Species 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 241000195620 Euglena Species 0.000 description 1
- 208000001860 Eye Infections Diseases 0.000 description 1
- 208000020564 Eye injury Diseases 0.000 description 1
- 206010015958 Eye pain Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- IECPWNUMDGFDKC-UHFFFAOYSA-N Fusicsaeure Natural products C12C(O)CC3C(=C(CCC=C(C)C)C(O)=O)C(OC(C)=O)CC3(C)C1(C)CCC1C2(C)CCC(O)C1C IECPWNUMDGFDKC-UHFFFAOYSA-N 0.000 description 1
- 108010035713 Glycodeoxycholic Acid Proteins 0.000 description 1
- WVULKSPCQVQLCU-UHFFFAOYSA-N Glycodeoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCC(O)=O)C)C1(C)C(O)C2 WVULKSPCQVQLCU-UHFFFAOYSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 101001133081 Homo sapiens Mucin-2 Proteins 0.000 description 1
- 101000972276 Homo sapiens Mucin-5B Proteins 0.000 description 1
- 101000972273 Homo sapiens Mucin-7 Proteins 0.000 description 1
- 101100306003 Homo sapiens POLR2A gene Proteins 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 206010020852 Hypertonia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 241000604820 Licaria triandra Species 0.000 description 1
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 108010034536 Mucin 5AC Proteins 0.000 description 1
- 102000009616 Mucin 5AC Human genes 0.000 description 1
- 102100034263 Mucin-2 Human genes 0.000 description 1
- 102100022494 Mucin-5B Human genes 0.000 description 1
- 102100022492 Mucin-7 Human genes 0.000 description 1
- 102000016943 Muramidase Human genes 0.000 description 1
- 108010014251 Muramidase Proteins 0.000 description 1
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 1
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 description 1
- JOCBASBOOFNAJA-UHFFFAOYSA-N N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid Chemical compound OCC(CO)(CO)NCCS(O)(=O)=O JOCBASBOOFNAJA-UHFFFAOYSA-N 0.000 description 1
- QNJOTBVHBNTEIT-UHFFFAOYSA-N N1=C(C=CC=C1)C1=C(C=C(C=C1CN)CN)CN Chemical compound N1=C(C=CC=C1)C1=C(C=C(C=C1CN)CN)CN QNJOTBVHBNTEIT-UHFFFAOYSA-N 0.000 description 1
- RFDAIACWWDREDC-UHFFFAOYSA-N Na salt-Glycocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCC(O)=O)C)C1(C)C(O)C2 RFDAIACWWDREDC-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 241000795633 Olea <sea slug> Species 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000000407 Pancreatic Cyst Diseases 0.000 description 1
- JKIJEFPNVSHHEI-UHFFFAOYSA-N Phenol, 2,4-bis(1,1-dimethylethyl)-, phosphite (3:1) Chemical compound CC(C)(C)C1=CC(C(C)(C)C)=CC=C1OP(OC=1C(=CC(=CC=1)C(C)(C)C)C(C)(C)C)OC1=CC=C(C(C)(C)C)C=C1C(C)(C)C JKIJEFPNVSHHEI-UHFFFAOYSA-N 0.000 description 1
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 244000207867 Pistia stratiotes Species 0.000 description 1
- 235000006440 Pistia stratiotes Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 241000168036 Populus alba Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 238000000944 Soxhlet extraction Methods 0.000 description 1
- MKRNVBXERAPZOP-UHFFFAOYSA-N Starch acetate Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)OC(C)=O)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 MKRNVBXERAPZOP-UHFFFAOYSA-N 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 206010042033 Stevens-Johnson syndrome Diseases 0.000 description 1
- 231100000168 Stevens-Johnson syndrome Toxicity 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- WBWWGRHZICKQGZ-UHFFFAOYSA-N Taurocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)C(O)C2 WBWWGRHZICKQGZ-UHFFFAOYSA-N 0.000 description 1
- 235000007253 Trigonella corniculata Nutrition 0.000 description 1
- 241001312528 Trigonella cretica Species 0.000 description 1
- 241001239195 Trigonella maritima Species 0.000 description 1
- 241000252559 Trigonella spicata Species 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 206010064996 Ulcerative keratitis Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 206010047513 Vision blurred Diseases 0.000 description 1
- BGYHLZZASRKEJE-UHFFFAOYSA-N [3-[3-(3,5-ditert-butyl-4-hydroxyphenyl)propanoyloxy]-2,2-bis[3-(3,5-ditert-butyl-4-hydroxyphenyl)propanoyloxymethyl]propyl] 3-(3,5-ditert-butyl-4-hydroxyphenyl)propanoate Chemical compound CC(C)(C)C1=C(O)C(C(C)(C)C)=CC(CCC(=O)OCC(COC(=O)CCC=2C=C(C(O)=C(C=2)C(C)(C)C)C(C)(C)C)(COC(=O)CCC=2C=C(C(O)=C(C=2)C(C)(C)C)C(C)(C)C)COC(=O)CCC=2C=C(C(O)=C(C=2)C(C)(C)C)C(C)(C)C)=C1 BGYHLZZASRKEJE-UHFFFAOYSA-N 0.000 description 1
- FZQSLXQPHPOTHG-UHFFFAOYSA-N [K+].[K+].O1B([O-])OB2OB([O-])OB1O2 Chemical compound [K+].[K+].O1B([O-])OB2OB([O-])OB1O2 FZQSLXQPHPOTHG-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 210000002159 anterior chamber Anatomy 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940006133 antiglaucoma drug and miotics carbonic anhydrase inhibitors Drugs 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000003464 asthenopia Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 229960004324 betaxolol Drugs 0.000 description 1
- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 229940093761 bile salts Drugs 0.000 description 1
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 description 1
- 150000004663 bisphosphonates Chemical class 0.000 description 1
- 239000003618 borate buffered saline Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229960002713 calcium chloride Drugs 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound 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)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 description 1
- 229960001091 chenodeoxycholic acid Drugs 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound 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)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 210000003683 corneal stroma Anatomy 0.000 description 1
- 230000004453 corneal transparency Effects 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 210000002726 cyst fluid Anatomy 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 229940099217 desferal Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 235000019820 disodium diphosphate Nutrition 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- GYQBBRRVRKFJRG-UHFFFAOYSA-L disodium pyrophosphate Chemical compound [Na+].[Na+].OP([O-])(=O)OP(O)([O-])=O GYQBBRRVRKFJRG-UHFFFAOYSA-L 0.000 description 1
- 229940038485 disodium pyrophosphate Drugs 0.000 description 1
- CDMADVZSLOHIFP-UHFFFAOYSA-N disodium;3,7-dioxido-2,4,6,8,9-pentaoxa-1,3,5,7-tetraborabicyclo[3.3.1]nonane;decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].O1B([O-])OB2OB([O-])OB1O2 CDMADVZSLOHIFP-UHFFFAOYSA-N 0.000 description 1
- PWWSSIYVTQUJQQ-UHFFFAOYSA-N distearyl thiodipropionate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)CCSCCC(=O)OCCCCCCCCCCCCCCCCCC PWWSSIYVTQUJQQ-UHFFFAOYSA-N 0.000 description 1
- XJWSAJYUBXQQDR-UHFFFAOYSA-M dodecyltrimethylammonium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)C XJWSAJYUBXQQDR-UHFFFAOYSA-M 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 210000000871 endothelium corneal Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000005081 epithelial layer Anatomy 0.000 description 1
- 239000000469 ethanolic extract Substances 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- FMMOOAYVCKXGMF-MURFETPASA-N ethyl linoleate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OCC FMMOOAYVCKXGMF-MURFETPASA-N 0.000 description 1
- 229940031016 ethyl linoleate Drugs 0.000 description 1
- JYYFMIOPGOFNPK-AGRJPVHOSA-N ethyl linolenate Chemical compound CCOC(=O)CCCCCCC\C=C/C\C=C/C\C=C/CC JYYFMIOPGOFNPK-AGRJPVHOSA-N 0.000 description 1
- JYYFMIOPGOFNPK-UHFFFAOYSA-N ethyl linolenate Natural products CCOC(=O)CCCCCCCC=CCC=CCC=CCC JYYFMIOPGOFNPK-UHFFFAOYSA-N 0.000 description 1
- 229940090028 ethyl linolenate Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 210000000744 eyelid Anatomy 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 235000020765 fenugreek extract Nutrition 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 229960004675 fusidic acid Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000003633 gene expression assay Methods 0.000 description 1
- 229940099347 glycocholic acid Drugs 0.000 description 1
- WVULKSPCQVQLCU-BUXLTGKBSA-N glycodeoxycholic acid Chemical compound C([C@H]1CC2)[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 WVULKSPCQVQLCU-BUXLTGKBSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- 239000001685 glycyrrhizic acid Substances 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 235000014304 histidine Nutrition 0.000 description 1
- 150000002411 histidines Chemical class 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 102000056037 human MUC5AC Human genes 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910001867 inorganic solvent Inorganic materials 0.000 description 1
- 239000003049 inorganic solvent Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 210000000554 iris Anatomy 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- 201000010666 keratoconjunctivitis Diseases 0.000 description 1
- 229960004752 ketorolac Drugs 0.000 description 1
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 description 1
- 210000004561 lacrimal apparatus Anatomy 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- FMMOOAYVCKXGMF-UHFFFAOYSA-N linoleic acid ethyl ester Natural products CCCCCC=CCC=CCCCCCCCC(=O)OCC FMMOOAYVCKXGMF-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 239000004325 lysozyme Substances 0.000 description 1
- 235000010335 lysozyme Nutrition 0.000 description 1
- 229960000274 lysozyme Drugs 0.000 description 1
- 238000002803 maceration Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005360 mashing Methods 0.000 description 1
- 238000000409 membrane extraction Methods 0.000 description 1
- IBIKHMZPHNKTHM-RDTXWAMCSA-N merck compound 25 Chemical compound C1C[C@@H](C(O)=O)[C@H](O)CN1C(C1=C(F)C=CC=C11)=NN1C(=O)C1=C(Cl)C=CC=C1C1CC1 IBIKHMZPHNKTHM-RDTXWAMCSA-N 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000000874 microwave-assisted extraction Methods 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 210000004944 mitochondria-rich cell Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 1
- 229960003702 moxifloxacin Drugs 0.000 description 1
- 208000022669 mucinous neoplasm Diseases 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 230000037125 natural defense Effects 0.000 description 1
- QEFAQIPZVLVERP-UHFFFAOYSA-N nepafenac Chemical compound NC(=O)CC1=CC=CC(C(=O)C=2C=CC=CC=2)=C1N QEFAQIPZVLVERP-UHFFFAOYSA-N 0.000 description 1
- 229960001002 nepafenac Drugs 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- SSDSCDGVMJFTEQ-UHFFFAOYSA-N octadecyl 3-(3,5-ditert-butyl-4-hydroxyphenyl)propanoate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)CCC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 SSDSCDGVMJFTEQ-UHFFFAOYSA-N 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- JBIMVDZLSHOPLA-LSCVHKIXSA-N olopatadine Chemical compound C1OC2=CC=C(CC(O)=O)C=C2C(=C/CCN(C)C)\C2=CC=CC=C21 JBIMVDZLSHOPLA-LSCVHKIXSA-N 0.000 description 1
- 229960004114 olopatadine Drugs 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000008012 organic excipient Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 210000000277 pancreatic duct Anatomy 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960003330 pentetic acid Drugs 0.000 description 1
- 238000005325 percolation Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- ALQUDFYROSGSNX-UHFFFAOYSA-N phospholane-2,3-dione Chemical compound O=C1CCPC1=O ALQUDFYROSGSNX-UHFFFAOYSA-N 0.000 description 1
- 229960001416 pilocarpine Drugs 0.000 description 1
- 229920002432 poly(vinyl methyl ether) polymer Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000056 polyoxyethylene ether Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 108010001062 polysaccharide-K Proteins 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- JVUYWILPYBCNNG-UHFFFAOYSA-N potassium;oxido(oxo)borane Chemical compound [K+].[O-]B=O JVUYWILPYBCNNG-UHFFFAOYSA-N 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate 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-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 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 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 229940045946 sodium taurodeoxycholate Drugs 0.000 description 1
- YXHRQQJFKOHLAP-FVCKGWAHSA-M sodium;2-[[(4r)-4-[(3r,5r,8r,9s,10s,12s,13r,14s,17r)-3,12-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]ethanesulfonate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 YXHRQQJFKOHLAP-FVCKGWAHSA-M 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 239000002294 steroidal antiinflammatory agent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000000194 supercritical-fluid extraction Methods 0.000 description 1
- 229960004492 suprofen Drugs 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound 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)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 description 1
- AWDRATDZQPNJFN-VAYUFCLWSA-N taurodeoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 AWDRATDZQPNJFN-VAYUFCLWSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- AODPIQQILQLWGS-GXBDJPPSSA-N tetrahydrocortisol Chemical compound C1[C@H](O)CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CC[C@@H]21 AODPIQQILQLWGS-GXBDJPPSSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- WUUHFRRPHJEEKV-UHFFFAOYSA-N tripotassium borate Chemical compound [K+].[K+].[K+].[O-]B([O-])[O-] WUUHFRRPHJEEKV-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound 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)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 1
- 229960001661 ursodiol Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/75—Rutaceae (Rue family)
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/54—Lauraceae (Laurel family), e.g. cinnamon or sassafras
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/04—Artificial tears; Irrigation solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Abstract
The present invention relates to compositions comprising one or more extracts and/or compounds having retinol-like activity and properties and methods of using the same to treat the eye.
Description
The application is a divisional application of an invention patent with an application date of 2019, 7, 24 and a application number of 201980050097.8, and is named as 'composition and method for treating eyes'.
Technical Field
The present invention relates to compositions comprising one or more extracts and/or compounds having retinol-like activity and properties and methods of using the same to treat the eye.
Background
"Dry eye is a multifactorial disease of the ocular surface characterized by a loss of tear film homeostasis and is associated with ocular symptoms where tear film instability and high osmotic pressure, ocular surface inflammation and damage, and sensory nerve abnormalities play a causative role. "Craig, j.p. et al," TFOS dess II definition and classification report, "Ocul surf.2017; volume 15, pages 276-283. Dry eye can be caused by abnormal or insufficient tear formation and insufficient mucin secretion (i.e., dry keratoconjunctivitis). Dry eye can be the result of a variety of underlying diseases, such as autoimmune diseases that damage the lacrimal glands (i.e., produce tears), such as rheumatoid arthritis, sjogren's syndrome, systemic lupus erythematosus, and systemic sclerosis and sarcoidosis. In eye surgery (such asSurgery) may also cause dry eye. Dry eye is estimated to affect more than thirty million people in the united states.
Regardless of the underlying pathology, dry eye generally involves rapid breakdown of the pre-ocular tear film, resulting in dehydration of the exposed outer surface. Normal tear formation is required to keep the cornea and conjunctiva moist, and this in turn helps to prevent ulceration of both, as well as to maintain corneal transparency. In addition, tears facilitate movement of the eyelids on the surface of the eye (e.g., blinking) and foreign matter removal from the eye. Tears typically also contain lysozyme, which can be used to prevent ocular infections. Dry eye can be associated with mild discomfort to severe pain in the eye. When dry eye occurs for a long period of time, it can cause blurred vision, a gritty and/or burning sensation, and itching. The condition may further lead to corneal ulceration and/or scarring if allowed to persist without treatment.
Dry eye includes eye pain or fatigue, increased frequency of blinking, and eye congestion. Furthermore, bacteria can enter through the scratch and cause infection, and if the scratch is deep enough, it can even affect a person's vision. In addition to eye fatigue, causes of dry eye include sjogren's syndrome, stevens-johnson syndrome, burns and eye injuries, as well as side effects of antihypertensive drugs, tranquilizers, eye drops for the treatment of glaucoma, and other such drugs.
The tear film is the body's natural defense against dry eye. The tear film contains ocular mucin and is essential for maintaining homeostasis of the wet ocular surface. Mucins are produced by, among other things, corneal epithelial cells in the eye. Mucins are glycoproteins expressed by epithelial tissue of mucosal surfaces. They protect tissues by acting as antioxidants and providing lubrication. Mucin genes associated with the tear film include MUC1, MUC2, MUC4, MUC5AC, MUC5B, MUC7 and MUC16.
Mucins are also useful as antimicrobial agents for general wound healing and are essential for overall eye health maintenance.
Thus, there is a need for ophthalmic pharmaceutical compositions that will facilitate and/or improve the production and/or release of mucins from and/or in the cornea.
The present inventors have discovered compounds and/or extracts having retinol-like properties and/or beneficial effects that can induce, promote and/or improve the production/release/delivery/excretion of mucin from and/or in the cornea.
Accordingly, aspects of the present invention relate to compositions comprising a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or beneficial effects to induce, promote and/or improve the production/release/delivery/excretion of mucin from and/or in the cornea.
Another aspect of the invention relates to a composition comprising a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or beneficial effects, which induces, promotes and/or improves the production/release/delivery/excretion of mucin from and/or in the cornea, which can be administered to a patient having a MUC5AC concentration in tear fluid of less than 6 (or about 6) ng/mg protein, optionally 8 (or about 8) ng/mg protein, such that the concentration of MUC5AC in tear fluid is raised to (or brought to) a concentration equal to or greater than 8 (or about 8) ng/mg protein to 15 (or about 15) ng/mg protein, optionally 9 (or about 9) ng/mg protein to 12 (or about 12) ng/mg protein.
In certain embodiments, the aforementioned concentration of MU5AC in tear fluid (i.e., equal to or greater than 8 (or about 8) ng/mg protein to 15 (or about 15) ng/mg protein, optionally 9 (or about 9) ng/mg protein to 12 (or about 12) ng/mg protein) is produced by a compound and/or extract having retinol-like properties and/or beneficial effects to induce, promote and/or improve mucin production/release/delivery/excretion from and/or in the cornea for a period of time of up to at least about 2 hours, optionally about 4 hours, optionally about 6 hours, optionally about 8 hours, optionally about 10 hours, optionally about 12 hours, or optionally about 12 to about 24 hours.
The concentration of MUC5AC in tears detailed above was determined using the Uchino method (described below in the definition).
Another aspect of the present invention relates to compositions comprising a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or beneficial effects which induce, promote and/or improve the production/release/delivery/excretion of mucin from and/or in the cornea for use in the treatment of dry eye.
Another aspect of the invention relates to methods of preventing and/or treating (e.g., reducing) ocular symptoms associated with dry eye and/or caused by reduced or low level production/release/delivery/excretion of mucin from and/or in the cornea by: administering a composition comprising a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or beneficial effects which induce, promote and/or improve the production/release/delivery/excretion of mucin from and/or in the cornea.
Another aspect of the invention relates to methods of promoting healing or increasing the rate of healing of wounds (e.g., ocular wounds not associated with dry eye, post-operative surgery, or non-specific wounds) in and/or on the eye of a patient by: administering a composition comprising a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or beneficial effects which induce, promote and/or improve the production/release/delivery/excretion of mucin from and/or in the cornea (i.e., increase the production/release/delivery/excretion of mucin from and/or in the cornea, in certain embodiments, above the concentration level of mucin produced by such patients without the administration (or absence) of a composition comprising a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or beneficial effects which induces, promotes and/or improves the production/release/delivery/excretion of mucin from and/or in the cornea).
Another aspect of the invention relates to a method of improving antimicrobial properties in a tear fluid of a patient (or tear film of the eye) by: administering a composition comprising a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or beneficial effects which induce, promote and/or improve the production/release/delivery/excretion of mucin from and/or in the cornea (i.e., increase the production/release/delivery/excretion of mucin from and/or in the cornea, in certain embodiments, above the concentration level of mucin produced by such patients without the administration (or absence) of a composition comprising a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or beneficial effects which induces, promotes and/or improves the production/release/delivery/excretion of mucin from and/or in the cornea).
Disclosure of Invention
The present invention relates to a method for producing/releasing/delivering/excreting mucin from and/or in the cornea (optionally, in a patient requiring such production/release/delivery/excretion of mucin), the method comprising the step of administering a composition comprising:
i) A safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects for the treatment of dry eye, said compound and/or extract selected from one or more of the following: a plant extract or source of extract from a plant of the genus acronychia, illicium, marigold, and/or trigonella; a bacterial extract or extract source of the genus actinomyces; and a compound of formula (I):
wherein-
The dotted line represents a single or double bond; optionally one of the dotted lines is a double bond;
R 1 represents H, a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms;
R 2 represents a linear, cyclic or branched, saturated or unsaturated carbonising chain containing from 1 to 20 carbon atoms; optionally methyl (-CH) 3 ) Or methylene (= CH) 2 ) A moiety; a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms, optionally from 1 to 10 carbon atoms, optionally 6 carbon atoms; optionally an aromatic moiety, optionally a phenyl moiety; optionally 2-methylpropan-1, 3-diene; and
ii) optionally, an ophthalmically acceptable carrier.
The present invention relates to a method for maintaining a concentration of MU5AC in tear fluid in the range of equal to or greater than 8 ng/mg protein to 15 ng/mg protein, comprising the step of administering a composition comprising:
i) A safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects for the treatment of dry eye, said compound and/or extract being selected from one or more of the following: a plant extract or source of extract from a plant of the genus acronychia, illicium, marigold, and/or trigonella; a bacterial extract or extract source of the genus actinomycete; and a compound of formula (I):
wherein-
The dotted line represents a single or double bond; optionally one of the dotted lines is a double bond;
R 1 represents H, a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms;
R 2 represents a linear, cyclic or branched, saturated or unsaturated carbonising chain containing from 1 to 20 carbon atoms; optionally methyl (-CH) 3 ) Or methylene (= CH) 2 ) A moiety; a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms, optionally from 1 to 10 carbon atoms, optionally 6 carbon atoms; optionally an aromatic moiety, optionally a phenyl moiety; optionally 2-methylpropan-1, 3-diene; and
ii) optionally, an ophthalmically acceptable carrier.
The present invention relates to a method for treating a patient suffering from reduced or low levels of production/release/delivery/excretion of mucin from and/or in the cornea, the method comprising the step of topically administering to the eye of the patient a composition comprising:
i) A safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects for the treatment of dry eye, said compound and/or extract selected from one or more of the following: a plant extract or source of extract from a plant of the genus acronychia, illicium, marigold, and/or trigonella; a bacterial extract or extract source of the genus actinomycete; and a compound of formula (I):
wherein-
The dotted line represents a single or double bond; optionally one of the dotted lines is a double bond;
R 1 represents HA linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms;
R 2 represents a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms; optionally methyl (-CH) 3 ) Or methylene (= CH) 2 ) A moiety; a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms, optionally from 1 to 10 carbon atoms, optionally 6 carbon atoms; optionally an aromatic moiety, optionally a phenyl moiety; optionally 2-methylpropan-1, 3-diene; and
ii) optionally, an ophthalmically acceptable carrier.
The present invention relates to methods for preventing or treating symptoms associated with dry eye, comprising the step of topically administering to a patient (optionally, in a patient in need of such prevention or reduction of dry eye symptoms) a composition comprising:
i) A safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects for the treatment of dry eye, said compound and/or extract selected from one or more of the following: a plant extract or source of extract from a plant of the genus acronychia, illicium, marigold, and/or trigonella; a bacterial extract or extract source of the genus actinomycete; and a compound of formula (I):
wherein-
The dotted line represents a single or double bond; optionally one of the dotted lines is a double bond;
R 1 represents H, a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms;
R 2 represents a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms; optionally methyl (-CH) 3 ) Or methylene (= CH) 2 ) A moiety; containing 1 to 20 carbon atoms, optionally 1 to 10 carbon atoms, optionallyA linear, cyclic or branched, saturated or unsaturated carbonising chain of 6 carbon atoms; optionally an aromatic moiety, optionally a phenyl moiety; optionally 2-methylpropan-1, 3-diene;
ii) one or more demulcents or soothing agents; and
iii) Optionally, an ophthalmically acceptable carrier.
The present invention relates to a method for promoting wound healing or increasing the rate of healing in and/or on the eye of a patient (optionally, in a patient in need of such eye wound healing), the method comprising the step of administering a composition (i.e., increasing production/release/delivery/excretion of mucin from and/or in the cornea, in certain embodiments, above the concentration level of mucin produced by such a patient in the absence of administration (or absence) of a composition comprising a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or beneficial effects) comprising:
i) A safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects for the treatment of dry eye, said compound and/or extract selected from one or more of the following: a plant extract or source of extract from a plant of the genus acronychia, illicium, marigold, and/or trigonella; a bacterial extract or extract source of the genus actinomyces; and a compound of formula (I):
wherein-
The dotted line represents a single or double bond; preferably one of the dotted lines is a double bond;
R 1 represents H, a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms;
R 2 represents a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms; preferably methyl (-CH) 3 ) Or methylene (= CH) 2 ) A moiety;
a represents a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably 6 carbon atoms; preferably an aromatic moiety, preferably a phenyl moiety; preferably 2-methylpropan-1, 3-diene,
ii) optionally, an ophthalmically acceptable carrier.
The present invention relates to a method for improving antimicrobial properties in the tear fluid of a patient (or tear film of the eye), optionally in a patient in need of such antimicrobial properties, the method comprising the step of administering a composition (i.e., increasing production/release/delivery/excretion of mucin from and/or in the cornea, in certain embodiments, above the concentration level of mucin produced by such a patient in the absence of administration (or lack thereof) of a composition comprising a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or beneficial effects) comprising:
i) A safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects for the treatment of dry eye, said compound and/or extract being selected from one or more of the following: a plant extract or extract source from a plant of the genus acronychia, pistia, marigold, and/or trigonella; a bacterial extract or extract source of the genus actinomycete; and a compound of formula (I):
wherein-
The dotted line represents a single or double bond; preferably one of the dotted lines is a double bond;
R 1 represents H, a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms;
R 2 represents a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms; preferably methyl (-CH) 3 ) Or methylene (= CH) 2 ) A moiety;
a represents a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably 6 carbon atoms; preferably an aromatic moiety, preferably a phenyl moiety; preferably 2-methylpropan-1, 3-diene,
ii) optionally, an ophthalmically acceptable carrier.
Drawings
Figure 1 depicts a bar graph showing MUC1, MUC4 and MUC16 gene expression induced in corneal epithelial cells by the lemon aspen (lemon aspen) extract.
Figure 2 depicts a bar graph showing the Mucin-1 secretion induced by lemon extract in aspen in corneal epithelial cells.
Detailed Description
It is believed that one skilled in the art can, based upon the description herein, utilize the present invention to its fullest extent. The following specific embodiments are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
The compositions of the present invention may comprise, consist of, or consist essentially of the elements, steps, and limitations described herein, as well as any of the additional or optional ingredients, components, or limitations described herein.
As used herein, the term "comprising (and grammatical variations thereof)" is used in an inclusive sense of "having" or "including" and not in an exclusive sense of "including only". As used herein, the terms "a" and "an" and "the" should be understood to encompass the plural as well as the singular.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety to the extent not inconsistent with this specification. As used herein, all percentages are by weight of the total composition, unless otherwise specified.
As used herein, the term "cornea" or "corneal" is, includes and/or relates to the transparent anterior portion of an eye covering the iris, pupil and anterior chamber, the layers of which transparent anterior portion include the corneal epithelial layer (including corneal epithelial cells), bowman's layer (also known as the anterior limiting membrane), corneal stroma (also the proper stroma), the posterior elastic layer (also the posterior limiting membrane) and the corneal endothelium (a simple squamous or low cubic monolayer of mitochondria-rich cells, about 5 μm thick).
As used herein, the phrase "reduced or low level of production/release/delivery/excretion of mucin from and/or in the cornea" refers to a MUC5AC concentration that is less than the MUC5AC concentration in normal human (i.e., non-diseased) tears, or in certain embodiments less than 6 nanograms per milligram of protein, optionally less than 8 nanograms per milligram of protein, as determined using the methods described in Uchino Y, uchino M, yokoi N, et al. Change in office tear mucin 5AC using visual display terminal: the Osaka study, jama ophthalmol, n2014;132 (8):985-992. The method (Uchino method) is reproduced as follows:
concentration of MUC5AC in lacrimal fluid
By enzyme-linked immunoassay (E90756 Hu; USCN Life Science). (see Maker AV, katabi N, gonen M et al, pancreatic cyst fluid and serum mucin levels predict abnormal proliferation of papillary mucinous tumors in pancreatic ducts, ann Surg Oncol.2011;18 (1): 199-206). All samples were analyzed according to the manufacturer's instructions. The absorbance was measured at 450nm and the standard solution in the kit was recombinant human MUC5AC. A protein assay kit (BCA protein assay kit; pierce) was used to determine the protein concentration in the tear sample. MUC5AC concentration was normalized to tear protein content and expressed as MUC5AC protein (ng)/total tear protein (mg).
As used herein, a composition that is "substantially free" of an ingredient refers to a composition having about 2% by weight or less of the ingredient (based on the total weight of the composition). Preferably, a composition that is substantially free of an ingredient has about 1% by weight or less of the ingredient (based on the total weight of the composition), more preferably about 0.5% by weight or less, more preferably about 0.1% by weight or less, more preferably about 0.05% by weight or less, more preferably about 0.01% by weight or less of the ingredient. In certain more preferred embodiments, a composition that is substantially free of an ingredient is free of that ingredient, that is, the composition is completely free of that ingredient.
As used herein, "ophthalmically acceptable" means that the ingredients described by the term are suitable for use in contact with tissue (e.g., soft eye tissue or periorbital skin tissue) without causing undue toxicity, incompatibility, instability, irritation, allergic response, and the like. As will be appreciated by those skilled in the art, ophthalmically acceptable salts are acidic/anionic or basic/cationic salts.
As used herein, the term "safe and effective amount" means an amount of the disclosed extract, compound, or composition that is up to sufficient to induce, promote, and/or improve production/release/delivery/excretion of mucin from and/or in the cornea, but is as little as sufficient to avoid serious side effects. The safe and effective amount of the compound, extract or composition will vary with such factors as the age, health and environmental exposure of the end user, the duration and nature of the treatment, the particular extract, ingredient or composition employed, and the particular pharmaceutically acceptable carrier employed.
The term "retinol-like properties and/or benefits" refers to the properties and/or benefits induced by retinol-like.
In certain embodiments, the invention as disclosed herein may be practiced in the absence of any compound or element (or group of compounds or elements) not specifically disclosed herein.
Generally, IUPAC nomenclature is used herein and is defined in accordance with the following terms.
The term "C1-8 alkyl" whether used alone or as part of a substituent group, refers to a saturated aliphatic branched or straight chain monovalent hydrocarbon radical having from 1 to 8 carbon atoms. For example, "C1-8 alkyl" specifically includes the groups methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, t-butyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 1-octyl, 2-octyl, 3-octyl, and the like. The term may also refer to the corresponding alkanediyl. The alkyl and alkanediyl groups may be attached to the core molecule via terminal carbon atoms or via carbon atoms in the chain. Similarly, any number of substituent variables may be attached to an alkyl or alkanediyl group as permitted by available valences.
The term "C 1-4 Alkyl "whether used alone or as part of a substituent group, refers to a saturated aliphatic branched or straight chain monovalent hydrocarbon or alkanediyl linking group having the specified number of carbon atoms wherein the group is derived by removal of one hydrogen atom from a carbon atom and the alkanediyl linking group is derived by removal of one hydrogen atom from each of two carbon atoms in the chain. The term "C 1-4 Alkyl "refers to a straight or branched chain arrangement of groups having 1 to 4 carbon atoms. For example, "C 1-4 Alkyl "specifically includes the groups methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, t-butyl, 1-butyl, and the like. Alkyl and alkanediyl groups may be attached to the core molecule via a terminal carbon atom or via a carbon atom in the chain. Similarly, any number of substituent variables may be attached to an alkyl or alkanediyl group as the available valences permit.
The term "C 2-4 Alkenyl "means alkenyl having 2 to 4 carbon atoms. For example, specifically included are the groups vinyl, propenyl, allyl (2-propenyl), butenyl, and the like. As described above, alkenyl groups may be similarly attached to the core molecule and further substituted as indicated.
The term "halogen" by itself or in combination with other terms refers to a halogen atom, such as fluorine, chlorine, bromine, or iodine.
The term "substituted" means that one or more hydrogen atoms on the core molecule have been replaced with a substituent that is available in a valence-permitting amount. The substitution is not limited to the core molecule, but may be carried out on a substituent such that the group becomes a linking group.
The term "independently selected" refers to two or more substituents that may be selected from a variable group of substituents, wherein the selected substituents may be the same or different.
The term "dependently selected" means that one or more substituent variables designated in the indicated combination for substitution in the core molecule (e.g., variables relating to the group of substituents appearing in a tabular listing of compounds).
Acceptable salts from inorganic bases include, for example, sodium or potassium salts and the like. Acceptable salts from organic bases include, for example, salts with primary, secondary, tertiary amines, and the like.
Compounds/extracts exhibiting retinol-like biological activity and/or properties
The present invention includes compounds and/or extracts having retinol-like properties and/or beneficial effects for the treatment of dry eye, comprising a compound and/or extract selected from or consisting of: a plant extract or extract source from the genus acronychia, pistia, marigold, and/or trigonella; a bacterial extract or extract source of the genus actinomyces; and a compound of formula (I):
wherein-
The dotted line represents a single or double bond; optionally one of the dotted lines is a double bond;
R 1 represents H, a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms;
R 2 represents a linear, cyclic or branched, saturated or unsaturated carbonising chain containing from 1 to 20 carbon atoms; optionally methyl (-CH) 3 ) Or methylene (= CH) 2 ) A moiety; a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms, optionally from 1 to 10 carbon atoms, optionally 6 carbon atoms;optionally an aromatic moiety, optionally a phenyl moiety; optionally 2-methylpropan-1, 3-diene.
Plant extracts of acronychia tangutica, cinnamomum kohlii, calendula and/or trigonella foenum graecum
In certain embodiments, the compound/extract exhibiting retinol-like properties and/or beneficial effects is or comprises an extract or extract source of the plants acronychia, cinnamomum kohlii, calendula and/or trigonella foenum graecum. The acronychia, pistia, marigold and/or fenugreek extract or source of such extract is obtained from a plant of the acronychia, pistia, marigold and/or fenugreek genera.
The Acronychia plants from which the extracts useful in the present invention are obtained include species such as Acronychia berrans, acronychia olea (also referred to herein as aspen lemon), acronychia acronoides, acronychia acuminata, acronychia baueritenii, acronychia choorehibium, acronychia short core Acronychia (Acronychia crassilacetala), acronychia annus, acronychia improforate, acronychia laevis, acronychia laurifolia, acronychia toruloris, acronychia oblongifolia, acronychia octandra, acronychia paravira, acronychia aceflouroidea, acronia acerolaria, acronychia barbata, or a combination of two or more species thereof (downy citrus). In one embodiment, the extract used in the present invention is obtained from Acronychia acinula.
The plants of the genus pistia from which extracts useful in the present invention are obtained include, for example, lica vernicosa, lica brittoniana, lica canella, lica cubensis, lica velutina, and lica triandra, and combinations of two or more thereof. About 40 species of illicium are reported to be unique to central and south america. In one embodiment, the extract used in the present invention is obtained from lica vernicosa.
About 15 to 20 species of marigold are reported to be present in southwestern asia, western asia, macaroni and mediterranean. Plants of the genus Calendula from which extracts useful in the present invention are obtained include, for example, calendula (field marigold); calendula maderensis (Madeiran marigold); and calendiula officinalis (pot marigold) and combinations of two or more thereof. In one embodiment, the extract used in the present invention is obtained from calendiula officinalis.
The plant of the genus Trigonella from which the extract useful in the present invention is obtained includes 36 known species of plants of the genus Trigonella, including, for example, trigonella foenum-graecum, trigonella balansae, trigonella corniculata, trigonella maritima, trigonella spicata, blue Trigonella (Trigonella calerulea), trigonella occulta, trigonella polytera, trigonella calliera, trigonella Cretica, and combinations of two or more thereof. Trigonella foenum-graecum or fenugreek (herb fenugreek) is known to be the best member of the genus fenugreek. In one embodiment, the extract used in the present invention is obtained from Trigonella foenum-graecum.
In certain embodiments, the extract used in the present invention is a mixture of extracts from plants of the acronychia, illicium, calendula and/or trigonella genus.
The extract of Licaria vernicosa useful in the present invention is available from Baruch S.Blumerg Institute, doyletown, pa. (formerly known as IVHR). In certain embodiments, one extract is from the woody part of the plant (E2) and a second extract is from the root of the plant (E3). In the nomenclature of IHVR collection, the two extracts were labeled IHVR _40256_g10=x-005348-001E002 and IHVR _40256 _10e =x-005346-001M002, respectively. The xylem and roots of Licaria vernicosa (Mez) Kostam can be collected from Guiana. 504.3g of dried ground woody plant material can be extracted with sufficient methanol, which can be dried under vacuum to provide 10.54g of crude methanol extract (E2) labeled X-005348-001E 002. 403.8g of dried ground root material can be extracted with sufficient methanol, which can be dried under vacuum to provide 18.11g of crude methanol extract labeled X-005346-001M002 (E3).
In certain embodiments, the acronychia and/or pistia extracts useful in the invention comprise a compound having formula II:
wherein:
R 1 selected from the group consisting of: c 1 -C 20 Alkyl radical, C 2 -C 20 Alkenyl radical, C 2 -C 20 Alkynyl and C 3 -C 8 Cycloalkyl or aryl;
R 2 selected from the group consisting of: hydrogen, hydroxy, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl or aryl, -OC 1 -C 6 Alkyl, -OC 2 -C 6 Alkenyl, -OC 2 -C 6 Alkynyl, -OC 3 -C 8 Cycloalkyl or aryl, thiols, -SC 1 -C 6 Alkyl, -SC 2 -C 6 Alkenyl, -SC 2 -C 6 Alkynyl, -SC 3 -C 8 Cycloalkyl or aryl, -NR 4 C 1 -C 6 Alkyl, -NR 4 C 2 -C 6 Alkenyl, -NR 4 C 2 -C 6 Alkynyl and-NR 4 C 3 -C 8 Cycloalkyl or aryl;
R 3 is selected from-CO 2 H、-CO 2 R 4 Or isosteric equivalents of carboxyl groups wherein R 4 Is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 3 -C 8 Cycloalkyl or aryl; and is
Y is- (CH) 2 -CH 2 ) -, - (CH \9552; CH) -or- (C.ident.C) -;
or an ophthalmically acceptable salt thereof.
In certain embodiments, the acronychia and/or pistia extracts useful in the present invention comprise a compound having formula II:
wherein:
R 1 selected from the group consisting of: c 5 -C 16 Alkyl radical, C 5 -C 16 Alkenyl and C 5 -C 16 Alkynyl, more preferably C 5 -C 16 Alkenyl groups including, for example, farnesyl;
R 2 selected from the group consisting of: hydrogen, hydroxy, -OC 1 -C 6 Alkyl, -OC 2 -C 6 Alkenyl, -OC 2 -C 6 Alkynyl, -OC 3 -C 8 Cycloalkyl, more preferably hydrogen, hydroxy, -OC 1 -C 6 Alkyl, even more preferably hydrogen or-OC 1 -C 3 An alkyl group;
R 3 selected from-CO 2 H、-CO 2 R 4 Wherein R is 4 Is C 1 -C 6 An isosteric equivalent of an alkyl, or carboxyl group; and is provided with
Y is- (CH) 2 -CH 2 ) -or- (CH 9552; CH) -;
or an ophthalmically acceptable salt thereof.
In certain embodiments, at least one of the compounds of formula II is present in the acronychia and/or synchrysepalae extract at a concentration of equal to or greater than 1% (or about 1%) to about 20%, or optionally about 7% (or about 7%) to about 10% (or about 10%) by weight of the acronychia and/or synchryseia extract.
In certain embodiments, the compounds of formula II useful in the present invention are in the form of an acid or alkyl ester selected from (or selected from the group consisting of) 3- (4-farnesyloxyphenyl) -propionic acid, 3- (4-farnesyloxy-3-hydroxyphenyl) -propionic acid, 3- (4-farnesyloxy-3-methoxyphenyl) -propionic acid, alkyl esters thereof (specifically, ethyl esters thereof), and combinations of two or more thereof.
In certain embodiments, the compound of formula II useful in the present invention is 3- (4-farnesyloxyphenyl) -propionic acid and/or the ethyl ester thereof.
In certain embodiments, the compound of formula II useful in the present invention is 3- (4-farnesyloxy-3-hydroxyphenyl) -propionic acid and/or the ethyl ester thereof.
In certain embodiments, the compound of formula II useful in the present invention is 3- (4-farnesyloxy-3-methoxyphenyl) -propionic acid and/or the ethyl ester thereof.
Compounds and extracts derived from acronychia species are described in US 9,220,928, which is incorporated herein by reference in its entirety.
In certain embodiments, the 3- (4-farnesyloxyphenyl) -propionic acid and/or ethyl ester thereof is present in the acronychia and/or strongylophora extract at a concentration of equal to or greater than 1% (or about 1%) to about 20%, or optionally about 7% (or about 7%) to about 10% (or about 10%) by weight of the acronychia and/or strongylophora extract.
Any of a variety of extracts of acronychia and/or pistia may be used in embodiments in which the method includes applying such an extract. The extract may be obtained from any part of the plant, such as fruit, seeds, bark, leaves, flowers, roots and wood.
In certain embodiments, the extract is obtained from the fruit of a plant. Suitable extracts of acronychia or pistia fruits, seeds, bark, leaves, flowers, roots and wood can be obtained using conventional methods including, but not limited to, by milling, maceration, pressing, squeezing, mashing, centrifugation, and/or processes such as cold percolation, stirring/distillation, microwave assisted extraction, supercritical/subcritical CO with or without polar modifiers 2 Compressed gas extraction, pressurized solvent extraction, accelerated solvent extraction, pressurized or normal hot water extraction, surfactant assisted pressurized hot water extraction, oil extraction, membrane extraction, soxhlet extraction, gold finger distillation/extraction, and/or processes disclosed, for example, in U.S. patents 7442391, 7473435, and 7537791 (all incorporated herein by reference) to Integrated chemical Technologies, LLC, etc., or by other methods such as solvent extraction, etc., to extract material directly from biomass. Comprising polar solvents, non-polar solvents or the likeAny of a variety of solvents, including combinations of two or more thereof, may be used in the process including solvent extraction.
Suitable polar solvents include polar inorganic solvents such as water and the like; polar organic solvents such as alcohols and corresponding organic acids, e.g. C including methanol, ethanol, propanol, butanol, etc 1 -C 8 Alcohols, organic acids including acetic, formic, propionic, and the like, including C 1 -C 8 Polyols and diols such as polyols/diols, and combinations of two or more thereof. Suitable non-polar solvents include non-polar organic solvents such as alkanes (including C) 1 -C 8 Alkanes), cycloalkanes (including C) 1 -C 8 Alkanes), alkyl ethers (including C) 1 -C 8 Alkyl ethers), petroleum ethers, ketones (including C) 1 -C 8 Ketones), methylene chloride, ethyl acetate, xylene, toluene, chloroform, vegetable oils, mineral oils, and the like. In another embodiment, extraction may be obtained by the above-described non-polar solvent or supercritical fluid extraction with or without a polar modifier, such as C 1 -C 8 Alcohol, water, C 1 -C 8 Polyol/diol or C 1 -C 8 An organic acid.
In one embodiment, the extract comprises an extract of acronychia. In another embodiment, the extract of the present invention comprises a combination of a polar extract and a non-polar extract from the fruit of acronychia tangutorum. In another embodiment, the extract of the present invention comprises an ethanol or glycolic acid extract of the fruit of acronychia tangutorum.
In one embodiment, the extract comprises an extract of lica vernicosa. In another embodiment, the extract of the present invention comprises a combination of polar and non-polar extracts from the wood of, or root of, licaria vernicosa. In another embodiment, the extract of the present invention comprises an ethanol extract from lica vernicosa wood or lica vernicosa root.
In another embodiment, the extract of the invention comprises by using a composition comprising water, C 1 -C 8 Alcohol, C 1 -C 8 Polyol, C 1 -C 8 Polar solvents of glycols and combinations of two or more thereof are polar extracts prepared from the extraction of the fruit of acronychia, the wood of lica vernicosa, or the root of lica vernicosa. In certain embodiments, one or more C are used 1 -C 4 Alcohol, C 1 -C 4 Polyol and/or C 1 -C 4 Glycol to extract the extract. In certain embodiments, the extract is prepared using a solvent comprising methanol, ethanol, or a combination thereof, in the presence or absence of water. In another embodiment, the extract is a polar extract extracted from the fruit of satsuma aurantiaca using a combination of alcohol and water. In another embodiment, the extract is a polar extract extracted from ground wood of lica vernicosa or ground roots of lica vernicosa using methanol.
In another embodiment, the extract comprises a non-polar extract prepared by extracting from the fruit of acronychia tangutorum, licaria veronica wood, or Licaria veronica root using a non-polar solvent comprising one or more C' s 1 -C 8 Alkane, C 1 -C 8 Cycloalkane, C 1 -C 8 Alkyl ethers, C 1 -C 8 Alkyl esters and/or chloroform, more preferably one or more C 1 -C 8 Alkane, C 1 -C 8 Alkyl esters and/or chloroform. In another embodiment, the non-polar extract is extracted from the fruit of acronychia tangutorum, licaria verniciosa wood, or Licaria verniciosa root using hexane, ethyl acetate, chloroform, or a mixture of two or more thereof. In another embodiment, the non-polar extract is extracted from the satsuma aurantifolia fruit using ethyl acetate.
In one embodiment, the extract comprises an extract of marigold. In another embodiment, the extract of the invention comprises a combination of polar and non-polar extracts of marigold petals. In another embodiment, the extract of the invention comprises a non-polar extract of marigold petals.
In one embodiment, the extract comprises an extract of fenugreek. In another embodiment, the extract of the present invention comprises a combination of polar and non-polar extracts of fenugreek leaves. In another embodiment, the extract of the present invention comprises a non-polar extract of fenugreek leaves.
In another embodiment, the calendula and/or trigonella extract is a non-polar extract prepared using a non-polar solvent comprising one or more C 1 -C 8 Alkane, C 1 -C 8 Cycloalkane, C 1 -C 8 Alkyl ethers, C 1 -C 8 Alkyl esters and/or chloroform, more preferably one or more C 1 -C 8 Alkane, C 1 -C 8 Alkyl esters and/or chloroform.
In another embodiment, the calendula and/or trigonella extract is a non-polar extract prepared using hexane, ethyl acetate, chloroform or a mixture of two or more thereof. In another embodiment, the extract is a non-polar extract prepared using ethyl acetate.
In one embodiment, the plant extract may be obtained by extracting a cell culture of a variety of plants, including cell cultures of acronychia, pistia, marigold, and/or trigonella. The cell culture extracted to obtain the plant extract used in the present invention may be in any form, including suspension cell cultures and the like.
Extracts of marigold and fenugreek can be obtained from Caitness Biotechnologies Ltd, UK (http:// www. Caittnessbiotechnology. Com /). These extracts are part of the Phytottre Natural Product Library, which is available to everyone. Alternatively, the extract may be obtained using a preparation method described as non-polar by caittress biotechnology ltd. and prepared with a mixture of methanol and dichloromethane. For details, please refer to the web page http:// caithtechnitology. In a typical extraction, a pre-weighed amount of dry powdered biomass was suspended in a mixture of methanol/dichloromethane (1). The suspension was then filtered and the filtrate was dried under reduced pressure to a solvent-free residue.
In certain embodiments, the extract of acronychia, pistia stratiotes, marigold, and/or fenugreek is present in the compositions of the invention in an amount of from about 0.001% to about 10%, optionally from about 0.001% to about 5%, or optionally from about 0.01% to about 1%, by weight of the composition.
Bacterial extracts of actinomycetes exhibiting retinol-like properties and/or beneficial effects
In certain embodiments, the compound/extract exhibiting retinol-like properties and/or beneficial effects is or comprises a bacterial extract of the genus actinomyces. Bacteria of the genus actinomycete include many well-characterized species, as well as some insufficiently characterized species, such as one collected from the united states and labeled as species a 5640. Samples of this bacteria were collected, grown in culture, and made into extracts. Extracts are part of the natural products collection (natural products collection) and are now under the control of the Barukenburg institute (Doylestrown, PA), formerly known as the hepatitis and Virus Institute (IHVR). Within the nomenclature of the IHVR collection, the extract is labeled IHVR _39565_f 7.
In one embodiment, the extract used in the present invention is obtained from an actinomycete species having the ability to produce a chemical composition similar to that produced by extract a 5640. In another embodiment, the bacterium is deposited in the united states and the strain is the same as previously designated species a 5640.
In certain embodiments, the extract of actinomyces is present in the compositions of the invention in an amount of from 0.001% to 10%, optionally from 0.001% to 5%, or optionally from 0.01% to 1%, by weight of the composition.
A compound of formula (I) exhibiting retinol-like biological activity and/or properties.
In certain embodiments, the compound/extract exhibiting retinol-like properties and/or beneficial effects is or comprises a compound of formula (I).
Wherein-
The dotted line represents a single or double bond; optionally one of the dotted lines is a double bond;
R 1 represents H, a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms;
R 2 represents a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms; optionally methyl (-CH) 3 ) Or methylene (= CH) 2 ) A moiety; a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms, optionally from 1 to 10 carbon atoms, optionally 6 carbon atoms; optionally an aromatic moiety, optionally a phenyl moiety; preferably 2-methylpropan-1, 3-diene.
In certain embodiments, the compounds of formula (I) include the corresponding salts of such metal ions, such as, but not limited to, li + 、Na + 、K + 、Ca 2+ Or Mg 2+ 。
In certain embodiments, the compound of formula I is:
(2E,4E,6E) -7- (1, 2, 3-hexamethyl-2, 3-dihydro-1H-inden-5-yl) -3-methyloctane-2, 4, 6-trienoic acid
Or alternatively
4- (1, 2, 3-hexamethyl-2, 3-dihydro-1H-inden-5-yl) vinyl) benzoic acid, and in each case derivatives thereof which exhibit retinoid-like activity. These compounds are referred to as compound 1 and compound 2, respectively, in examples 6 and 7 below.
<xnotran> I , (2E,4E,6E) -7- (1,1,2,2,3,3- -2,3- -1H- -5- ) -3- -2,4,6- 4- (1- (1,1,2,2,3,3- -2,3- -1H- -5- ) ) , . </xnotran>
Mixtures of any of the above compounds/extracts/extract sources that exhibit retinol-like properties and/or beneficial effects may also be used.
Compounds and extracts of formula I are described in U.S. patent publication 2019/0091122, which is incorporated herein by reference in its entirety.
In certain embodiments, the compound of formula I is present in the compositions of the present invention in an amount from about 0.0001% to about 20%, optionally from about 0.001% to about 10%, optionally from about 0.01% to about 5%, or optionally from about 0.2% to about 2%, by weight of the composition. In another embodiment, the compound of formula I is present in the compositions of the present invention in an amount from about 0.0001% to about 1%, optionally from about 0.001% to about 1%, or optionally from about 0.01% to about 1%, by weight of the composition.
Compositions the present inventors have found that compounds and/or extracts having retinol-like properties and/or beneficial effects can facilitate and/or improve the delivery/excretion of mucins from corneal epithelial cells.
Penetration enhancer
In certain embodiments, the compositions of the present invention optionally comprise a penetration enhancer.
Suitable penetration enhancers include (selected from or consisting of the group consisting of) alone or in combination: surfactants such as saponin, polyoxyethylene ethers of fatty acids (such as polyoxyethylene 4-, 9-, 10-, and 23-lauryl ether, polyoxyethylene 10-, and 20-cetyl ether, polyoxyethylene 10-, and 20-stearyl ether), sorbitan monooleate, sorbitan monolaurate, polyoxyethylene sorbitan (such as polyoxyethylene sorbitan monolaurate), decahydrocarbyl quaternary ammonium bromide, and dodecyl trimethyl ammonium bromide; chelating agents such as natural polyacids (e.g., citric acid), phosphates (e.g., disodium pyrophosphate), phosphonates, bisphosphonates (e.g., hydroxyethylidene diphosphonic acid), aminocarboxylic acids (e.g., ethylenediaminetetraacetic acid (EDTA) and disodium EDTA) and ethylenediamine-N, N' -disuccinic acid (EDDS)); bile salts and acids such as cholic acid, deoxycholic acid, glycocholic acid, glycodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, sodium cholate, sodium glycocholate, sodium deoxycholate, sodium taurodeoxycholate, chenodeoxycholic acid, and ursodeoxycholic acid; fusidic acid derivatives, glycyrrhizic acid and ammonium glycyrrhizinate, and saponin EDTA, fusidic acid, polyoxyethylene 9-lauryl ether, polyoxyethylene 20-stearyl ether, glycocholate or a mixture of any of the above.
The concentration of the permeation enhancer applied should be the minimum amount necessary to increase absorption of the compound and/or extract through the mucus or other barrier membrane of the eye. Generally, ranges from 0.01% (or about 0.01%), optionally from 0.05% (or about 0.05%), optionally from 0.1% (or about 0.1%), optionally from 0.15% (or about 0.15%), optionally from 0.2% (or about 0.2%), optionally from 0.25% (or about 0.25%) to 2% (or about 2%), optionally to 2.5% (or about 2.5%), optionally to 3% (or about 3%), optionally to 3.5%, (or about 3.5%), optionally to 4% (or about 4%), optionally to 4.5% (or about 4.5%), optionally to 5% (or about 5%), optionally to 5.5% (or about 5.5%), optionally to 6% (or about 6%), optionally to 6.5% (or about 6.5%), optionally to 7% (or about 7%), optionally to 7.5% (or about 7.5%), optionally to 8% (or about 8%), optionally to 8.5% (or about 8.5%), optionally to 9% (or about 9%), optionally to 9.5% (or about 9.5%), optionally to 10% (or about 10%), optionally to 10.5% (or about 10.5%), optionally to 11% (or about 11%), optionally to 11.5% (or about 11.5%), optionally to 12% (or about 12%), optionally to 12.5% (or about 12.5%), optionally to 13% (or about 13%), optionally to 13.5% (or about 13.5%), optionally to 14% (or about 14%), optionally, a concentration (w/v) of up to 14.5% (or about 14.5%), optionally up to 15% (or about 15%), optionally up to 15.5% (or about 15.5%), optionally up to 16% (or about 16%), optionally up to 16.5% (or about 16.5%), optionally up to 17% (or about 17%), optionally up to 17.5% (or about 17.5%), optionally up to 18% (or about 18%), optionally up to 18.5% (or about 18.5%), optionally up to 19% (or about 19%), optionally up to 19.5% (or about 19.5%), optionally up to 20% (or about 20%) of the total composition may be used in the compositions of the invention.
Ophthalmologically acceptable carrier
The compositions of the present invention also comprise an aqueous, oil-in-water, or water-in-oil emulsion carrier. The carrier is ophthalmically acceptable. Useful oil-in-water and water-in-oil carriers can be found in U.S. patent publication 20030165545A1 and U.S. patents 9480645, 8828412, and 8496976, each of which is incorporated herein by reference in its entirety.
The ophthalmically acceptable carrier (or composition of the present invention) may optionally comprise one or more additional excipients and/or one or more additional active ingredients. Examples of such optional components are described below.
Excipients commonly used in ophthalmic compositions include, but are not limited to, demulcents, tonicity agents, preservatives, chelating agents, buffering agents (other than and in addition to the organic acids of the present invention), and surfactants. Other excipients include solubilizers, stabilizers, comfort enhancers, polymers, emollients, pH adjusters (not and in addition to the organic acids of the present invention) and/or lubricants. Any of a variety of excipients may be used in the compositions of the invention, including mixtures of water, water and water-miscible solvents, such as vegetable or mineral oils containing from 0.5% to 5% of a non-toxic water-soluble polymer, natural products such as agar and acacia, starch derivatives such as starch acetate and hydroxypropyl starch, and other synthetic products such as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyethylene oxide, and preferably cross-linked polyacrylic acid and mixtures thereof.
Demulcents or soothing agents for use with embodiments of the present invention include, but are not limited to, cellulose derivatives (such as hydroxyethylcellulose, methylcellulose, hypromellose, or mixtures thereof), hyaluronic acid, tamarind seed extract, glycerin, polyvinylpyrrolidone, polyethylene oxide, polyethylene glycol, propylene glycol, and polyacrylic acid, and mixtures thereof. In certain embodiments, one or more of hyaluronic acid, propylene glycol, tamarind seed extract, glycerin, and/or polyethylene glycol 400 is a soothing or soothing agent. In certain embodiments, the soothing or soothing agent is selected from hyaluronic acid, tamarind seed extract, or mixtures thereof.
The compositions of the present invention are ophthalmically suitable for administration to the eye of a subject. The term "aqueous" generally refers to an aqueous formulation wherein the excipient is greater than about 50%, more preferably greater than about 75%, and specifically greater than about 90% water by weight. In certain embodiments, the compositions of the present invention are substantially free of compounds that irritate the eye. In certain embodiments, the compositions of the present invention are substantially free of free fatty acids and C 1 To C 4 An alcohol. In certain embodiments, the compositions of the present invention comprise less than 40% (or about 40%), optionally less than 35% (or about 35%), optionally less than 30% (or about 30%), optionally less than 25% (or about 25%), optionally less than 20% (or about 20%), optionally less than 15% (or about 15%), optionally less than 10% (or about 10%) or optionally less than 5% (or about 5%) non-alcohol, organic excipient or solvent by weight of the total composition. These drops may be delivered in single dose ampoules, preferably sterile, so that no bacteriostatic component is required in the formulation. Alternatively, the drops may be delivered in a multi-dose bottle which may preferably include means to extract any preservatives from the composition as it is delivered, such means being known in the art.
In certain embodiments, the compositions of the present invention are isotonic or slightly hypotonic in order to combat the hypertonicity of tears caused by evaporation and/or disease. This may require tonicity agents to bring the osmolality of the formulation to or near 210-320 millimoles per kilogram (mOsm/kg). The compositions of the present invention typically have an osmolality in the range of 220-320mOsm/kg, or optionally in the range of 235-300 mOsm/kg. Ophthalmic compositions will generally be formulated as sterile aqueous solutions.
The degree of penetration of the compositions of the present invention may be adjusted with tonicity agents to a value compatible with the intended use of the composition. For example, the permeability of the composition can be adjusted to approximate the permeability of normal tears, which is equivalent to about 0.9w/v% sodium chloride in water. Examples of suitable tonicity adjusting agents include, but are not limited to, sodium chloride, potassium chloride, calcium chloride, and magnesium chloride; dextrose; glycerol; propylene glycol; mannitol; sorbitol, and the like, and mixtures thereof. In one embodiment, a combination of sodium chloride and potassium chloride is used to adjust the tonicity of the composition.
The compositions of the present invention may also be used to administer pharmaceutically active compounds. Such compounds include, but are not limited to, glaucoma therapeutics, analgesics, anti-inflammatory and anti-allergic drugs, and antimicrobial agents. More specific examples of pharmaceutically active compounds include betaxolol, timolol, pilocarpine, carbonic anhydrase inhibitors, and prostaglandins; a dopaminergic antagonist; postoperative antihypertensive agents such as p-aminocclonidine (alaclonidine); anti-infective agents such as ciprofloxacin, moxifloxacin, and tobramycin; non-steroidal and steroidal anti-inflammatory agents such as naproxen, diclofenac, nepafenac, suprofen, ketorolac, tetrahydrocortisol, and dexamethasone; dry eye therapeutic agents, e.g., PDE4 inhibitors; and antiallergic drugs such as H1/H4 inhibitors, olopatadine, or mixtures thereof.
It is also contemplated that the concentration of the ingredients comprising the formulations of the present invention may vary. One of ordinary skill in the art will appreciate that the concentration may vary depending on the addition, substitution, and/or subtraction of ingredients in a given formulation.
In certain embodiments, the compositions of the present invention may have a pH compatible with the intended use, and typically range from 4 (or about 4) to 10 (or about 10), optionally from 6 (or about 6) to 8 (to about 8), optionally from 6.5 (or about 6.5) to 7.5 (or about 7.5), or optionally from 6.8 (or about 6.8) to 7.2 (or about 7.2).
In certain embodiments, various conventional buffering agents may be employed, such as phosphates, borates, citrates, acetates, histidines, tris, bis-tris, and the like, and mixtures thereof. Borate buffers include boric acid and salts thereof, such as sodium or potassium borate. Potassium tetraborate or metaborate may also be used, which in solution produces boric acid or a borate salt. Hydrated salts, such as sodium borate decahydrate, may also be used. Phosphate buffers include phosphoric acid and its salts; for example, M 2 HPO 4 And MH 2 PO4, where M is an alkali metal such as sodium and potassium. Hydrated salts may also be used. In one embodiment of the invention, na is used 2 HPO 4 .7H 2 O and NaH 2 PO 2 .H 2 O as a buffer. The term phosphate also includes compounds that produce phosphoric acid or phosphate in solution. In addition, organic counterions to the above-mentioned buffers can also be used. The concentration of the buffer typically varies between about 0.01w/v% and 2.5w/v%, more preferably between about 0.05w/v% and about 0.5 w/v%.
In certain embodiments, the compositions of the present invention have a viscosity ranging from about 1cps to about 500cps, optionally from about 10cps to about 200cps, or optionally from about 10cps to about 100cps when measured using a TA Instrument AR2000 rheometer. The TA Instrument AR2000 rheometer should be used with the AR2000 flow test method of the TA rheologic Advantage software, the rheometer having a 40mm steel plate geometry; the viscosity range should be obtained by measuring the steady-state flow rate, which is controlled at a shear rate of 0 sec-1 to 200 sec-1.
In certain embodiments, the compositions of the present invention may be used as an eye drop solution, an eye wash solution, a contact lens lubricating and/or rewetting solution, a spray, a mist, or any other form of applying the composition to the eye.
The compositions of the present invention may also be used in the form of a wetting solution for contact lenses. In certain embodiments, as a wetting solution, the compositions of the present invention may be sealed in a blister package and also adapted to undergo a sterilization process.
Examples of blister packages and sterilization techniques are disclosed in the following references, which are incorporated herein by reference in their entirety: U.S. Pat. nos. D435,966;4,691,820;5,467,868;5,704,468;5,823,327;6,050,398, 5,696,686;6,018,931;5,577,367; and 5,488,815. This part of the manufacturing process provides another method of treating an ophthalmic device with an anti-allergic agent by adding the anti-allergic agent to the solution prior to sealing the package, followed by sterilization of the package. This is the preferred method of treating ophthalmic devices with anti-allergic agents.
Sterilization may be performed at different temperatures and time periods. Preferred sterilization conditions range from about 8 hours at about 100 ℃ to about 0.5 minutes at about 150 ℃. More preferred sterilization conditions range from about 2.5 hours at about 115 ℃ to about 5.0 minutes at about 130 ℃. The most preferred sterilization conditions are at about 124 ℃ for about 18 minutes.
When used as a wetting solution, the compositions of the present invention may be water-based solutions. Typical wetting solutions include, but are not limited to, saline solutions, other buffers, and deionized water. In certain embodiments, the wetting solution is an aqueous solution of deionized water or an aqueous salt solution containing salts including, but not limited to, sodium chloride, sodium borate, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, or their corresponding potassium salts. These ingredients are typically combined to form a buffer solution comprising an acid and its conjugate base, such that the addition of the acid and base causes only a relatively minor change in pH. In certain embodiments, the pH of the wetting solution is as described above. The buffer may additionally comprise 2- (N-morpholino) ethanesulfonic acid (MES), sodium hydroxide, 2-bis (hydroxymethyl) -2,2',2 "-nitrilotriethanol, N-tris (hydroxymethyl) methyl-2-aminoethanesulfonic acid, citric acid, sodium citrate, sodium carbonate, sodium bicarbonate, acetic acid, sodium acetate, ethylenediaminetetraacetic acid, and the like, and combinations thereof. Preferably, the solution is a borate buffered saline solution or a phosphate buffered saline solution or deionized water. Particularly preferred solutions contain from about 500ppm to about 18,500ppm sodium borate, most particularly preferably about 1000ppm sodium borate.
If any ingredients incorporated into the wetting solution undergo oxidative degradation, agents may be added to stabilize the wetting solution containing such ingredients. Such "oxidative stabilizers" include, but are not limited to, chelating agents (such as EDTA, dequest, desferal, silica), chitin derivatives (such as chitosan, cellulose and its derivatives, and N, N', N "-hexa (2-pyridyl) -1,3, 5-tris (aminomethyl) benzene), and certain macrocyclic ligands (such as crown ethers, ligands containing junctions and chains). See, david A.Leigh et al, angew.Chem int. Editor, 2001, vol.40, no. 8, pp.1538-1542, and Jean-Claude chamboron et al, pure & appl.chem.,1990, vol.62, no. 6, pp.1027-1034. The oxidation stabilizer may include other compounds that inhibit oxidation, such as selected from the group consisting of: 2,2', 6' -hexa (1, 1-dimethylethyl) 4,4',4"- [ (2, 4, 6-trimethyl-1, 3, 5-benzenetriyl) -trimethylene ] -trisphenol (Irganox 1330), 1,3, 5-tris [3, 5-bis (1, 1-dimethylethyl) 4-hydroxybenzyl ] -1H,3H,5H-1,3, 5-triazine-2, 4, 6-trione, pentaerythritol tetrakis [3- [3, 5-bis (1, 1-dimethylethyl) -4-hydroxyphenyl ] -propionate ], octadecyl-3- [3, 5-bis (1, 1-dimethylethyl) -4-hydroxyphenyl ] -propionate, tris [2, 4-bis (1, 1-dimethylethyl) -phenyl ] -phosphite, 2' -dioctadecyloxy) -5,5' -spirocyclo-bis (1, 3, 2-dioxophospholane), dioctadecyl disulfide, didodecyl-3, 3' -thiobispropionate, dioctadecyl-3, 3' -thiobispropionate, butylhydroxytoluene, ethylene bis [3, 3-bis [3- (1, 3-dimethylethyl) -4-hydroxyphenyl ] -propionate, and mixtures thereof. Preferred oxidation stabilizers are diethylenetriaminepentaacetic acid ("DTPA"), or salts of DTPA such as CaNa3DTPA, znNa3DTPA, and Ca2DTPA. See U.S. patent application 60/783,557 entitled "Methods for Stabilizing oxygen reactive Pharmaceutical Compositions," filed 2006, 3, 17, and its corresponding non-provisional filed application, which is incorporated herein by reference in its entirety. In certain embodiments, the concentration of the oxidation stabilizer in the solution is from about 2.5 micromoles/liter to about 5000 micromoles/liter, optionally from about 20 micromoles/liter to about 1000 micromoles/liter, optionally from about 100 micromoles/liter to about 1000 micromoles/liter, or optionally from about 100 micromoles/liter to about 500 micromoles/liter.
In particular embodiments, the compositions of the present invention are formulated for administration at any frequency of administration, including weekly, once every five days, once every three days, once every two days, twice daily, three times daily, four times daily, five times daily, six times daily, eight times daily, hourly or more. This dosing frequency is also maintained for a variable duration of time, depending on the therapeutic needs of the user. The duration of a particular treatment regimen may vary from a single administration to a regimen lasting months or years. One of ordinary skill in the art will be familiar with determining a particular indicated treatment regimen.
Compositions and products comprising such compositions of the present invention can be prepared using methods well known to those of ordinary skill in the art.
Examples
Any compositions of the present invention described in the following examples illustrate specific embodiments of the compositions of the present invention, but are not intended to be limiting. Other modifications may occur to those skilled in the art without departing from the spirit and scope of the invention.
The following test methods were used in the examples:
example 1
The fractions of the lemon extract in aspen showed increased MUC1, MUC4 and MUC16 gene expression in human corneal epithelial 3D tissue when treated in culture.
Human corneal epithelial 3D tissue was purchased from MatTek corporation (Ashland, MA, USA). After receiving the human corneal epithelial 3D tissue, the tissue was incubated overnight in MatTek assay medium according to the manufacturer's instructions. Human corneal epithelial 3D tissue was divided into three treatment groups of at least three tissues per group. The lemon extract in aspen was added to the medium containing human corneal epithelial tissue of two of the treatment groups, respectively, to produce a medium concentration of 0.001% (w/v) or 0.01% (w/v), respectively. Corneal epithelial tissue in all four treatment groups was incubated for two days. The lemon extract of aspen used was supplied and extracted from south cross plant, knockrow Nsw, australia. After two days of incubation, mucin 1 (MUC 1), mucin 4 (MUC 4) and mucin 16 (MUC 16) were analyzed for gene expression. After two days of incubation, human corneal epithelial 3D tissue was cut in half and half of the tissue was lysed in 350 μ L of lysis buffer consisting of 100 parts RLT buffer (RNeasy Mini kit, qiagen, valencia, CA) to one part 2-mercaptoethanol. RNA was extracted from the solution using the RNeasy Mini Kit (Qiagen, valencia, calif.) according to the manufacturer's instructions and eluted in 25. Mu.L of RNase-free water.
Reverse Transcription (RT) was performed using the Applied Biosystems High Capacity Reverse Transcription Kit (ThermoFisher Scientific, bridgewater, NJ). Gene expression assays for mucin-1 (MUC 1), mucin-4 (MUC 4), and mucin-16 (MUC 16) polymerase (RNA) II polypeptide A (POLR 2A) and Master Mix, sold under the trade name TAQMAN, were purchased from ThermoFisher Scientific (Bridgewater, NJ). Use ofMaster Mix (ThermoFisher Scientific, bridgewater, NJ) performed the qPCR analysis and run the qPCR analysis on a real-time PCR system sold under the trade name QUANTSTUDIO 7Flex System (ThermoFisher Scientific, bridgewater, NJ). The expression of the MUC1, MUC4 and MUC16 genes was normalized to the expression of the human POLR2A housekeeping gene. Fold changes were calculated and a two-tailed two-sample student's t-test was performed (Microsoft Office Excel 2007, microsoft, redmond, wa, usa) compared to untreated controls (UT). The results are shown in FIG. 1.
Example 2
The composition of the lemon extract in aspen showed increased mucin-1 secretion in human corneal epithelial 3D tissue when treated in culture medium.
Human corneal epithelial 3D tissue was purchased from MatTek corporation (Ashland, MA, USA). After receiving the human corneal epithelial 3D tissue, the tissue was incubated overnight in MatTek assay medium according to the manufacturer's instructions. Human corneal epithelial 3D tissue was divided into three treatment groups of at least three tissues per group. The lemon extract in aspen was added to the medium containing human corneal epithelial tissue of two of the treatment groups, respectively, to produce a medium concentration of 0.001% (w/v) or 0.01% (w/v), respectively. Corneal epithelial tissue in all four treatment groups was incubated for two days. Two days later, media was collected using the human mucin-1 (CA 15-3) enzyme-linked immunosorbent assay (ELISA) kit (EHMUC 1, thermoFisher Scientific, bridgewater, NJ) for determination of mucin 1 secretion following the manufacturer's protocol. To assess activity, colorimetric changes were measured using a microplate reader (SpectraMax M2E, molecular Devices, sunnyvale, calif., USA). The assay employs standard enzyme-linked immunoassay techniques, so that there is a linear correlation between mucin-1 concentration in the sample and colorimetric changes. A standard curve is generated with mucin-1 concentration as the x-axis and absorbance as the y-axis, indicating the corresponding mucin-1 concentration. The results are shown in figure 2 below.
Example 3
Solutions can be prepared that include one or more compounds and/or extracts of the invention having retinol-like properties and/or beneficial effects, as shown in examples 3-7.
Table 1 shows the components of such formulations (as shown in formulations 3A-3D), which can be incorporated as described below using conventional mixing techniques.
TABLE 1
* Can be adjusted to osmotic pressure of 280mOsm/Kg-290mOsm/Kg
* Can be adjusted to pH 7.2
* Optionally, an amount up to 100% w/w%
For examples 3A-3D: sodium hyaluronate may be provided by contiro a.s. (DOLNI, DOBROUC, CZECH REPUBLIC).
For examples 3A-3D: aspen lemon extract (Abacross) TM Fruit extract of Acronychia tangutica) can be prepared from AsclepiadaceaeSupplied by Knockrow Nsw, australia.
For examples 3A-3D: polysorbate 20 can be provided by Merck KGaA (DARMSTADT, GERMANY).
For examples 3A-3D: polysorbate 80 can be provided by Merck KGaA (DARMSTADT, GERMANY).
For examples 5A-5B: polyethylene glycol 400 can be provided by Clariant Produkte (Burgkirchen, GERMANY).
For examples 3A-3D: boric acid can be provided by Merck KGaA (DARMSTADT, GERMANY).
For examples 3A-3D: sodium borate may be provided by Merck KGaA (DARMSTADT, GERMANY).
For examples 3A-3D: sodium chloride may be supplied by Caldic (DusseldoRF, GERMANY).
For examples 3A-3D: potassium chloride may be supplied by Merck KGaA (DARMSTADT, GERMANY).
For examples 3A-3D: calcium chloride dihydrate can be supplied by Merck KGaA (DARMSTADT, germann).
For examples 3A-3D: magnesium chloride may be provided by KGaA (DARMSTADT, GERMANY).
For examples 3A-3D: polyquaternium-42 (33% aqueous) may be supplied by DSM BIOMEDICAL (BERKELEY, CA, USA).
For examples 3A-3D: sodium chlorite dihydrate can be supplied by Oxychem (WICHITA, KS, USA).
For examples 3A-3D: the 1N sodium hydroxide may be supplied by VWR (RADPER, PA, USA).
For examples 3A-3D: the 1N hydrochloric acid may be supplied by VWR (RANDER, PA, USA).
Solution 3A can be prepared as follows:
1. To a 1500ml beaker was added 800 grams of purified water USP.
2. To the above material were added 10g of polysorbate 80 and 50g of polysorbate 20. The solution was mixed until both were completely mixed and dissolved.
3. To the above material was added 1.0g of lemon extract in Aspongopus. The solution was mixed until the aspen lemon extract dissolved.
4. The solution was filtered through a 0.45 micron filter and poured back into a 1500ml beaker.
5. To the solution obtained in step 4 was added 2.0 g of sodium hyaluronate. The solution was mixed to completely dissolve the sodium hyaluronate.
6. The following ingredients were then added in order, dissolved and then added: 2.5 grams of polyethylene glycol 400, 6.0 grams of boric acid, 0.05 grams of sodium borate, 1.0 grams of potassium chloride, 0.06 grams of calcium chloride dihydrate, 0.06 grams of magnesium chloride, and 0.0015 grams of polyquaternium-42 (aqueous solution).
7. While continuing to mix, 0.14 grams of sodium chlorite dihydrate was added and mixed until dissolved.
8. The osmotic pressure of the formulation was measured and adjusted to 280mOsm/Kg with sodium chloride.
9. The pH of the formulation was adjusted to pH 7.2 using 1N sodium hydroxide and/or 1N hydrochloric acid.
10. The solution was adjusted to 1000.0 grams using purified water USP and mixed for 10 minutes to completely homogenize.
11. The solution was filtered using a 0.22 micron filter.
Solution 3B can be prepared as follows:
1. To a 1500ml beaker was added 800 grams of purified water USP.
2. To the above material were added 2g of polysorbate 80 and 10g of polysorbate 20. The solution was mixed until both were completely mixed and dissolved.
3. 0.1g of lemon extract in Aspongopus was added to the above mixture. The solution was mixed until the aspen lemon extract dissolved.
4. The solution was filtered through a 0.45 micron filter and poured back into a 1500ml beaker.
5. To the solution of step 4 was added 3.0 grams of sodium hyaluronate. The solution was mixed to completely dissolve the sodium hyaluronate.
6. The following ingredients were then added in order, dissolved and then added: 2.5 grams of polyethylene glycol 400, 6.0 grams of boric acid, 0.05 grams of sodium borate, 1.0 grams of potassium chloride, 0.06 grams of calcium chloride dihydrate, 0.06 grams of magnesium chloride, and 0.0015 grams of polyquaternium-42 (aqueous solution).
7. While mixing was continued, 0.14 grams of sodium chlorite dihydrate was added and mixed until dissolved.
8. The osmotic pressure of the formulation was measured and adjusted to 280mOsm/Kg with sodium chloride.
9. The pH of the formulation was adjusted to pH 7.2 using 1N sodium hydroxide and/or 1N hydrochloric acid.
10. The solution was adjusted to 1000.0 grams using purified water USP and mixed for 10 minutes to completely homogenize.
11. The solution was filtered using a 0.22 micron filter.
Solution 3C can be prepared as follows:
1. To a 1500ml beaker was added 800 grams of purified water USP.
2. To the above material were added 10g of polysorbate 80 and 20g of polysorbate 20. The solution was mixed until both were completely mixed and dissolved.
3. To the above material was added 1.0g of lemon extract in Aspongopus. The solution was mixed until the lemon in aspen extract dissolved.
4. The solution was filtered through a 0.45 micron filter and poured back into a 1500ml beaker.
5. To the solution of step 4 was added 1.5 grams of sodium hyaluronate. The solution was mixed to completely dissolve the sodium hyaluronate.
6. The following ingredients were then added in order, dissolving each ingredient and then adding the latter: 6.0 grams boric acid, 0.05 grams sodium borate, 1.0 gram potassium chloride, 0.06 gram calcium chloride dihydrate, 0.06 gram magnesium chloride and 0.0015 gram polyquaternium-42 (aqueous solution).
7. While mixing was continued, 0.14 grams of sodium chlorite dihydrate was added and mixed until dissolved.
8. The osmotic pressure of the formulation was measured and adjusted to 280mOsm/Kg with sodium chloride.
9. The pH of the formulation was adjusted to pH 7.2 using 1N sodium hydroxide and/or 1N hydrochloric acid.
10. The solution was adjusted to 1000.0 grams using purified water USP and mixed for 10 minutes to completely homogenize.
11. The solution was filtered using a 0.22 micron filter.
Solution 3D can be prepared as follows:
1. To a 1500ml beaker was added 800 grams of purified water USP.
2. To the above material were added 2g of polysorbate 10 and 50g of polysorbate 20. The solution was mixed until both were completely mixed and dissolved.
3. 0.1g of lemon extract in Aspongopus was added to the above mixture. The solution was mixed until the aspen lemon extract dissolved.
4. The solution was filtered through a 0.45 micron filter and poured back into a 1500ml beaker.
5. To the solution of step 4 was added 1.5 grams of sodium hyaluronate. The solution was mixed to completely dissolve the sodium hyaluronate.
6. The following ingredients were then added in order, dissolved and then added: 6.0 grams boric acid, 0.05 grams sodium borate, 1.0 gram potassium chloride, 0.06 grams calcium chloride dihydrate, 0.06 grams magnesium chloride and 0.0015 grams polyquaternium-42 (aqueous solution).
7. While continuing to mix, 0.14 grams of sodium chlorite dihydrate was added and mixed until dissolved.
8. The osmotic pressure of the formulation was measured and adjusted to 280mOsm/Kg with sodium chloride.
9. The pH of the formulation was adjusted to pH 7.2 using 1N sodium hydroxide and/or 1N hydrochloric acid.
10. The solution was adjusted to 1000.0 grams using purified water USP and mixed for 10 minutes to complete homogeneity.
11. The solution was filtered using a 0.22 micron filter.
Example 4
Table 2 shows the components of the formulations of the present invention (as shown in formulations 4A-4D), which can be incorporated as described below using conventional mixing techniques.
TABLE 2
* Can be adjusted to osmotic pressure of 280mOsm/Kg-290mOsm/Kg
* Can be adjusted to pH 7.2
* Optionally, an amount up to 100 wt/wt%
For examples 4C-4D: sodium hyaluronate may be provided by contiro a.s. (DOLNI, DOBROUC, CZECH REPUBLIC).
For examples 4C-4D: the tamarind seed polysaccharide can be provided by INDENA (mirano, ITALY).
For examples 4A-4D: aspen lemon extract (Abacross) TM Extract of the fruit of satsuma aurantiaca) can be provided by southern cross (Knockrow Nsw, australia).
For examples 4A-4D: polysorbate 20 can be provided by Merck KGaA (DARMSTADT, GERMANY).
For examples 4A-4D: polysorbate 80 may be provided by Merck KGaA (DARMSTADT, GERMANY).
For examples 6C-6D: polyethylene glycol 400 can be provided by Clariant Produkte (Burgkirchen, GERMANY).
For examples 4A-4D: the boronic acid can be provided by Merck KGaA (DARMSTADT, GERMANY).
For examples 4A-4D: sodium borate may be supplied by Merck KGaA (DARMSTADT, GERMANY).
For examples 4A-4D: sodium chloride may be supplied by Caldic (DUSSELDORF, GERMANY).
For examples 4A-4D: potassium chloride may be supplied by Merck KGaA (DARMSTADT, GERMANY).
For examples 4A-4D: hypromellose E3 2910 may be supplied by DOW CHEMICAL (PLAQUEMINE, LOUISIANA, USA).
For examples 4A-4D: glycerol can be supplied by Emery Oleochemicals GmbH (DUSSELDORF, GERMANY).
For examples 4A-4D: disodium phosphate may be supplied by Merck KGaA (DARMSTADT, GERMANY).
For examples 4A-4D: sodium citrate may be supplied by Merck KGaA (DARMSTADT, germann).
For examples 4A-4D: sodium lactate may be provided as sodium lactate (50% aqueous solution) from Merck KGaA (DARMSTADT, GERMANY).
For examples 4A-4D: glucose can be supplied by Roquette Freres (lastem, FRANCE).
For examples 4A-4D: glycine can be supplied by Merck KGaA (DARMSTADT, GERMANY).
For examples 4A-4D: the ascorbic acid is obtained from DSM Nutritional Products (DRAKEMYRE, SCOTLAND, UK).
For examples 4A-4D: polyquaternium 42 may be provided by DSM BIOMEDICAL (BERKELEY, CA) as Polyquaternium 42 (33% aqueous solution).
For examples 4A-4D: disodium edetate may be supplied by Merck NV/SA (OVERIJSE, BELGIUM).
For examples 4A-4D: the 1N sodium hydroxide may be supplied by VWR (RADPER, PA, USA).
For examples 4A-4D: the 1N hydrochloric acid may be supplied by VWR (RANDER, PA, USA).
For examples 6A-6D: sodium chlorite dihydrate can be supplied by Oxychem (WICHITA, KS, USA).
Solution 4A can be prepared as follows:
1. To a 1500ml beaker was added 800 grams of purified water USP.
2. To the above material were added 10g of polysorbate 80 and 50g of polysorbate 20. The solution was mixed until both were completely mixed and dissolved.
3. 1.0g of lemon extract in Aspen was added to the above material. The solution was mixed until the aspen lemon extract dissolved.
4. The solution was filtered through a 0.45 micron filter and poured back into a 1500ml beaker.
5. To the above solution was added 1.98 g hypromellose E3 Premium. The solution was mixed until the hypromellose E3 Premium was dissolved.
6. The following ingredients were then added in order, dissolved and then added: 2.50 grams glycerol, 4.0 grams boric acid, 0.22 grams sodium borate, 0.27 grams disodium phosphate, 4.00 grams sodium citrate dihydrate, 1 gram potassium chloride, 0.57 grams sodium lactate (50% aqueous solution), 0.13 grams magnesium chloride, 0.036 grams glucose, 0.0002 grams glycine, 0.0001 grams ascorbic acid, 0.10 grams edetate disodium, 0.030 grams polyquaternium-42 (33% aqueous solution), and 0.14 grams sodium chlorite.
7. The osmotic pressure of the solution was measured and adjusted to 280mOsm with sodium chloride.
8. The pH of the solution was measured and adjusted to 7.2 with 1N sodium hydroxide and/or 1N hydrochloric acid.
9. The solution was brought to 1,000.00 g with purified water and mixed for 10 minutes.
10. The solution was filtered using a 0.22 micron filter.
Solution 4B can be prepared as follows:
1. To a 1500ml beaker was added 800 grams of purified water USP.
2. To the above material were added 10g of polysorbate 80 and 50g of polysorbate 20. The solution was mixed until both were completely mixed and dissolved.
3. To the above material was added 1.0g of lemon extract in Aspongopus. The solution was mixed until the aspen lemon extract dissolved.
4. The solution was filtered through a 0.45 micron filter and poured back into a 1500ml beaker.
5. To the above solution was added 1.98 g of hypromellose E3 Premium. The solution was mixed until the hypromellose E3 Premium was dissolved.
6. The following ingredients were then added in order, dissolving each ingredient and then adding the latter: 2.50 grams glycerol, 4.0 grams boric acid, 0.22 grams sodium borate, 0.27 grams disodium phosphate, 4.00 grams sodium citrate dihydrate, 1 gram potassium chloride, 0.57 grams sodium lactate (50% aqueous solution), 0.13 grams magnesium chloride, 0.036 grams glucose, 0.0002 grams glycine, 0.0001 grams ascorbic acid, 0.05 grams disodium edetate, 0.015 grams polyquaternium-42 (33% aqueous solution), and 0.14 grams sodium chlorite.
7. The osmolality of the solution was measured and adjusted to 280mOsm with sodium chloride.
8. The pH of the solution was measured and adjusted to 7.2 with 1N sodium hydroxide and/or 1N hydrochloric acid.
9. The solution was brought to 1,000.00 g with purified water and mixed for 10 minutes.
10. The solution was filtered using a 0.22 micron filter.
Solution 4C can be prepared as follows:
1. To a 1500ml beaker was added 800 grams of purified water USP.
2. To the above material were added 2g of polysorbate 80 and 10g of polysorbate 20. The solution was mixed until both were completely mixed and dissolved.
3. 0.1g of lemon extract in Aspen was added to the above. The solution was mixed until the aspen lemon extract dissolved.
4. The solution was filtered through a 0.45 micron filter and poured back into a 1500ml beaker.
5. To the solution of step 4 was added 1.2 grams of sodium hyaluronate. The solution was mixed to completely dissolve the sodium hyaluronate.
6. 2.0 Krestin kernel polysaccharide was added to the above solution. The solution was mixed to completely dissolve the tamarind seed polysaccharide.
7. To the above solution was added 1.98 g of hypromellose E3 Premium. The solution was mixed until hypromellose E3 Premium was dissolved.
8. The following ingredients were then added in order, dissolving each ingredient and then adding the latter: 2.50 grams of polyethylene glycol 400, 2.50 grams of glycerol, 4.0 grams of boric acid, 0.22 grams of sodium borate, 0.27 grams of disodium phosphate, 4.00 grams of sodium citrate dihydrate, 1 gram of potassium chloride, 0.57 grams of sodium lactate (50% aqueous solution), 0.13 grams of magnesium chloride, 0.036 grams of glucose, 0.0002 grams of glycine, 0.0001 grams of ascorbic acid, 0.10 grams of edetate disodium, 0.030 grams of polyquaternium-42 (33% aqueous solution), and 0.14 grams of sodium chlorite.
9. The osmolality of the solution was measured and adjusted to 280mOsm with sodium chloride.
10. The pH of the solution was measured and adjusted to 7.2 with 1N sodium hydroxide and/or 1N hydrochloric acid.
11. The solution was brought to 1,000.00 g with purified water and mixed for 10 minutes.
12. The solution was filtered using a 0.22 micron filter.
Solution 4D can be prepared as follows:
1. To a 1500ml beaker was added 800 grams of purified water USP.
2. To the above material were added 2g of polysorbate 80 and 10g of polysorbate 20. The solution was mixed until both were completely mixed and dissolved.
3. 0.1g of lemon extract in Aspongopus was added to the above mixture. The solution was mixed until the aspen lemon extract dissolved.
4. The solution was filtered through a 0.45 micron filter and poured back into a 1500ml beaker.
5. To the solution of step 4 was added 1.2 grams of sodium hyaluronate. The solution was mixed to completely dissolve the sodium hyaluronate.
6. To the above solution was added 2.0 kr tamarind kernel polysaccharide. The solution was mixed to completely dissolve the tamarind seed polysaccharide.
7. To the above solution was added 1.98 g of hypromellose E3 Premium. The solution was mixed until the hypromellose E3 Premium was dissolved.
8. The following ingredients were then added in order, dissolved and then added: 2.50 grams of polyethylene glycol 400, 2.50 grams of glycerol, 4.0 grams of boric acid, 0.22 grams of sodium borate, 0.27 grams of disodium phosphate, 4.00 grams of sodium citrate dihydrate, 1 gram of potassium chloride, 0.57 grams of sodium lactate (50% aqueous solution), 0.13 grams of magnesium chloride, 0.036 grams of glucose, 0.0002 grams of glycine, 0.0001 grams of ascorbic acid, 0.10 grams of disodium edetate, 0.015 grams of polyquaternium-42 (33% aqueous solution), and 0.14 grams of sodium chlorite.
9. The osmolality of the solution was measured and adjusted to 280mOsm with sodium chloride.
10. The pH of the solution was measured and adjusted to 7.2 with 1N sodium hydroxide and/or 1N hydrochloric acid.
11. The solution was brought to 1,000.00 g using purified water and mixed for 10 minutes.
12. The solution was filtered using a 0.22 micron hydrophilic filter.
Example 5
Table 3 shows the components of the formulations of the present invention (as shown in formulations 5A and 5B), which can be incorporated as described below using conventional mixing techniques.
TABLE 3
* Can be adjusted to osmotic pressure of 280mOsm/Kg-290mOsm/Kg
* Can be adjusted to pH 7.2
* Optionally, an amount up to 100% w/w%
For examples 5A-5B: sodium hyaluronate can be provided by continro a.s. (DOLNI, DOBROUC, CZECH REPUBLIC).
For examples 5A-5B: aspen lemon extract (Abacross) TM Extract of the fruit of acronychia tangutica) can be provided by southern cross plant, knockrow Nsw, australia.
For examples 5A-5B: polysorbate 20 can be provided by Merck KGaA (DARMSTADT, GERMANY).
For examples 5A-5B: polysorbate 80 may be provided by Merck KGaA (DARMSTADT, GERMANY).
For examples 5A-5B: polyethylene glycol 400 can be provided by Clariant Produkte (Burgkirchen, GERMANY).
For examples 5A-5B: the boronic acid can be provided by Merck KGaA (DARMSTADT, GERMANY).
For examples 5A-5B: sodium borate may be provided by Merck KGaA (DARMSTADT, GERMANY).
For examples 5A-5B: sodium chloride may be supplied by Caldic (DUSSELDORF, GERMANY).
For examples 5A-5B:1N sodium hydroxide can be supplied by VWR (RANDER, PA, USA).
For examples 5A-5B: the 1N hydrochloric acid may be supplied by VWR (RANDER, PA, USA).
For examples 5A-5B: lumuluse GRH-40 can be supplied by VANTAGE (GURNEE, IL, USA).
For examples 5A-5B: ultra refined castor oil may be supplied by CRODA (EDISON, NJ, USA).
For examples 5A-5B: ethyl linoleate can be supplied by SIGMA-ALDRICH (st.
For examples 5A-5B: retinyl palmitate may be supplied from SIGMA-ALDRICH (ST. LOUIS, MO, USA).
For examples 5A-5B: polyquaternium-42 (33% aqueous solution) may be supplied by DSM BIOMEDICAL (BERKELEY, CA, USA).
For example 5B: tamarind seed polysaccharides can be provided by INDENA (MILAN, ITALY).
Solution 5A can be prepared as follows:
1. To a 50ml beaker was added 5.0 grams of Lumulus GRH-40.
2. While mixing, 6.25 grams of ultra-refined castor oil was added.
3. Then 1 gram of ethyl linolenate and 0.5 gram of retinyl palmitate were added and mixed until homogeneous.
4. To a separate 1500ml beaker was added 500 grams of purified water.
5. To the above material were added 2g of polysorbate 80 and 10g of polysorbate 20. The solution was mixed until both were completely dissolved.
6. 0.1g of lemon extract in aspen was added to the above. The solution was mixed until the aspen lemon extract dissolved.
7. The solution was filtered through a 0.45 micron filter and poured back into a 1500ml beaker.
8. To the solution obtained in step 7 was added 2.0 g of sodium hyaluronate. The solution was mixed to completely dissolve the sodium hyaluronate.
9. The following ingredients were then added in order, dissolved and then added: 2.5 grams of polyethylene glycol 400, 6.0 grams of boric acid, 0.06 grams of sodium borate, and grams of polyquaternium-42 (33% aqueous solution).
10. The contents of step 3 were added and mixed using a homogenizer until homogeneous.
11. The osmotic pressure of the formulation was measured and adjusted to 280mOsm/Kg with sodium chloride.
12. The pH of the formulation was adjusted to pH 7.2 using 1N sodium hydroxide and/or 1N hydrochloric acid.
13. The solution was adjusted to 1000.0 grams using purified water USP and mixed for 10 minutes until completely homogeneous.
14. The solution was filtered using a 0.22 micron filter.
Solution 5B can be prepared as follows:
1. To a 50ml beaker was added 5.0 grams of Lumulus GRH-40.
2. While mixing, 6.25 grams of ultra-refined castor oil was added.
3. The homogeneous solution is set aside for future use.
4. To a separate 1500ml beaker was added 500 grams of purified water.
5. To the above material were added 10g of polysorbate 80 and 50g of polysorbate 20. The solution was mixed until both were completely dissolved.
6. 1.0g of lemon extract in aspen was added to the above. The solution was mixed until the aspen lemon extract dissolved.
7. The solution was filtered through a 0.45 micron filter and poured back into a 1500ml beaker.
8. To the solution of step 7 was added 1.0g of sodium hyaluronate. The solution was mixed to completely dissolve the sodium hyaluronate.
9. Next, 2.0 kr tamarind kernel polysaccharide was added. The solution was mixed to completely dissolve the tamarind seed polysaccharide.
10. The following ingredients were then added in order, dissolving each ingredient and then adding the latter: 2.5 grams of polyethylene glycol 400, 6.0 grams of boric acid, 0.06 grams of sodium borate, and 0.045 grams of polyquaternium-42 (33% aqueous solution).
11. The contents of step 3 were added and mixed using a homogenizer until homogeneous.
12. The osmotic pressure of the formulation was measured and adjusted to 280mOsm/Kg with sodium chloride.
13. The pH of the formulation was adjusted to pH 7.2 using 1N sodium hydroxide and/or 1N hydrochloric acid.
14. The solution was adjusted to 1000.0 grams using purified water USP and mixed for 10 minutes until completely homogeneous.
15. The solution was filtered using a 0.22 micron filter.
Example 6
Table 4 shows the components of the formulations of the present invention (as shown in formulations 6A and 6B), which can be incorporated as described below using conventional mixing techniques.
TABLE 4
* Adjusting to osmotic pressure of 280mOsm/Kg-290mOsm/Kg
* Adjusting to pH 7.2
* Moderate to 100 wt/wt%
* (2E, 4E, 6E) -7- (1, 2, 3-hexamethyl-2, 3-dihydro-1H-inden-5-yl) -3-methyloctane-2, 4, 6-trienoic acid
For examples 6A-6B: sodium hyaluronate may be provided by contiro a.s. (DOLNI, DOBROUC, CZECH REPUBLIC).
For example 6A: actinomycete species a5640 extract (IHVR harvested bacterial extract designated IHVR _39565 _f7according to the IHVR harvested nomenclature) can be provided by barcuch s.
For example 6B: compound 1 can be supplied by Sigma-Aldrich.
For examples 6A-6B: polysorbate 20 can be provided by Merck KGaA (DARMSTADT, GERMANY).
For examples 6A-6B: polysorbate 80 may be provided by Merck KGaA (DARMSTADT, GERMANY).
For example 8A: polyethylene glycol 400 can be provided by Clariant Produkte (Burgkirchen, GERMANY).
For examples 6A-6B: boric acid can be provided by Merck KGaA (DARMSTADT, GERMANY).
For examples 6A-6B: sodium borate may be supplied by Merck KGaA (DARMSTADT, GERMANY).
For examples 6A-6B: sodium chloride may be supplied by Caldic (DUSSELDORF, GERMANY).
For examples 6A-6B: potassium chloride can be supplied by Merck KGaA (DARMSTADT, GERMANY).
For examples 6A-6B: calcium chloride dihydrate can be supplied by Merck KGaA (DARMSTADT, germann).
For examples 6A-6B: magnesium chloride may be provided by KGaA (DARMSTADT, GERMANY).
For examples 6A-6B: polyquaternium-42 (33% aqueous solution) may be supplied by DSM BIOMEDICAL (BERKELEY, CA, USA).
For examples 6A-6B: sodium chlorite dihydrate can be supplied by Oxychem (WICHITA, KS, USA).
For examples 6A-6B:1N sodium hydroxide can be supplied by VWR (RANDER, PA, USA).
For examples 6A-6B: the 1N hydrochloric acid may be supplied by VWR (RANDER, PA, USA).
Solution 6A can be prepared as follows:
1. To a 1500ml beaker was added 800 grams of purified water USP.
2. To the above material were added 10g of polysorbate 80 and 100g of polysorbate 20. The solution was mixed until both were completely mixed and dissolved.
3. To the above material was added 50.0g of actinomycete extract. The solution was mixed until the actinomycete extract was dissolved.
4. The solution was filtered through a 0.45 micron filter and poured back into a 1500ml beaker.
5. To the solution of step 4 was added 3.0 grams of sodium hyaluronate. The solution was mixed to completely dissolve the sodium hyaluronate.
6. The following ingredients were then added in order, dissolving each ingredient and then adding the latter: 2.5 grams of polyethylene glycol 400, 6.0 grams of boric acid, 0.05 grams of sodium borate, 1.0 grams of potassium chloride, 0.06 grams of calcium chloride dihydrate, 0.06 grams of magnesium chloride, and 0.0015 grams of polyquaternium-42 (aqueous solution).
7. While mixing was continued, 0.14 grams of sodium chlorite dihydrate was added and mixed until dissolved.
8. The osmotic pressure of the formulation was measured and adjusted to 280mOsm/Kg with sodium chloride.
9. The pH of the formulation was adjusted to pH 7.2 using 1N sodium hydroxide and/or 1N hydrochloric acid.
10. The solution was adjusted to 1000.0 grams using purified water USP and mixed for 10 minutes to complete homogeneity.
11. The solution was filtered using a 0.22 micron filter.
Solution 6B can be prepared as follows:
1. To a 1500ml beaker was added 800 grams of purified water USP.
2. To the above material were added 10g of polysorbate 80 and 75g of polysorbate 20. The solution was mixed until both were completely mixed and dissolved.
3. To the above material was added 50.0g of Compound I. The solution was mixed until compound I was dissolved.
4. The solution was filtered through a 0.45 micron filter and poured back into a 1500ml beaker.
5. To the solution of step 4 was added 1.5 grams of sodium hyaluronate. The solution was mixed to completely dissolve the sodium hyaluronate.
6. The following ingredients were then added in order, dissolved and then added: 6.0 grams boric acid, 0.05 grams sodium borate, 1.0 gram potassium chloride, 0.06 gram calcium chloride dihydrate, 0.06 gram magnesium chloride and 0.0015 gram polyquaternium-42 (aqueous solution).
7. While continuing to mix, 0.14 grams of sodium chlorite dihydrate was added and mixed until dissolved.
8. The osmotic pressure of the formulation was measured and adjusted to 280mOsm/Kg with sodium chloride.
9. The pH of the formulation was adjusted to pH 7.2 using 1N sodium hydroxide and/or 1N hydrochloric acid.
10. The solution was adjusted to 1000.0 grams using purified water USP and mixed for 10 minutes to completely homogenize.
11. The solution was filtered using a 0.22 micron filter.
Example 7
Table 5 shows the components of the formulations of the present invention (as shown in formulations 7A to 7B), which may be incorporated as described below using conventional mixing techniques.
TABLE 5
* Adjusting to osmotic pressure of 280mOsm/Kg-290mOsm/Kg
* Adjusting to pH 7.2
* Moderate to 100.00% volume
*4- (1, 2, 3-hexamethyl-2, 3-dihydro-1H-inden-5-yl) ethenyl) benzoic acid
For examples 7A-7B: sodium hyaluronate may be provided by contiro a.s. (DOLNI, DOBROUC, CZECH REPUBLIC).
For examples 7A-7B: tamarind seed polysaccharides can be provided by INDENA (MILANO, ITALY).
For example 7A: actinomycete species a5640 extract (IHVR harvested bacterial extract labeled IHVR _39565 _f7according to IHVR harvesting nomenclature) can be provided by Baruch s.
For example 7B: compound 2 can be supplied by Sigma-Aldrich.
For examples 7A-7B: polysorbate 20 can be provided by Merck KGaA (DARMSTADT, GERMANY).
For examples 7A-7B: polysorbate 80 may be provided by Merck KGaA (DARMSTADT, GERMANY).
For examples 7A-7B: polyethylene glycol 400 can be provided by Clariant Produkte (Burgkirchen, GERMANY).
For examples 7A-7B: boric acid can be provided by Merck KGaA (DARMSTADT, GERMANY).
For examples 7A-7B: sodium borate may be supplied by Merck KGaA (DARMSTADT, GERMANY).
For examples 7A-7B: sodium chloride may be supplied by Caldic (DUSSELDORF, GERMANY).
For examples 7A-7B: potassium chloride may be supplied by Merck KGaA (DARMSTADT, GERMANY).
For examples 7A-7B: hypromellose E3 2910 may be provided by DOW CHEMICAL (PLAQUEMINE, LOUISIANA, USA).
For examples 7A-7B: glycerol can be supplied by Emery Oleochemicals GmbH (DUSSELDORF, GERMANY).
For examples 7A-7B: disodium phosphate may be supplied by Merck KGaA (DARMSTADT, GERMANY).
For examples 7A-7B: sodium citrate may be supplied by Merck KGaA (DARMSTADT, germann).
For examples 7A-7B: sodium lactate may be provided as sodium lactate (50% aqueous solution) from Merck KGaA (DARMSTADT, GERMANY).
For examples 7A-7B: glucose can be supplied by Roquette Freres (lastem, FRANCE).
For examples 7A-7B: glycine can be supplied by Merck KGaA (DARMSTADT, GERMANY).
For examples 7A-7B: ascorbic acid can be obtained from DSM Nutritional Products (DRAKEMYRE, SCOTLAND, UK).
For examples 7A-7B: polyquaternium 42 may be provided by DSM BIOMEDICAL (BERKELEY, CA) as Polyquaternium 42 (33% aqueous solution).
For examples 7A-7B: disodium edetate may be supplied by Merck NV/SA (OVERIJSE, BELGIUM).
For examples 7A-7B:1N sodium hydroxide can be supplied by VWR (RANDER, PA, USA).
For examples 7A-7B: the 1N hydrochloric acid may be supplied by VWR (RANDER, PA, USA).
For examples 7A-7B: sodium chlorite dihydrate can be supplied by Oxychem (WICHITA, KS, USA).
Solution 7A can be prepared as follows:
1. To a 1500ml beaker was added 800 grams of purified water USP.
2. To the above material were added 10g of polysorbate 80 and 100g of polysorbate 20. The solution was mixed until both were completely mixed and dissolved.
3. To the above material was added 50g of actinomycete extract. The solution was mixed until the actinomycete extract was dissolved.
4. The solution was filtered through a 0.45 micron filter and poured back into a 1500ml beaker.
5. To the solution of step 4 was added 1.2 grams of sodium hyaluronate. The solution was mixed to completely dissolve the sodium hyaluronate.
6. To the above solution was added 2.0 kr tamarind kernel polysaccharide. The solution was mixed to completely dissolve the tamarind seed polysaccharide.
7. To the above solution was added 1.98 g of hypromellose E3 Premium. The solution was mixed until the hypromellose E3 Premium was dissolved.
8. The following ingredients were then added in order, dissolving each ingredient and then adding the latter: 2.50 grams of polyethylene glycol 400, 2.50 grams of glycerol, 4.0 grams of boric acid, 0.22 grams of sodium borate, 0.27 grams of disodium phosphate, 4.00 grams of sodium citrate dihydrate, 1 gram of potassium chloride, 0.57 grams of sodium lactate (50% aqueous solution), 0.13 grams of magnesium chloride, 0.036 grams of glucose, 0.0002 grams of glycine, 0.0001 grams of ascorbic acid, 0.10 grams of edetate disodium, 0.030 grams of polyquaternium-42 (33% aqueous solution), and 0.14 grams of sodium chlorite.
9. The osmolality of the solution was measured and adjusted to 280mOsm with sodium chloride.
10. The pH of the solution was measured and adjusted to 7.2 with 1N sodium hydroxide and/or 1N hydrochloric acid.
11. The solution was brought to 1,000.00 g with purified water and mixed for 10 minutes.
12. The solution was filtered using a 0.22 micron filter.
Solution 7B can be prepared as follows:
1. To a 1500ml beaker was added 800 grams of purified water USP.
2. To the above material were added 10g of polysorbate 80 and 30g of polysorbate 20. The solution was mixed until both were completely mixed and dissolved.
3. To the above material was added 5.0g of Compound I. The solution was mixed until compound I was dissolved.
4. The solution was filtered through a 0.45 micron filter and poured back into a 1500ml beaker.
5. To the solution of step 4 was added 1.2 grams of sodium hyaluronate. The solution was mixed to completely dissolve the sodium hyaluronate.
6. To the above solution was added 2.0 kr tamarind kernel polysaccharide. The solution was mixed to completely dissolve the tamarind seed polysaccharide.
7. To the above solution was added 1.98 g hypromellose E3 Premium. The solution was mixed until hypromellose E3 Premium was dissolved.
8. The following ingredients were then added in order, dissolving each ingredient and then adding the latter: 2.50 grams of polyethylene glycol 400, 2.50 grams of glycerol, 4.0 grams of boric acid, 0.22 grams of sodium borate, 0.27 grams of disodium phosphate, 4.00 grams of sodium citrate dihydrate, 1 gram of potassium chloride, 0.57 grams of sodium lactate (50% aqueous solution), 0.13 grams of magnesium chloride, 0.036 grams of glucose, 0.0002 grams of glycine, 0.0001 grams of ascorbic acid, 0.10 grams of disodium edetate, 0.015 grams of polyquaternium-42 (33% aqueous solution), and 0.14 grams of sodium chlorite.
9. The osmolality of the solution was measured and adjusted to 280mOsm with sodium chloride.
10. The pH of the solution was measured and adjusted to 7.2 with 1N sodium hydroxide and/or 1N hydrochloric acid.
11. The solution was brought to 1,000.00 g with purified water and mixed for 10 minutes.
12. The solution was filtered using a 0.22 micron hydrophilic filter.
Embodiments of the invention:
1. A method for the production/release/delivery/excretion of mucin from and/or in the cornea (optionally, in patients requiring such production/release/delivery/excretion of mucin), the method comprising the step of administering a composition comprising:
i) A safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects for the treatment of dry eye, said compound and/or extract being selected from one or more of the following: a plant extract or source of extract from a plant of the genus acronychia, illicium, marigold, and/or trigonella; a bacterial extract or extract source of the genus actinomycete; and a compound of formula (I):
wherein-
The dotted line represents a single or double bond; optionally one of the dotted lines is a double bond;
R 1 represents H, a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms;
R 2 represents a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms; optionally methyl (-CH) 3 ) Or methylene (= CH) 2 ) A moiety; containing 1 to 20 carbon atoms, optionally 1 to 10 carbon atoms; optionally a linear, cyclic or branched, saturated or unsaturated carbonising chain of 6 carbon atoms; optionally an aromatic moiety, optionally a phenyl moiety; optionally 2-methylpropan-1, 3-diene; and
ii) optionally, an ophthalmically acceptable carrier.
2. The method of embodiment 1 (or any of the following embodiments), wherein the compound and/or extract having retinol-like properties and/or beneficial effects is a plant extract or extract source from acronychia and/or pistia plants.
3. The method according to embodiments 1 and/or 2 (or any of the following embodiments), wherein the compound and/or extract having retinol-like properties and/or beneficial effects is a plant extract or extract source from a plant of the acronychia genus.
4. The method of any one or combination of embodiments 1-3 (or any one of the following embodiments), wherein the plant extract or extract source from a acronychia plant is selected from the group consisting of: acronychia berrans, acronychia Acronychia, acronychia acronycis, acronychia acuminates, acronychia bauerelini, acronychia choorehillum, elaeis crassa, acronychia euglena, acronychia annus, acronychia impedorate, acronychia laevisis, acronychia laurifolia, acronychia littoralis, populus alba, acronhia octandra, acronychia parviflora, acronhia pauciflora, acronychia pedunculata, acronychia pubescens, acronychia glabra species (Batavirus), acronhia sudosa, acronhiconospora stita, acronychia oxyphylla, and combinations of two or more thereof.
5. The method of any one or combination of embodiments 1-4 (or any one of the following embodiments), wherein the plant extract or extract source from a acronychia plant is acronychia pedunculata.
6. The method of any one or combination of embodiments 1-5 (or any one of the following embodiments), wherein the plant extract of acronychia and/or pistia comprises from about 1% to about 20%, by weight of the extract, of the compound of formula II
Wherein:
R 1 selected from the group consisting of: c 1 -C 20 Alkyl radical, C 2 -C 20 Alkenyl radical, C 2 -C 20 Alkynyl and C 3 -C 8 Cycloalkyl or aryl;
R 2 selected from the group consisting of: hydrogen, hydroxy, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl or aryl, -OC 1 -C 6 Alkyl, -OC 2 -C 6 Alkenyl, -OC 2 -C 6 Alkynyl, -OC 3 -C 8 Cycloalkyl or aryl, thiols, -SC 1 -C 6 Alkyl, -SC 2 -C 6 Alkenyl, -SC 2 -C 6 Alkynyl, -SC 3 -C 8 Cycloalkyl or aryl, -NR 4 C 1 -C 6 Alkyl, -NR 4 C 2 -C 6 Alkenyl, -NR 4 C 2 -C 6 Alkynyl and-NR 4 C 3 -C 8 Cycloalkyl or aryl;
R 3 selected from-CO 2 H、-CO 2 R 4 Or isosteric equivalents of carboxyl groups wherein R 4 Is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 3 -C 8 Cycloalkyl or aryl; and is
Y is- (CH) 2 -CH 2 ) -, - (CH 9552; CH) -or- (C.ident.C) -.
7. The method of any one or combination of embodiments 1-6 (or any one of the following embodiments), wherein the plant extract of acronychia and/or pistia comprises from about 1% to about 20%, by weight of the extract, of the compound of formula II
Wherein:
R 1 selected from the group consisting of: c 5 -C 16 Alkyl radical, C 5 -C 16 Alkenyl and C 5 -C 16 Alkynyl, more preferably C 5 -C 16 Alkenyl groups including, for example, farnesyl;
R 2 selected from the group consisting of: hydrogen, hydroxy, -OC 1 -C 6 Alkyl, -OC 2 -C 6 Alkenyl, -OC 2 -C 6 Alkynyl, -OC 3 -C 8 Cycloalkyl, more preferably hydrogen, hydroxy, -OC 1 -C 6 Alkyl, even more preferably hydrogen or-OC 1 -C 3 An alkyl group;
R 3 is selected from-CO 2 H、-CO 2 R 4 Wherein R is 4 Is C 1 -C 6 An isosteric equivalent of an alkyl, or carboxyl group; and is
Y is- (CH) 2 -CH 2 ) -or- (CH \9552; CH) -.
8. The method of any one or combination of embodiments 1-7 (or any one of the following embodiments), wherein the compound of formula (II) is in the form of an acid or alkyl ester selected from the group consisting of 3- (4-farnesyloxyphenyl) -propionic acid, 3- (4-farnesyloxy-3-hydroxyphenyl) -propionic acid, 3- (4-farnesyloxy-3-methoxyphenyl) -propionic acid, alkyl esters thereof, and combinations of two or more thereof.
9. The method of any one or combination of embodiments 1-8 (or any one of the following embodiments), wherein the compound of formula II useful in the invention is 3- (4-farnesyloxyphenyl) -propionic acid and/or the ethyl ester thereof.
10. The method of any one or combination of embodiments 1-9 (or any one of the following embodiments), wherein the compound and/or extract having retinol-like properties and/or beneficial effects is a plant extract or extract source from a plant of the genus cinnamomum.
11. The method of any one or combination of embodiments 1-10 (or any one of the following embodiments), wherein the plant extract or extract source from a plant of the genus cinnamomum kotoense is selected from the group consisting of: licaria verniciosa, licaria brittoniana, licaria canella, licaria cubensis, licaria velutina, and Licaria triandra, and combinations of two or more thereof.
12. The method of any one or combination of embodiments 1-11 (or any one of the following embodiments), wherein the plant extract or extract source from a plant of the genus cinnamomum is Licaria vernicosa.
13. The method of any one or combination of embodiments 1-12 (or any one of the following embodiments), wherein the compound and/or extract having retinol-like properties and/or beneficial effects is a bacterial extract or extract source of the genus actinomycete.
14. The method of any one or combination of embodiments 1-13 (or any one of the following embodiments), wherein the compound and/or extract having retinol-like properties and/or beneficial effects is a bacterial extract or extract source of actinomycete species a 5640.
15. The method according to any one or combination of embodiments 1-14 (or any one of the following embodiments), wherein the compound and/or extract having retinol-like properties and/or beneficial effects comprises a compound of formula (I):
wherein-
The dotted line represents a single or double bond; optionally one of the dotted lines is a double bond;
R 1 represents H, a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms;
R 2 represents a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms; a linear, cyclic or branched, saturated or unsaturated carbonising chain containing from 1 to 20 carbon atoms.
16. <xnotran> 1 15 ( ) , I (2E,4E,6E) -7- (1,1,2,2,3,3- -2,3- -1H- -5- ) -3- -2,4,6- 4- (1- (1,1,2,2,3,3- -2,3- -1H- -5- ) ) , . </xnotran>
17. A method for maintaining a concentration of MU5AC in tear fluid in the range of equal to or greater than 8 ng/mg protein to 15 ng/mg protein (optionally in a patient in need of such maintenance), comprising the step of administering a composition comprising:
i) A safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects for the treatment of dry eye, said compound and/or extract being selected from one or more of the following: a plant extract or extract source from a plant of the genus acronychia, pistia, marigold, and/or trigonella; a bacterial extract or extract source of the genus actinomyces; and a compound of formula (I):
wherein-
The dotted line represents a single or double bond;
R 1 represents H, a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms;
R 2 represents a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms; preferably methyl (-CH) 3 ) Or methylene (= CH) 2 ) A moiety;
a represents a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms; and
ii) optionally, an ophthalmically acceptable carrier.
18. A method for treating a patient suffering from reduced or low levels of production/release/delivery/excretion of mucin from and/or in the cornea, comprising the step of topically administering to the eye of the patient a composition comprising:
i) A safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects for the treatment of dry eye, said compound and/or extract being selected from one or more of the following: a plant extract or extract source from a plant of the genus acronychia, pistia, marigold, and/or trigonella; a bacterial extract or extract source of the genus actinomycete; and a compound of formula (I):
wherein-
The dotted line represents a single or double bond; preferably one of the dotted lines is a double bond;
R 1 represents H, a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms;
R 2 represents a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms; preferably methyl (-CH) 3 ) Or methylene (= CH) 2 ) A moiety;
a represents a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably 6 carbon atoms; preferably an aromatic moiety, preferably a phenyl moiety; preferably 2-methylpropan-1, 3-diene,
ii) optionally, an ophthalmically acceptable carrier.
19. A method for preventing or treating symptoms associated with dry eye, comprising the step of topically administering (optionally, in a patient in need of such prevention or treatment) a composition comprising:
i) A safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects for the treatment of dry eye, said compound and/or extract selected from one or more of the following: a plant extract or source of extract from a plant of the genus acronychia, illicium, marigold, and/or trigonella; a bacterial extract or extract source of the genus actinomyces; and a compound of formula (I):
wherein-
The dotted line represents a single or double bond; preferably one of the dotted lines is a double bond;
R 1 represents H, a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms;
R 2 represents a linear, cyclic or branched, saturated or unsaturated carbonising chain containing from 1 to 20 carbon atoms; preferably methyl (-CH) 3 ) Or methylene (= CH) 2 ) A moiety;
a represents a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably 6 carbon atoms; preferably an aromatic moiety, preferably a phenyl moiety; preferably 2-methylpropan-1, 3-diene;
ii) one or more demulcents or soothing agents; and
iii) Optionally, an ophthalmically acceptable carrier.
20. A method for promoting healing or increasing the rate of healing of a wound in and/or on the eye (optionally, of a patient in need of such promotion of healing or increase in the rate of healing), comprising the step of administering a composition comprising:
i) A safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects for the treatment of dry eye, said compound and/or extract being selected from one or more of the following: a plant extract or source of extract from a plant of the genus acronychia, illicium, marigold, and/or trigonella; a bacterial extract or extract source of the genus actinomycete; and a compound of formula (I):
wherein-
The dotted line represents a single or double bond; preferably one of the dotted lines is a double bond;
R 1 represents H, a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms;
R 2 represents a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms; preferably methyl (-CH) 3 ) Or methylene (= CH) 2 ) A moiety;
a represents a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably 6 carbon atoms; preferably an aromatic moiety, preferably a phenyl moiety; preferably 2-methylpropan-1, 3-diene,
ii) optionally, an ophthalmically acceptable carrier.
21. A method for improving antimicrobial properties in tear fluid (optionally, tear fluid of a patient in need of such improved tear properties), comprising the step of administering a composition comprising:
i) A safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects for the treatment of dry eye, said compound and/or extract being selected from one or more of the following: a plant extract or extract source from a plant of the genus acronychia, pistia, marigold, and/or trigonella; a bacterial extract or extract source of the genus actinomycete; and a compound of formula (I):
wherein-
The dotted line represents a single or double bond; preferably one of the dotted lines is a double bond;
R 1 represents H, straight, cyclic or branched chain saturated containing from 1 to 20 carbon atoms
Or an unsaturated carbonising chain;
R 2 represents a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms; preferably methyl (-CH) 3 ) Or methylene (= CH) 2 ) A moiety;
a represents a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably 6 carbon atoms; preferably an aromatic moiety, preferably a phenyl moiety; preferably 2-methylpropan-1, 3-diene,
ii) optionally, an ophthalmically acceptable carrier.
Claims (16)
1. Use of a safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects in the manufacture of a composition for the treatment of dry eye by production/release/delivery/excretion of mucin from and/or in the cornea, wherein said compound and/or extract is selected from one or more of the following: a plant extract or extract source from a plant of the genus cinnamomum, calendula and/or trigonella; a bacterial extract or extract source of the genus actinomyces; and a compound of formula (I):
wherein-
The dotted line represents a single or double bond; optionally one of the dotted lines is a double bond;
R 1 represents H, a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms;
R 2 represents a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms; optionally methyl (-CH) 3 ) Or methylene (= CH) 2 ) A moiety; a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms, optionally from 1 to 10 carbon atoms, optionally 6 carbon atoms; optionally an aromatic moiety, optionally a phenyl moiety; optionally 2-methylpropan-1, 3-diene; and
wherein the composition optionally comprises an ophthalmically acceptable carrier.
2. The use of claim 1, wherein the plant extract of genus litsea comprises from about 1% to about 20%, by weight of the extract, of the compound of formula II
Wherein:
R 1 selected from the group consisting of: c 1 -C 20 Alkyl radical, C 2 -C 20 Alkenyl radical, C 2 -C 20 Alkynyl and C 3 -C 8 Cycloalkyl or aryl;
R 2 selected from the group consisting of: hydrogen, hydroxy, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl or aryl, -OC 1 -C 6 Alkyl, -OC 2 -C 6 Alkenyl, -OC 2 -C 6 Alkynyl, -OC 3 -C 8 Cycloalkyl or aryl, thiols, -SC 1 -C 6 Alkyl, -SC 2 -C 6 Alkenyl, -SC 2 -C 6 Alkynyl, -SC 3 -C 8 Cycloalkyl or aryl, -NR 4 C 1 -C 6 Alkyl, -NR 4 C 2 -C 6 Alkenyl, -NR 4 C 2 -C 6 Alkynyl and-NR 4 C 3 -C 8 Cycloalkyl or aryl;
R 3 is selected from-CO 2 H、-CO 2 R 4 Or isosteric equivalents of carboxyl groups wherein R 4 Is C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 3 -C 8 Cycloalkyl or aryl; and is provided with
Y is- (CH) 2 —CH 2 ) -, - (CH \9552; CH) -or- (C.ident.C) -.
3. The use of claim 2, wherein the plant extract of genus litsea comprises from about 1% to about 20%, by weight of the extract, of the compound of formula II
Wherein:
R 1 selected from the group consisting of: c 5 -C 16 Alkyl radical, C 5 -C 16 Alkenyl and C 5 -C 16 Alkynyl, more preferably C 5 -C 16 Alkenyl groups including, for example, farnesyl;
R 2 selected from the group consisting of: hydrogen, hydroxy, -OC 1 -C 6 Alkyl, -OC 2 -C 6 Alkenyl, -OC 2 -C 6 Alkynyl, -OC 3 -C 8 Cycloalkyl, more preferably hydrogen, hydroxy, -OC 1 -C 6 Alkyl, even more preferably hydrogen or-OC 1 -C 3 An alkyl group;
R 3 selected from-CO 2 H、-CO 2 R 4 Wherein R is 4 Is C 1 -C 6 An isosteric equivalent of an alkyl, or carboxyl group; and is
Y is- (CH) 2 -CH 2 ) -or- (CH \9552; CH) -.
4. The use of claim 3, wherein the compound of formula (II) is in the form of an acid or alkyl ester selected from the group consisting of 3- (4-farnesyloxyphenyl) -propionic acid, 3- (4-farnesyloxy-3-hydroxyphenyl) -propionic acid, 3- (4-farnesyloxy-3-methoxyphenyl) -propionic acid, alkyl esters thereof, and combinations of two or more thereof.
5. Use according to claim 4, wherein the compound of formula II useful in the present invention is 3- (4-farnesyloxyphenyl) -propionic acid and/or the ethyl ester thereof.
6. Use according to claim 1, wherein the compound and/or extract having retinol-like properties and/or beneficial effects is a plant extract or extract source from plants of the genus cinnamomum.
7. The use according to claim 6, wherein the plant extract or extract source from plants of the genus Litsea is selected from the group consisting of:Licaria vernicosa、Licaria brittoniana、Licaria canella、Licaria cubensis、Licaria velutinaandLicaria triandraand combinations of two or more thereof.
8. The use of claim 6, wherein the plant extract or extract source from a plant of the genus Lithospermum isLicaria vernicosa。
9. Use according to claim 1, wherein the compound and/or extract having retinol-like properties and/or beneficial effects is a bacterial extract or extract source of said actinomycete genus.
10. Use according to claim 9, wherein the compound and/or extract having retinol-like properties and/or beneficial effects is a bacterial extract or extract source of actinomycete species a 5640.
11. Use according to claim 1, wherein said compound and/or extract having retinol-like properties and/or beneficial effects comprises a compound of formula (I):
wherein-
The dotted line represents a single or double bond; optionally, one of the dotted lines is a double bond;
R 1 represents H, a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms;
R 2 represents a linear, cyclic or branched, saturated or unsaturated carbonising chain containing from 1 to 20 carbon atoms; a linear, cyclic or branched, saturated or unsaturated carbonising chain containing from 1 to 20 carbon atoms.
12. <xnotran> 11 , I (2E,4E,6E) -7- (1,1,2,2,3,3- -2,3- -1H- -5- ) -3- -2,4,6- 4- (1- (1,1,2,2,3,3- -2,3- -1H- -5- ) ) , . </xnotran>
13. Use of a safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects in the manufacture of a composition for maintaining the concentration of MU5AC in tear fluid in the range of equal to or more than 8 ng/mg protein to 15 ng/mg protein, wherein said compound and/or extract is selected from one or more of the following: a plant extract or extract source from a plant of the genus cinnamomum, calendula and/or trigonella; a bacterial extract or extract source of the genus actinomycete; and a compound of formula (I):
wherein-
The dotted line represents a single or double bond;
R 1 represents H, a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms;
R 2 represents a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms; preferably methyl (-CH) 3 ) Or methylene (= CH) 2 ) A moiety;
a represents a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms; and
wherein the composition optionally comprises an ophthalmically acceptable carrier.
14. Use of a safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects in the preparation of a composition for the treatment of dry eye in a patient suffering from reduced or low level of production/release/delivery/excretion of mucin from and/or in the cornea, wherein said compound and/or extract is selected from one or more of the following: a plant extract or extract source from a plant of the genus cinnamomum, calendula and/or trigonella; a bacterial extract or extract source of the genus actinomycete; and a compound of formula (I):
wherein-
The dotted line represents a single or double bond; preferably one of the dotted lines is a double bond;
R 1 represents H, a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms;
R 2 represents a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms; preferably methyl (-CH) 3 ) Or methylene (= CH) 2 ) A moiety;
a represents a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably 6 carbon atoms; preferably an aromatic moiety, preferably a phenyl moiety; preferably 2-methylpropan-1, 3-diene; and wherein the composition optionally comprises an ophthalmically acceptable carrier.
15. Use of a safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects in the manufacture of a composition for promoting wound healing or increasing the rate of healing in and/or on the eye of a patient, wherein said compound and/or extract is selected from one or more of the following: a plant extract or extract source from a plant of the genus cinnamomum, calendula and/or trigonella; a bacterial extract or extract source of the genus actinomycete; and a compound of formula (I):
wherein-
The dotted line represents a single or double bond; preferably one of the dotted lines is a double bond;
R 1 represents H, a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms;
R 2 represents a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms; preferably methyl (-CH) 3 ) Or methylene (= CH) 2 ) A moiety;
a represents a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably 6 carbon atoms; preferably an aromatic moiety, preferably a phenyl moiety; preferably 2-methylpropan-1, 3-diene; and wherein the composition optionally comprises an ophthalmically acceptable carrier.
16. Use of a safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects in the manufacture of a composition for improving antimicrobial properties in the tear fluid of a patient, wherein said compound and/or extract is selected from one or more of the following: a plant extract or extract source from a plant of the genus cinnamomum, calendula and/or trigonella; a bacterial extract or extract source of the genus actinomycete; and a compound of formula (I):
wherein-
The dotted line represents a single or double bond; preferably one of the dotted lines is a double bond;
R 1 represents H, a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms;
R 2 represents a linear, cyclic or branched, saturated or unsaturated carbonising chain comprising from 1 to 20 carbon atoms; preferably methyl (-CH) 3 ) Or methylene (= CH) 2 ) A moiety;
a represents a linear, cyclic or branched, saturated or unsaturated, carbonising chain comprising from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably 6 carbon atoms; preferably an aromatic moiety, preferably a phenyl moiety; preferably 2-methylpropan-1, 3-diene; and wherein the composition optionally comprises an ophthalmically acceptable carrier.
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862703943P | 2018-07-27 | 2018-07-27 | |
US62/703943 | 2018-07-27 | ||
US16/519166 | 2019-07-23 | ||
US16/519,166 US10966948B2 (en) | 2019-07-23 | 2019-07-23 | Compositions and methods for treating the eye |
PCT/IB2019/056344 WO2020021480A2 (en) | 2018-07-27 | 2019-07-24 | Compositions and methods for treating the eye |
CN201980050097.8A CN112888450A (en) | 2018-07-27 | 2019-07-24 | Compositions and methods for treating the eye |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980050097.8A Division CN112888450A (en) | 2018-07-27 | 2019-07-24 | Compositions and methods for treating the eye |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115671090A true CN115671090A (en) | 2023-02-03 |
Family
ID=68051851
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980050097.8A Pending CN112888450A (en) | 2018-07-27 | 2019-07-24 | Compositions and methods for treating the eye |
CN202211161743.8A Pending CN115671090A (en) | 2018-07-27 | 2019-07-24 | Compositions and methods for treating the eye |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980050097.8A Pending CN112888450A (en) | 2018-07-27 | 2019-07-24 | Compositions and methods for treating the eye |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP3829614A2 (en) |
JP (1) | JP7374987B2 (en) |
KR (1) | KR20210038635A (en) |
CN (2) | CN112888450A (en) |
AU (1) | AU2019311848A1 (en) |
BR (1) | BR112021001092A2 (en) |
CA (1) | CA3107726A1 (en) |
WO (1) | WO2020021480A2 (en) |
ZA (1) | ZA202101342B (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA3107707A1 (en) | 2018-07-27 | 2020-01-30 | Johnson & Johnson Surgical Vision, Inc. | Compositions and methods for treating the eye |
US11197841B2 (en) | 2019-07-23 | 2021-12-14 | Johnson & Johnson Surgical Vision, Inc. | Compositions and methods for treating the eye |
US10966948B2 (en) | 2019-07-23 | 2021-04-06 | Johnson & Johnson Surgical Vision, Inc. | Compositions and methods for treating the eye |
EP3824895A1 (en) * | 2019-11-19 | 2021-05-26 | Johnson & Johnson Consumer Inc. | Compositions and methods for treating the eye |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USD435966S1 (en) | 1999-01-29 | 2001-01-09 | Johnson & Johnson Vision Care, Inc. | Contact lens container |
US7442391B2 (en) | 2002-01-25 | 2008-10-28 | Integrated Botanical Technologies, Llc | Bioactive botanical cosmetic compositions and processes for their production |
US20030165545A1 (en) | 2002-01-30 | 2003-09-04 | Allergan, Inc. | Ophthalmic compositions including oil-in-water emulsions, and methods for making and using same |
EP2491939B1 (en) | 2004-01-12 | 2017-09-20 | ISP Investments LLC | Bioactive compositions from theacea plants and processes for their production and use |
WO2007098471A2 (en) | 2006-02-21 | 2007-08-30 | Integrated Botanical Technologies, Llc | Parthenolide free bioactive ingredients from feverfew (tanacetum parthenium) and processes for their production |
WO2010071941A1 (en) | 2008-12-24 | 2010-07-01 | Ecobiotics Ltd | Plant extracts from acronychia species and their use |
US9480645B2 (en) | 2009-06-02 | 2016-11-01 | Abbott Medical Optics Inc. | Omega-3 oil containing ophthalmic emulsions |
US20100305046A1 (en) | 2009-06-02 | 2010-12-02 | Abbott Medical Optics Inc. | Stable cyclosporine containing ophthalmic emulsion for treating dry eyes |
MY172185A (en) | 2009-06-05 | 2019-11-15 | Allergan Inc | Artificial tears and therapeutic uses |
AU2018341099B2 (en) | 2017-09-28 | 2023-11-02 | Johnson & Johnson Consumer Inc. | Cosmetic compositions and method of treating the skin |
CA3107707A1 (en) | 2018-07-27 | 2020-01-30 | Johnson & Johnson Surgical Vision, Inc. | Compositions and methods for treating the eye |
-
2019
- 2019-07-24 BR BR112021001092-0A patent/BR112021001092A2/en unknown
- 2019-07-24 CA CA3107726A patent/CA3107726A1/en active Pending
- 2019-07-24 KR KR1020217005786A patent/KR20210038635A/en unknown
- 2019-07-24 WO PCT/IB2019/056344 patent/WO2020021480A2/en active Application Filing
- 2019-07-24 AU AU2019311848A patent/AU2019311848A1/en active Pending
- 2019-07-24 CN CN201980050097.8A patent/CN112888450A/en active Pending
- 2019-07-24 EP EP19773527.7A patent/EP3829614A2/en active Pending
- 2019-07-24 CN CN202211161743.8A patent/CN115671090A/en active Pending
- 2019-07-24 JP JP2021504364A patent/JP7374987B2/en active Active
-
2021
- 2021-02-26 ZA ZA2021/01342A patent/ZA202101342B/en unknown
Non-Patent Citations (2)
Title |
---|
AKITO ODAKA等: "Efficacy of retinol palmitate eye drops for dry eye in rabbits with lacrimal gland resection.", CLINICAL OPHTHALMOLOGY, pages 1585 - 1593 * |
SHIZUKA KOH等: "Clinical utility of 3% diquafosol ophthalmic solution in the treatment of dry eyes.", CLINICAL OPHTHALMOLOGY, pages 865 - 872 * |
Also Published As
Publication number | Publication date |
---|---|
CA3107726A1 (en) | 2020-01-30 |
WO2020021480A3 (en) | 2020-04-30 |
KR20210038635A (en) | 2021-04-07 |
CN112888450A (en) | 2021-06-01 |
EP3829614A2 (en) | 2021-06-09 |
ZA202101342B (en) | 2023-03-29 |
WO2020021480A2 (en) | 2020-01-30 |
JP7374987B2 (en) | 2023-11-07 |
AU2019311848A1 (en) | 2021-01-21 |
BR112021001092A2 (en) | 2021-04-20 |
JP2021533096A (en) | 2021-12-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11931331B2 (en) | Compositions and methods for treating the eye | |
CN115671090A (en) | Compositions and methods for treating the eye | |
EP3824895A1 (en) | Compositions and methods for treating the eye | |
US11806327B2 (en) | Compositions and methods for treating the eye | |
CN112654359A (en) | Compositions and methods for treating the eye | |
CN112930189A (en) | Compositions and methods for treating the eye | |
US11197841B2 (en) | Compositions and methods for treating the eye | |
CN112933118A (en) | Compositions and methods for treating the eye | |
AU2022246418B2 (en) | Compositions and methods for treating the eye | |
US11969454B2 (en) | Compositions and methods for treating the eye | |
RU2802365C2 (en) | Compositions and methods of treating eye disorders | |
RU2806301C2 (en) | Compositions and methods for treating eye disorders | |
US20210145916A1 (en) | Compositions and Methods for Treating the Eye | |
RU2802625C2 (en) | Compositions and methods of treating eye disorders | |
EP3824877A1 (en) | Compositions and methods for treating the eye | |
US11969451B2 (en) | Compositions and methods for treating the eye | |
US20210145909A1 (en) | Compositions and Methods for Treating the Eye |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |