JP5668476B2 - カルシニューリン阻害剤またはmTOR阻害剤を含む眼科用組成物 - Google Patents
カルシニューリン阻害剤またはmTOR阻害剤を含む眼科用組成物 Download PDFInfo
- Publication number
- JP5668476B2 JP5668476B2 JP2010528993A JP2010528993A JP5668476B2 JP 5668476 B2 JP5668476 B2 JP 5668476B2 JP 2010528993 A JP2010528993 A JP 2010528993A JP 2010528993 A JP2010528993 A JP 2010528993A JP 5668476 B2 JP5668476 B2 JP 5668476B2
- Authority
- JP
- Japan
- Prior art keywords
- voclosporin
- pharmaceutical composition
- composition
- eye
- octoxynol
- 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.)
- Active
Links
- 239000000203 mixture Substances 0.000 title claims description 342
- 229940122739 Calcineurin inhibitor Drugs 0.000 title claims description 48
- 101710192106 Calcineurin-binding protein cabin-1 Proteins 0.000 title claims description 46
- 102100024123 Calcineurin-binding protein cabin-1 Human genes 0.000 title claims description 46
- 229940124302 mTOR inhibitor Drugs 0.000 title claims description 37
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 title claims description 37
- 229960005289 voclosporin Drugs 0.000 claims description 151
- 239000000693 micelle Substances 0.000 claims description 138
- BICRTLVBTLFLRD-PTWUADNWSA-N voclosporin Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C=C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O BICRTLVBTLFLRD-PTWUADNWSA-N 0.000 claims description 127
- 108010057559 voclosporin Proteins 0.000 claims description 124
- 229920004914 octoxynol-40 Polymers 0.000 claims description 53
- 239000000243 solution Substances 0.000 claims description 47
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 43
- 239000008194 pharmaceutical composition Substances 0.000 claims description 43
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 claims description 38
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 38
- 230000000699 topical effect Effects 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 31
- 229920000642 polymer Polymers 0.000 claims description 31
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 29
- 108010036949 Cyclosporine Proteins 0.000 claims description 25
- 239000000463 material Substances 0.000 claims description 25
- 206010023332 keratitis Diseases 0.000 claims description 21
- 239000002202 Polyethylene glycol Substances 0.000 claims description 20
- 229920001223 polyethylene glycol Polymers 0.000 claims description 20
- 229960001265 ciclosporin Drugs 0.000 claims description 19
- 208000024891 symptom Diseases 0.000 claims description 19
- 229930105110 Cyclosporin A Natural products 0.000 claims description 18
- 239000007864 aqueous solution Substances 0.000 claims description 18
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims description 18
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims description 18
- 229960002930 sirolimus Drugs 0.000 claims description 18
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 claims description 17
- 229930003427 Vitamin E Natural products 0.000 claims description 16
- 239000000227 bioadhesive Substances 0.000 claims description 16
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 16
- 239000011709 vitamin E Substances 0.000 claims description 16
- 229940046009 vitamin E Drugs 0.000 claims description 16
- 235000019165 vitamin E Nutrition 0.000 claims description 16
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 15
- 208000030533 eye disease Diseases 0.000 claims description 15
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 15
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 15
- 201000010666 keratoconjunctivitis Diseases 0.000 claims description 15
- 208000002780 macular degeneration Diseases 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 claims description 14
- 229960001967 tacrolimus Drugs 0.000 claims description 14
- 206010046851 Uveitis Diseases 0.000 claims description 12
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 12
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims description 11
- 206010013774 Dry eye Diseases 0.000 claims description 11
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 claims description 11
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 claims description 11
- 208000035475 disorder Diseases 0.000 claims description 11
- 229930003799 tocopherol Natural products 0.000 claims description 11
- 235000010384 tocopherol Nutrition 0.000 claims description 11
- 229960001295 tocopherol Drugs 0.000 claims description 11
- 239000011732 tocopherol Substances 0.000 claims description 11
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 10
- 206010010741 Conjunctivitis Diseases 0.000 claims description 9
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 9
- 229960005330 pimecrolimus Drugs 0.000 claims description 9
- KASDHRXLYQOAKZ-ZPSXYTITSA-N pimecrolimus Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](Cl)[C@H](OC)C1 KASDHRXLYQOAKZ-ZPSXYTITSA-N 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 230000002757 inflammatory effect Effects 0.000 claims description 8
- 239000003112 inhibitor Substances 0.000 claims description 8
- 208000023275 Autoimmune disease Diseases 0.000 claims description 7
- 206010012688 Diabetic retinal oedema Diseases 0.000 claims description 7
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 7
- 229920000148 Polycarbophil calcium Polymers 0.000 claims description 7
- 201000011190 diabetic macular edema Diseases 0.000 claims description 7
- 238000001704 evaporation Methods 0.000 claims description 7
- 229950005134 polycarbophil Drugs 0.000 claims description 7
- 208000002691 Choroiditis Diseases 0.000 claims description 6
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 claims description 6
- 208000003971 Posterior uveitis Diseases 0.000 claims description 6
- 229960005167 everolimus Drugs 0.000 claims description 6
- 230000000887 hydrating effect Effects 0.000 claims description 6
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 5
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 claims description 5
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 5
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 5
- 206010069664 atopic keratoconjunctivitis Diseases 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 229960000235 temsirolimus Drugs 0.000 claims description 5
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 claims description 5
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 claims description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 206010039705 Scleritis Diseases 0.000 claims description 3
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 3
- 208000010217 blepharitis Diseases 0.000 claims description 3
- 230000005764 inhibitory process Effects 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 208000023715 Ocular surface disease Diseases 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims description 2
- GZCGUPFRVQAUEE-KCDKBNATSA-N aldehydo-D-galactose Chemical compound OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-KCDKBNATSA-N 0.000 claims 1
- 238000009472 formulation Methods 0.000 description 155
- 210000001508 eye Anatomy 0.000 description 109
- 210000001519 tissue Anatomy 0.000 description 69
- 239000003814 drug Substances 0.000 description 64
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 63
- 229940079593 drug Drugs 0.000 description 62
- 239000004094 surface-active agent Substances 0.000 description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 238000012360 testing method Methods 0.000 description 30
- 241000283973 Oryctolagus cuniculus Species 0.000 description 28
- 238000010494 dissociation reaction Methods 0.000 description 28
- 230000005593 dissociations Effects 0.000 description 27
- 201000010099 disease Diseases 0.000 description 26
- 239000000607 artificial tear Substances 0.000 description 25
- 210000001525 retina Anatomy 0.000 description 22
- 238000011282 treatment Methods 0.000 description 21
- 210000004087 cornea Anatomy 0.000 description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- 239000012528 membrane Substances 0.000 description 16
- 238000011587 new zealand white rabbit Methods 0.000 description 16
- 235000000346 sugar Nutrition 0.000 description 16
- 102000004631 Calcineurin Human genes 0.000 description 15
- 108010042955 Calcineurin Proteins 0.000 description 15
- 210000000795 conjunctiva Anatomy 0.000 description 15
- 239000000546 pharmaceutical excipient Substances 0.000 description 15
- 235000002639 sodium chloride Nutrition 0.000 description 15
- 238000010790 dilution Methods 0.000 description 14
- 239000012895 dilution Substances 0.000 description 14
- 241001465754 Metazoa Species 0.000 description 13
- 238000002835 absorbance Methods 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000872 buffer Substances 0.000 description 12
- 239000006196 drop Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 239000012530 fluid Substances 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 239000008367 deionised water Substances 0.000 description 11
- 229910021641 deionized water Inorganic materials 0.000 description 11
- 230000004054 inflammatory process Effects 0.000 description 11
- 210000004379 membrane Anatomy 0.000 description 11
- 239000010409 thin film Substances 0.000 description 11
- 206010061218 Inflammation Diseases 0.000 description 10
- 230000006378 damage Effects 0.000 description 10
- 238000011156 evaluation Methods 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 201000004569 Blindness Diseases 0.000 description 9
- 210000001742 aqueous humor Anatomy 0.000 description 9
- 229940046731 calcineurin inhibitors Drugs 0.000 description 9
- 210000003161 choroid Anatomy 0.000 description 9
- 210000000744 eyelid Anatomy 0.000 description 9
- 210000000554 iris Anatomy 0.000 description 9
- 230000008929 regeneration Effects 0.000 description 9
- 238000011069 regeneration method Methods 0.000 description 9
- 210000003786 sclera Anatomy 0.000 description 9
- 239000001488 sodium phosphate Substances 0.000 description 9
- 241000282472 Canis lupus familiaris Species 0.000 description 8
- ZDQSOHOQTUFQEM-NURRSENYSA-N ascomycin Chemical group C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](O)[C@H](OC)C1 ZDQSOHOQTUFQEM-NURRSENYSA-N 0.000 description 8
- 229930182912 cyclosporin Natural products 0.000 description 8
- 238000009826 distribution Methods 0.000 description 8
- 230000004410 intraocular pressure Effects 0.000 description 8
- 239000007951 isotonicity adjuster Substances 0.000 description 8
- 210000004561 lacrimal apparatus Anatomy 0.000 description 8
- 210000001328 optic nerve Anatomy 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 206010025421 Macule Diseases 0.000 description 7
- 239000004677 Nylon Substances 0.000 description 7
- 210000004204 blood vessel Anatomy 0.000 description 7
- 239000007853 buffer solution Substances 0.000 description 7
- 229920001778 nylon Polymers 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000003755 preservative agent Substances 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 241000701022 Cytomegalovirus Species 0.000 description 6
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 6
- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 description 6
- 206010038934 Retinopathy proliferative Diseases 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 210000004240 ciliary body Anatomy 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 230000004438 eyesight Effects 0.000 description 6
- 239000000194 fatty acid Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 230000007794 irritation Effects 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 208000021971 neovascular inflammatory vitreoretinopathy Diseases 0.000 description 6
- 230000006785 proliferative vitreoretinopathy Effects 0.000 description 6
- 238000011105 stabilization Methods 0.000 description 6
- -1 tacrolimus Chemical compound 0.000 description 6
- 210000004127 vitreous body Anatomy 0.000 description 6
- 208000002177 Cataract Diseases 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 108010016648 Immunophilins Proteins 0.000 description 5
- 102000000521 Immunophilins Human genes 0.000 description 5
- 208000027418 Wounds and injury Diseases 0.000 description 5
- ZDQSOHOQTUFQEM-XCXYXIJFSA-N ascomycin Natural products CC[C@H]1C=C(C)C[C@@H](C)C[C@@H](OC)[C@H]2O[C@@](O)([C@@H](C)C[C@H]2OC)C(=O)C(=O)N3CCCC[C@@H]3C(=O)O[C@H]([C@H](C)[C@@H](O)CC1=O)C(=C[C@@H]4CC[C@@H](O)[C@H](C4)OC)C ZDQSOHOQTUFQEM-XCXYXIJFSA-N 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 239000003889 eye drop Substances 0.000 description 5
- 229940012356 eye drops Drugs 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 230000002209 hydrophobic effect Effects 0.000 description 5
- 229920001684 low density polyethylene Polymers 0.000 description 5
- 239000004702 low-density polyethylene Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000009885 systemic effect Effects 0.000 description 5
- 230000004393 visual impairment Effects 0.000 description 5
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 208000010412 Glaucoma Diseases 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 206010020565 Hyperaemia Diseases 0.000 description 4
- 102000000588 Interleukin-2 Human genes 0.000 description 4
- 108010002350 Interleukin-2 Proteins 0.000 description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 4
- 206010029113 Neovascularisation Diseases 0.000 description 4
- 208000003435 Optic Neuritis Diseases 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 210000001124 body fluid Anatomy 0.000 description 4
- 210000005252 bulbus oculi Anatomy 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 4
- 238000012377 drug delivery Methods 0.000 description 4
- 208000027993 eye symptom Diseases 0.000 description 4
- 239000010408 film Substances 0.000 description 4
- 239000007850 fluorescent dye Substances 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol Substances OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 229920001477 hydrophilic polymer Polymers 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000001050 lubricating effect Effects 0.000 description 4
- 210000001165 lymph node Anatomy 0.000 description 4
- 238000005057 refrigeration Methods 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 230000004489 tear production Effects 0.000 description 4
- 238000011200 topical administration Methods 0.000 description 4
- 230000000007 visual effect Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- 102000001493 Cyclophilins Human genes 0.000 description 3
- 108010068682 Cyclophilins Proteins 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 206010015958 Eye pain Diseases 0.000 description 3
- 206010022941 Iridocyclitis Diseases 0.000 description 3
- 206010024214 Lenticular opacities Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241001469893 Oxyzygonectes dovii Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- 206010052428 Wound Diseases 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 201000004612 anterior uveitis Diseases 0.000 description 3
- 229960000686 benzalkonium chloride Drugs 0.000 description 3
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000010839 body fluid Substances 0.000 description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000003246 corticosteroid Substances 0.000 description 3
- 229960001334 corticosteroids Drugs 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
- 229910000397 disodium phosphate Inorganic materials 0.000 description 3
- 235000019800 disodium phosphate Nutrition 0.000 description 3
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 3
- 230000003511 endothelial effect Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 230000002538 fungal effect Effects 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 229940074046 glyceryl laurate Drugs 0.000 description 3
- 229920001903 high density polyethylene Polymers 0.000 description 3
- 239000004700 high-density polyethylene Substances 0.000 description 3
- 208000027866 inflammatory disease Diseases 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229940070765 laurate Drugs 0.000 description 3
- 230000033001 locomotion Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 3
- 235000019799 monosodium phosphate Nutrition 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 3
- 239000002736 nonionic surfactant Substances 0.000 description 3
- 229940049964 oleate Drugs 0.000 description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 3
- 229920001983 poloxamer Polymers 0.000 description 3
- 239000004417 polycarbonate Substances 0.000 description 3
- 229920000515 polycarbonate Polymers 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- ARIWANIATODDMH-UHFFFAOYSA-N rac-1-monolauroylglycerol Chemical compound CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 description 3
- 231100000241 scar Toxicity 0.000 description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 description 3
- 235000011008 sodium phosphates Nutrition 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 3
- 150000003712 vitamin E derivatives Chemical class 0.000 description 3
- HNLXNOZHXNSSPN-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CC(C)(C)CC(C)(C)C1=CC=C(OCCOCCOCCOCCOCCOCCOCCO)C=C1 HNLXNOZHXNSSPN-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 238000012371 Aseptic Filling Methods 0.000 description 2
- 206010003645 Atopy Diseases 0.000 description 2
- 241000282465 Canis Species 0.000 description 2
- 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 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 208000026350 Inborn Genetic disease Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 206010023644 Lacrimation increased Diseases 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 208000022873 Ocular disease Diseases 0.000 description 2
- 102100027913 Peptidyl-prolyl cis-trans isomerase FKBP1A Human genes 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 2
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 208000017442 Retinal disease Diseases 0.000 description 2
- 206010038910 Retinitis Diseases 0.000 description 2
- 208000007014 Retinitis pigmentosa Diseases 0.000 description 2
- 108010006877 Tacrolimus Binding Protein 1A Proteins 0.000 description 2
- 239000004809 Teflon Substances 0.000 description 2
- 229920006362 Teflon® Polymers 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000035508 accumulation Effects 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000002942 anti-growth Effects 0.000 description 2
- 102000023732 binding proteins Human genes 0.000 description 2
- 108091008324 binding proteins Proteins 0.000 description 2
- 230000035587 bioadhesion Effects 0.000 description 2
- 208000002352 blister Diseases 0.000 description 2
- 238000009530 blood pressure measurement Methods 0.000 description 2
- 229910021538 borax Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 210000003683 corneal stroma Anatomy 0.000 description 2
- 230000001054 cortical effect Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000002939 deleterious effect Effects 0.000 description 2
- 238000002296 dynamic light scattering Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 210000000981 epithelium Anatomy 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 208000016361 genetic disease Diseases 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 230000004073 interleukin-2 production Effects 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 230000000622 irritating effect Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 210000000826 nictitating membrane Anatomy 0.000 description 2
- 239000002997 ophthalmic solution Substances 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229960000502 poloxamer Drugs 0.000 description 2
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 2
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 210000003488 posterior eye segment Anatomy 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 210000001747 pupil Anatomy 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 2
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000002207 retinal effect Effects 0.000 description 2
- 210000003583 retinal pigment epithelium Anatomy 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 235000010339 sodium tetraborate Nutrition 0.000 description 2
- 238000000527 sonication Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000012430 stability testing Methods 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 230000035882 stress Effects 0.000 description 2
- 230000036561 sun exposure Effects 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 2
- 230000003868 tissue accumulation Effects 0.000 description 2
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 2
- 210000001745 uvea Anatomy 0.000 description 2
- 208000029257 vision disease Diseases 0.000 description 2
- 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 1
- JTOKYIBTLUQVQV-QRVTZXGZSA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-30-[(1r)-1-hydroxyethyl]-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontan Chemical compound C\C=C\C[C@@H](C)[C@@H](O)[C@@H]1N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C(=O)[C@H]([C@@H](C)O)NC1=O JTOKYIBTLUQVQV-QRVTZXGZSA-N 0.000 description 1
- UCOQITKXMNKTKF-MXGZYYNMSA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28,30-decamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23 Chemical compound C\C=C\C[C@@H](C)[C@@H](O)[C@@H]1N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C(=O)[C@H](C)NC1=O UCOQITKXMNKTKF-MXGZYYNMSA-N 0.000 description 1
- ZNVBEWJRWHNZMK-SYOLRUPNSA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21,30-tri(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,2 Chemical compound C\C=C\C[C@@H](C)[C@@H](O)[C@@H]1N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C(=O)[C@H](C(C)C)NC1=O ZNVBEWJRWHNZMK-SYOLRUPNSA-N 0.000 description 1
- ZMKGDQSIRSGUDJ-VSROPUKISA-N (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-30-propyl-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,1 Chemical compound CCC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O ZMKGDQSIRSGUDJ-VSROPUKISA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- OEZPKXDBWNXBRE-UHFFFAOYSA-N 2,3-bis(2-hydroxyethoxy)propyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCC(OCCO)COCCO OEZPKXDBWNXBRE-UHFFFAOYSA-N 0.000 description 1
- OVSKIKFHRZPJSS-UHFFFAOYSA-N 2,4-D Chemical compound OC(=O)COC1=CC=C(Cl)C=C1Cl OVSKIKFHRZPJSS-UHFFFAOYSA-N 0.000 description 1
- SXZNSSDAHFSAPB-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CC(C)(C)CC(C)(C)c1ccc(OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO)cc1 SXZNSSDAHFSAPB-UHFFFAOYSA-N 0.000 description 1
- GKFYMSIYJJSQAO-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOC1=CC=C(C=C1)C(C)(C)CC(C)(C)C GKFYMSIYJJSQAO-UHFFFAOYSA-N 0.000 description 1
- BPZYKPINOMFZGY-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CC(C)(C)CC(C)(C)c1ccc(OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO)cc1 BPZYKPINOMFZGY-UHFFFAOYSA-N 0.000 description 1
- AFYLOVCVJUMURG-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CC(C)(C)CC(C)(C)c1ccc(OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO)cc1 AFYLOVCVJUMURG-UHFFFAOYSA-N 0.000 description 1
- AIOCLJDAYKBSTO-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CC(C)(C)CC(C)(C)C1=CC=C(OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO)C=C1 AIOCLJDAYKBSTO-UHFFFAOYSA-N 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- WLCZTRVUXYALDD-IBGZPJMESA-N 7-[[(2s)-2,6-bis(2-methoxyethoxycarbonylamino)hexanoyl]amino]heptoxy-methylphosphinic acid Chemical compound COCCOC(=O)NCCCC[C@H](NC(=O)OCCOC)C(=O)NCCCCCCCOP(C)(O)=O WLCZTRVUXYALDD-IBGZPJMESA-N 0.000 description 1
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 230000003844 B-cell-activation Effects 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 102000000584 Calmodulin Human genes 0.000 description 1
- 108010041952 Calmodulin Proteins 0.000 description 1
- 241000282832 Camelidae Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 240000008886 Ceratonia siliqua Species 0.000 description 1
- 235000013912 Ceratonia siliqua Nutrition 0.000 description 1
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 1
- 206010008685 Chondritis Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010051625 Conjunctival hyperaemia Diseases 0.000 description 1
- 206010010726 Conjunctival oedema Diseases 0.000 description 1
- 208000006069 Corneal Opacity Diseases 0.000 description 1
- 206010010996 Corneal degeneration Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 244000303965 Cyamopsis psoralioides Species 0.000 description 1
- 206010048843 Cytomegalovirus chorioretinitis Diseases 0.000 description 1
- 206010012667 Diabetic glaucoma Diseases 0.000 description 1
- 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 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000001351 Epiretinal Membrane Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241001428166 Eucheuma Species 0.000 description 1
- 208000001860 Eye Infections Diseases 0.000 description 1
- 206010052140 Eye pruritus Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 241000699694 Gerbillinae Species 0.000 description 1
- 102000018997 Growth Hormone Human genes 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 206010023642 Lacrimation decreased Diseases 0.000 description 1
- 208000031471 Macular fibrosis Diseases 0.000 description 1
- 241000555676 Malassezia Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102000008135 Mechanistic Target of Rapamycin Complex 1 Human genes 0.000 description 1
- 108010035196 Mechanistic Target of Rapamycin Complex 1 Proteins 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 1
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 1
- 206010030043 Ocular hypertension Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241001111421 Pannus Species 0.000 description 1
- 201000010183 Papilledema Diseases 0.000 description 1
- 102000045595 Phosphoprotein Phosphatases Human genes 0.000 description 1
- 108700019535 Phosphoprotein Phosphatases Proteins 0.000 description 1
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 229920001328 Polyvinylidene chloride Polymers 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 108091030071 RNAI Proteins 0.000 description 1
- 206010038848 Retinal detachment Diseases 0.000 description 1
- 206010038886 Retinal oedema Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 240000001058 Sterculia urens Species 0.000 description 1
- 235000015125 Sterculia urens Nutrition 0.000 description 1
- 241000187391 Streptomyces hygroscopicus Species 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 206010042674 Swelling Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 206010047571 Visual impairment Diseases 0.000 description 1
- 208000000208 Wet Macular Degeneration Diseases 0.000 description 1
- 241001454727 Xenos Species 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000005299 abrasion Methods 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 239000002160 alpha blocker Substances 0.000 description 1
- 229940124308 alpha-adrenoreceptor antagonist Drugs 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 210000002159 anterior chamber Anatomy 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 210000003403 autonomic nervous system Anatomy 0.000 description 1
- 238000011888 autopsy Methods 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- 229940125388 beta agonist Drugs 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 230000002902 bimodal effect Effects 0.000 description 1
- 239000012867 bioactive agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 230000004378 blood-retinal barrier Effects 0.000 description 1
- 210000004155 blood-retinal barrier Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000010322 bone marrow transplantation Methods 0.000 description 1
- 210000001775 bruch membrane Anatomy 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 108010044481 calcineurin phosphatase Proteins 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 230000006727 cell loss Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229960003260 chlorhexidine Drugs 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 230000001886 ciliary effect Effects 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 208000021921 corneal disease Diseases 0.000 description 1
- 231100000269 corneal opacity Toxicity 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 208000001763 cytomegalovirus retinitis Diseases 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 201000004400 dacryoadenitis Diseases 0.000 description 1
- 230000004300 dark adaptation Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000030609 dephosphorylation Effects 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- CCAFPWNGIUBUSD-UHFFFAOYSA-N diethyl sulfoxide Chemical compound CCS(=O)CC CCAFPWNGIUBUSD-UHFFFAOYSA-N 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 208000027720 dry mucous membrane Diseases 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 210000003162 effector t lymphocyte Anatomy 0.000 description 1
- 150000002066 eicosanoids Chemical class 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000000871 endothelium corneal Anatomy 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 210000003560 epithelium corneal Anatomy 0.000 description 1
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 description 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 208000011323 eye infectious disease Diseases 0.000 description 1
- 230000004424 eye movement Effects 0.000 description 1
- 208000024519 eye neoplasm Diseases 0.000 description 1
- 230000000193 eyeblink Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000009368 gene silencing by RNA Effects 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940075529 glyceryl stearate Drugs 0.000 description 1
- 230000021061 grooming behavior Effects 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 229920000591 gum Polymers 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 239000000416 hydrocolloid Substances 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229920013821 hydroxy alkyl cellulose Polymers 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 229940030216 hypotears Drugs 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 229960004716 idoxuridine Drugs 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000004317 lacrimation Effects 0.000 description 1
- 150000002596 lactones Chemical group 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000005567 liquid scintillation counting Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229940076783 lucentis Drugs 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 210000004373 mandible Anatomy 0.000 description 1
- 210000004175 meibomian gland Anatomy 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 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
- 244000005700 microbiome Species 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000002911 mydriatic effect Effects 0.000 description 1
- 210000003007 myelin sheath Anatomy 0.000 description 1
- 239000002539 nanocarrier Substances 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 210000004083 nasolacrimal duct Anatomy 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 229940000041 nervous system drug Drugs 0.000 description 1
- HYWYRSMBCFDLJT-UHFFFAOYSA-N nimesulide Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1=CC=CC=C1 HYWYRSMBCFDLJT-UHFFFAOYSA-N 0.000 description 1
- 229960000965 nimesulide Drugs 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- GSGDTSDELPUTKU-UHFFFAOYSA-N nonoxybenzene Chemical compound CCCCCCCCCOC1=CC=CC=C1 GSGDTSDELPUTKU-UHFFFAOYSA-N 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- ZPIRTVJRHUMMOI-UHFFFAOYSA-N octoxybenzene Chemical compound CCCCCCCCOC1=CC=CC=C1 ZPIRTVJRHUMMOI-UHFFFAOYSA-N 0.000 description 1
- 229920002113 octoxynol Polymers 0.000 description 1
- 229940066429 octoxynol Drugs 0.000 description 1
- 229920004905 octoxynol-10 Polymers 0.000 description 1
- 229920004906 octoxynol-11 Polymers 0.000 description 1
- 229920004907 octoxynol-12 Polymers 0.000 description 1
- 229920004908 octoxynol-13 Polymers 0.000 description 1
- 229920004909 octoxynol-16 Polymers 0.000 description 1
- 229920004910 octoxynol-20 Polymers 0.000 description 1
- 229920004912 octoxynol-30 Polymers 0.000 description 1
- 229920004913 octoxynol-33 Polymers 0.000 description 1
- 229920004915 octoxynol-70 Polymers 0.000 description 1
- 229920002114 octoxynol-9 Polymers 0.000 description 1
- 229940098514 octoxynol-9 Drugs 0.000 description 1
- 201000008106 ocular cancer Diseases 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940054534 ophthalmic solution Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229940042717 optimmune Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 208000035824 paresthesia Diseases 0.000 description 1
- 238000003921 particle size analysis Methods 0.000 description 1
- 230000009057 passive transport Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229940032067 peg-20 stearate Drugs 0.000 description 1
- 229940008456 peg-32 oleate Drugs 0.000 description 1
- 229940119519 peg-32 stearate Drugs 0.000 description 1
- 229960003407 pegaptanib Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 239000005033 polyvinylidene chloride Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229960003876 ranibizumab Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 239000000310 rehydration solution Substances 0.000 description 1
- 230000004264 retinal detachment Effects 0.000 description 1
- 201000011195 retinal edema Diseases 0.000 description 1
- 210000001210 retinal vessel Anatomy 0.000 description 1
- ZCBUQCWBWNUWSU-SFHVURJKSA-N ruboxistaurin Chemical compound O=C1NC(=O)C2=C1C(C1=CC=CC=C11)=CN1CCO[C@H](CN(C)C)CCN1C3=CC=CC=C3C2=C1 ZCBUQCWBWNUWSU-SFHVURJKSA-N 0.000 description 1
- 229950000261 ruboxistaurin Drugs 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 230000036573 scar formation Effects 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 235000012046 side dish Nutrition 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 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 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 229950011392 sorbitan stearate Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000010414 supernatant solution Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 229940080150 systane Drugs 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 210000001138 tear Anatomy 0.000 description 1
- 230000004488 tear evaporation Effects 0.000 description 1
- BJORNXNYWNIWEY-UHFFFAOYSA-N tetrahydrozoline hydrochloride Chemical compound Cl.N1CCN=C1C1C2=CC=CC=C2CCC1 BJORNXNYWNIWEY-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 229920001664 tyloxapol Polymers 0.000 description 1
- 229960004224 tyloxapol Drugs 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 241001446247 uncultured actinomycete Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000006496 vascular abnormality Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 229940028445 visine Drugs 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 208000005494 xerophthalmia Diseases 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- 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
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/14—Decongestants or antiallergics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Ophthalmology & Optometry (AREA)
- Immunology (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Dispersion Chemistry (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Transplantation (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本明細書に開示された実施態様は、安定なカルシニューリン阻害剤またはmTOR阻害剤を含む眼科用組成物、およびより具体的には開示組成物を使用する眼疾患および/または症状を処置する方法に関する。
眼の前面に対する疾患および損傷は、米国において医療的眼科処置のために来院する主要原因である。これらの疾患および損傷は、最も痛みが伴う眼の症状の一つに位置づけられ、障害および失明となり得る。眼表面の主な臨床的問題には、眼表面の乾燥、涙液層異常および関連合併症;病理学および瘢痕化の原因となる眼表面の創傷;角膜変性ジストロフィーおよび遺伝的疾患;炎症性疾患;および外側の眼の感染が挙げられる。眼の疾患および損傷は、痒み、涙眼から視覚障害にわたる兆候を有し得る。それ故に、なんらかの疾患が次第に悪化するか、または他の重大な問題の誘因となり得るので、眼の問題を迅速に解決することが重要である。殆どの眼疾患に関する薬理学的管理には、液滴として眼の表面へ溶液を局所適用することが挙げられる。前眼部の組織に最終的に到達する局所適用される該薬物用量が比較的少量であるにも関わらず、一般的に投与される薬物濃度が非常に高いため、局所製剤は有効性を維持する。
カルシニューリン阻害剤またはmTOR阻害剤を含む眼科用組成物は、本発明に開示される。本開示内容の眼科用組成物は、混合ミセルの水溶液である。本明細書に開示された眼科用組成物は生体適合性であって、眼の症状を処置するために該眼への局所適用に特に有用である。本明細書に示した局面に従って、カルシニューリン阻害剤またはmTOR阻害剤;約10を超えるHLB指数を有する第一の界面活性剤;および約13を超えるHLB指数を有する第二の界面活性剤を包含しており、ここで該第一の界面活性剤のHLB指数および該第二の界面活性剤のHLB指数との間の絶対相違が約3を超えており、該組成物が混合ミセルを形成する医薬組成物を提供するものである。
本明細書に開示した実施態様に従って、添付の図面を参照してさらに説明され、この類似した構造はいくつかの図表を通じて数字等により言及される。提示された図面は、本発明に開示された実施態様の原理を説明するために位置づけられる以外には重点をおく必要はない。
本明細書にて開示した実施態様は、混合ミセルの局所適用形態においてカルシニューリン阻害剤またはmTOR阻害剤を含む医薬組成物に関する。本開示内容の医薬組成物は、患者または被検対象における眼の症状を、処置する、減少させる、改善する、および緩和することが判った。実施態様において、該組成物を、炎症性の眼の表面疾患などの眼疾患の処置に使用できる。かかる疾患の例示には、ドライアイ症候群(DES)、シェーングレン症候群、ブドウ膜炎、結膜炎(伝染性結膜炎)、角膜炎、角結膜炎、春季角結膜炎(VKC)、アトピー性角結膜炎(AKC)、痕跡性結膜炎などの眼の表面の自己免疫障害、眼瞼炎および強膜炎等が挙げられるが、これに限定するものではない。
一般的に、全ての使用した試薬は購入でき、別途記載がなければさらに精製を必要とせずに使用される。ボクロスポリン(ボクロスポリン、LX211、ISA247)を、Isotechnika, Inc.(Edmonton, Alberta, Canada)から得た。Isotechnikaから入手したストックを、Lux Biosciences(the New Jersey Center for Biomaterials)により保存した;シクロスポリンAをXenos Bioresources,Inc.(Santa Barbara, CA)から得た;シロリムスおよびタクロリムスをHaorui Pharma-Cheminc.から得た。ビタミンE TPGS(NF Grade)をEastman Chemical Companyから得て、IGEPAL CA-897 (オクトキシノール-40)をRhodia, Inc.から得た。滅菌脱イオン水を、EASY Pure UV Compact Ultra Pure Water System(Barnstead、IA)を用いて研究所内で調製した。Kollidon(登録商標)30 (PVP)およびKollidon(登録商標)90 F (Povidone K 90)をBASFから得た。ヒドロキシエチルセルロース,100 cpsおよび5000 cps を、Spectrum, Methocel(登録商標)から得て、HPMCを、Colorcon, Noveon(登録商標)を得て、ポリカルボフィルをLubrizol Advanced Materialsから得た。
表1に示した基本的な2X 製剤を、実施例1に記載した第二のプロトコールに記載したとおりに調製した。該カルシニューリンまたはmTOR阻害剤が、ボクロスポリン、シクロスポリンA、シロリムスおよびタクロリムスである基本製剤を調製した。50 mLの製剤として一つの調製物では;緩衝液混合物を表2に示した成分量を脱イオン水(25 mL)に溶解して調製し、2X緩衝液を調製した。2X緩衝液混合物を、別の保存剤を含んだものと含まないものとの双方を調製した。
様々な膜の型を、0.2 wt% ボクロスポリンを含有する製剤のフィルター滅菌に使用するために試験した。0.22μm 孔サイズの膜は、様々な材、例えばナイロン、テフロン、およびポリカーボネート等であった。膜からの回収物を、上記した薬剤含量のHPLC決定により評価して、遠心分離したサンプルと比較した。濾過効率比較試験についての結果を表5Aおよび5Bに示した。一般的に、0.22 μmのナイロン、テフロン、およびポリカーボネート膜は各々、濾過滅菌のために容認出来ることが判った。
該製剤の透明度を視覚的かつUV-可視光分光光度計を用いて400nmでのサンプルの吸光度を記録することにより測定した。製剤の1mlおよび対応する薬物を含まない賦形剤をプラスチックキュベットに入れ、吸光度を400 nmで記録した。水をブランクとして使用した。好ましい局面において、該混合ミセル製剤は、400 nmで約0.1未満の吸光度を有する透明な製剤である。400nmでの吸光度を、表4Aおよび表9-14の希釈実験において様々な製剤について示した。
ボクロスポリン製剤を希釈試験にて評価した。この目的は、眼と類似した条件下で製剤を希釈に供することであった。試験した各製剤中のボクロスポリン濃度は0.2 wt%であった。表3Aに記載した製剤を、薬局の店頭で購入できる人工涙液(OTC)の様々なブランドを用いて各々1:1、1:5および1:10で混合した。Systane(登録商標)(潤滑点眼薬、Alcon, Inc.; Visine(登録商標)(潤滑点眼薬、Pfizer,Inc.; Refresh Tears(登録商標)(潤滑点眼薬), Allergan, Inc.;およびHypo Tears(登録商標)(潤滑点眼薬), Novartisを用いた。測定を周囲条件下で行った。該データ(400 nmでの吸光度)を表9から14Aに示した。結果は濁度増加がないことを示した、故に溶液からのボクロスポリンの沈殿はなかった。
表3Aに示した製剤を、0.2 wt%のボクロスポリン/容量を含む製剤および含まない製剤による解離温度を決定するために試験した。〜60℃の一定温度の水浴を準備し、薬物を含むサンプルを試験するために使用した。製剤を含有するガラスバイアルを、該製剤中に温度計を差して水浴に入れた。ある程度の濁度が視覚的に観察されると直ぐに、温度の読み取りを行った。濁った溶液を室温まで冷やし、該薬物は混合ミセルに戻り、その結果全ての溶液が再度透明となった。再安定化のための時間(視覚的な透明度の回復)を記録した。ボクロスポリンを含むサンプルについてのデータを表15に示した。ヒートブロックを用いて加熱し、類似様式で薬物を含まないサンプルを試験した。ボクロスポリンを含まないサンプルについてのデータを表16に示した。
表19. 解離温度: 5%(v/v) PEG 400の添加に関する効果
混合ミセルの平均粒子サイズおよび多分散指数を、動的光散乱技術を用いて測定し(Brookhaven 90Plus particle size analyzer、Holtsville、NY)、3つの測定値の平均をとった。様々な溶液を、使い捨てのプラスチックセル中にいれた。サンプル容量(200μL)を、粒子サイズを決定するために用いた。0.2 wt% ボクロスポリンを含む実施例2に調製したとおりの製剤について粒子サイズおよび多分散性を表21に示した。0.2 wt% ボクロスポリンおよびPVP-K-90を含む製剤は、非常に狭いサイズ分布を有する13.3nmの平均ミセル直径および0.005の多分散度を示した。これに対して、0.2 wt% ボクロスポリンおよびHECを含む製剤は、23.8の平均ミセル直径を示したが、広い二峰性の粒子サイズ分布により0.482の大きな多分散性となった。
液滴あたりに送達されるカルシニューリン阻害剤の量を決定するために、各製剤に対する該液滴重量および容量を決定した。液滴サイズは製剤の表面張力に依存するので、表3Aに記載したとおり0.2wt% ボクロスポリン/容量を含有する2つの製剤を、送達される液滴サイズおよび容量について試験した。PVP-K-90を含有する該製剤およびHPMC(各々0.5 mL)を含有する該製剤を、製造供給元により提供される0.8 mLの最大容量BFS(blow-fill-seal) 容器中に個々に充填した。ボトル材はLDPEであり、該試験を大気条件の下で行った。各製剤の10滴の液滴を風袋ディッシュ(tared dish)に入れて、秤量した。同様に、10滴の製剤の液滴を測定シリンダーに入れて、容量を記録した。データを、表24および25に示した。
安定性および製剤適合性試験を、医薬的送達のために好適な3つの異なる型の容器で行った。実施例1の6つの製剤の既知容量を、3つの異なる型の容器、即ち、LDPE、ポリプロピレンおよび塩化ポリビニルに移して、室温で貯蔵した。予め決定した時間間隔にて(0、6、24 および48時間)、該サンプルをその容器から取り出し、HPLC法により薬剤含量について分析した。様々な型の容器に貯蔵された製剤は、試験期間中に薬剤含量の低下を示さなかった。
生理食塩水に対するボクロスポリンを含有する混合ミセル製剤(1X 基本製剤、表3Aア欄1、0.2wt%または0.5 wt% ボクロスポリン、各々一匹のウサギにて)の忍容性を試験するためにウサギで研究を行った。健全な若い成体のニュージーランドの白色ウサギ(3-4 Kg)(New Zealand albino rabbit)を試験に使用した。生理食塩水の一滴(おおよそ30μL)を眼に入れ、ボクロスポリンを含む製剤の一滴をもう一方のウサギの眼に入れた。下記の観察されたパラメーター:眼の瞬き、流涙、瞳孔のサイズ、充血、眼の動き、における相違は認められなかった。
さらなる試験を、様々な混合ミセル製剤の忍容性を試験するためにウサギにおいて行った。表26および27に示した製剤F1-F16をこれらの試験に使用した。
健康な若い成体のニュージーランド白色ウサギ(3-4 Kg)をこの試験に使用した。ボクロスポリンを含む製剤(LX211)の一滴(おおよそ30μL)をウサギの眼に点眼した。各製剤を3回試験した。
局所ボクロスポリンを評価するオープンラベルの一群のパイロット効率試験を計画し、行った。該試験は、イヌ科乾性角結膜炎(KCS)の処置のために本明細書にて開示した実施態様に関する組成物中の0.2 wt% ボクロスポリンの有効性を実証することを目的とする。該試験は、涙液産生の評価[シルマー涙液試験により測定した場合(STT)]、角膜の臨床的知見の応答、および参加する眼科医の全体評価に及ぶ。
表33.様々なカルシニューリンおよびmTOR阻害剤を含有する製剤
表35: 生体適合性の人工涙液組成物
本開示内容の人工涙液組成物の成分が、眼の組織に対して本来刺激性でないことを示すために、人工涙液に関する眼の忍容性および毒性を決定するために試験を行った。
・顕微鏡の眼の評価:
顕微鏡の眼の評価方式を、青色のフィルターの挿入を含めた細隙灯生体顕微鏡の使用後の眼の所見に用いて蛍光色素染料の保持について評価した。創傷は、人工涙液組成物適用(1日あたりに8回)の投薬前および14日間後に行った間接検眼鏡検査において見られなかった。
人工涙液組成物の適用の試験前および14日後に行ったウサギの内部眼圧(IOP)の平均眼圧測定法(Tono-pen)による測定値は11-17 mm/Hg圧の間であり、正常な生理学的範囲(10-20/mm Hg)内であった。要するに、IOP効果は、投与した局所処置(1日あたりに8回)との関連においては観察されなかった。
両眼フラッシュERGを、ISCEVプロトコールおよびHMsERGユニットを用いてウサギにおいて行った。双方暗順応条件下で10cd.s/m2および30Hzフリッカー刺激による、また10cd.s/m2を用いる高強度の刺激に対する最大のa波およびb波の振幅の予備的評価は、人工の涙液組成物の適用(1日あたりに8回)の14日間後にいずれかの所見も示さなかった。
人工の涙液組成物の適用(1日あたりに8回)の14日後に組織学的所見はなかった。
糖付加剤、例えばトレハロース、マンノース、D-ガラクトースおよびラクトースを、本開示の多様な製剤に添加し、安定性試験を様々な温度で行った。糖を再水和(rehydration)工程中に該製剤に添加するか(外部に)、または薄いフィルムの作成前に添加した(内部に)。該製剤は、アジュバントの糖の存在下では安定となることが判った。
製剤(100 mL)に必要とされる薬物(約0.2%、即ち200mg)、ビタミンE TPGS (約2.5%、即ち2.5g)およびオクトキシノール-40(約0.05/0.1%、即ち50/100 mg)の算出量を秤量した。薬物(200mg)、TPGS(約2.5g)およびオクトキシノール-40(約50/100 mg)を、約2ml、約1mlおよび約50/100μLの95%エタノールの各々に溶解した。糖について、約1gのトレハロースを、約4.5 mlの水/エタノール混合物(約2.5 ml 水+約2.0 ml エタノール)に別々に溶解し、他の含有物と混合した。同じ水:エタノールの比率を、異なる糖含量を含む製剤を調製するために使用した。該混合物を、薄いフィルムを形成するように終夜真空下にて蒸発させた。該薄いフィルムを脱イオン水(約45 mL)に溶解させて、混合ミセルの完全な形成を確実にするためにおおよそ45分間超音波処理を行った。
該製剤は、安定性試験の開始前の室温では澄んでおり、透明であることが判った。観察されたミセルサイズは12−14nmの範囲であった。オクトキシノール-40およびトレハロースを含む製剤の例示は次のとおりである:
この試験の目的は、眼の適用後の本開示内容の0.2%14C-放射性色素ボクロスポリン組成物(眼科用溶液)の反復投与による経時的分布および蓄積可能性、性別の相違、およびメラニン色素結合の可能性を、ニュージーランド白色ウサギ(NZW)およびダッチ・ベルト(Dutch Belted)ウサギ(DB)の眼の組織、涙および血液中の放射性活性を決定することにより評価することであった。
NZWウサギ (30匹雌/8匹雄)を、単回用量(SD)にておよび7日間の反復用量(RD)試験(表38を参照されたい)に使用した。DBウサギ(16匹雌)を、単回用量試験(表39を参照されたい)に使用した。動物は、処理されない(コントロール)か、または7日間の間に1回または毎日の局所眼用量(混合ミセル製剤中に0.2% 14C-ボクロスポリン(35μL)、片方または両眼に)が投与された。血液および眼の組織の放射活性レベルを、燃焼の後の液体シンチレーション計測により計画された時点で評価した。死亡、罹患または臨床的刺激の兆候は、いずれのウサギにおいてもおこらなかった。
b 処置群2(SD群)に対する投与前濃度として使用した。
c 薬物動態評価(SD群)に使用した。
d 処置群5(RD群)に対する投与前濃度として使用した。
e 薬物動態評価(MD群)に使用した。
b. 処置群2(SD群)に対する投与前濃度として使用した。
c. 薬物動態評価(MD群)に使用した。
14Cボクロスポリン-誘導放射活性について選択した薬物動態パラメーター(Cmax、AUC、Tmaxおよびt1/2)を、NZWおよびDBウサギ各々について表40および41にまとめた。単回用量投与後に、眼の組織内へ薬物の迅速な浸透(放射活性として測定した)が、最も高い濃度(>1mg eq/g組織)にて、瞼、結膜、角膜、瞬膜および涙内で起こり、最も低い濃度(1-11 ng eq/g組織)にて、房水および硝子体液、および水晶体で起きた。他の眼の組織は、ボクロスポリンおよび/または関連残留物の様々なレベル(20-223ng eq/g組織)に達した。図2は、雌のニュージーランド白色ウサギへの0.2%14C-ボクロスポリン混合ミセル製剤の1回(1日)の局所適用の後の14C-ボクロスポリンの組織レベルを示す。ボクロスポリンの治療レベルを24時間の基準で注目すると、一日に一回(QD)の投薬が本発明に開示した実施態様の水性混合ミセル組成物を用いて可能であることを支持するものであった。
14C-ボクロスポリンの眼の暴露に対する眼の暴露は、14Cボクロスポリン(35μL、70ng)の一日に1回の両眼投与7日間後に角膜、涙腺、虹彩/毛様体および水晶体中で2.8から6.7倍増加した(表40を参照されたい)。複数回の投薬後に(表40-43および図3-7を参照されたい)、Cmax-反復用量:Cmax-単回用量の比率が選択された組織内で上昇したとしても、ボクロスポリンの全体レベルは、最小の組織蓄積を示す表面組織レベルを十分に下回る。また、単回または反復投薬後の同程度のt1/2は、最小の組織蓄積を強く示唆した。
14C-ボクロスポリンのDBウサギへの単回投薬後の、眼の組織濃度(例えば、Cmax)は、NZWウサギとは有意に相違せず、メラニン結合がないことを示唆している(表42を参照されたい)。
Claims (24)
- 下記のものを含んでいる医薬組成物:
ボクロスポリン、シクロスポリンA、ピメクロリムス、タクロリムス、シロリムス、テムシロリムス、エベロリムス、その医薬上許容し得る塩およびその組合せからなる群から選択されるカルシニューリン阻害剤または哺乳類ラパマイシン標的(mTOR)阻害剤;
ビタミンE トコフェロールポリエチレングリコールサクシネート(TPGS);および
オクトキシノール-40、
ここで、該組成物は混合ミセルを形成する。 - 下記のものを含んでいる医薬組成物:
ボクロスポリン、シクロスポリンA、ピメクロリムス、タクロリムス、その医薬上許容し得る塩およびその組合せからなる群から選択されるカルシニューリン阻害剤;
ビタミンE トコフェロールポリエチレングリコールサクシネート(TPGS);および
オクトキシノール-40、
ここで該組成物は眼組織への局所適用に好適である。 - 該カルシニューリン阻害剤が、ボクロスポリンである、請求項2記載の医薬組成物。
- 下記のものを含んでいる医薬組成物:
シロリムス、テムシロリムス、エベロリムス、その医薬上許容し得る塩およびその組合せからなる群から選択される哺乳類ラパマイシン標的(mTOR)阻害剤;
ビタミンE トコフェロールポリエチレングリコールサクシネート(TPGS);および
オクトキシノール-40、
ここで該組成物が眼組織への局所適用に好適である。 - 混合ミセルを形成する、請求項2または4記載の医薬組成物。
- 光学的に透明な混合ミセルを形成する、請求項2または4記載の医薬組成物。
- 下記工程を含む、混合ミセル組成物を調製する方法:
カルシニューリン阻害剤または哺乳類ラパマイシン標的(mTOR)阻害剤を、ビタミンE トコフェロールポリエチレングリコールサクシネート(TPGS)およびオクトキシノール-40と混合して、溶媒を形成する工程(ここで、カルシニューリン阻害剤またはmTOR阻害剤は、ボクロスポリン、シクロスポリンA、ピメクロリムス、タクロリムス、シロリムス、テムシロリムス、エベロリムス、その医薬上許容し得る塩およびその組合せからなる群から選択される)、
該溶媒溶液を蒸発させて、固体様物質を形成させる工程、
該固体様物質を、水溶液を用いて水和する工程、および
該固体様混合物を溶解して、混合ミセル組成物を生成する工程、
ここで該混合ミセル組成物は光学的に透明である。 - 該水溶液中で生体接着性ポリマーを混合する工程をさらに含んでおり、該生体接着性ポリマーがPVP-K-30、PVP-K-90、HPMC、HEC、およびポリカルボフィルからなる群から選択される、請求項7記載の方法。
- 該カルシニューリン阻害剤がボクロスポリンである、請求項7記載の方法。
- 該ボクロスポリンが、混合ミセル組成物中に0.01%〜10%で存在する、請求項9記載の方法。
- 下記のものを含んでいる医薬組成物:
ボクロスポリン;
ビタミンE トコフェロールポリエチレングリコールサクシネート(TPGS);および
オクトキシノール-40、
ここで該組成物は眼組織への局所適用に好適である。 - 下記のものを含んでいる医薬組成物:
シクロスポリンA;
ビタミンE トコフェロールポリエチレングリコールサクシネート(TPGS);および
オクトキシノール-40、
ここで該組成物は眼組織への局所適用に好適である。 - 下記のものを含んでいる医薬組成物:
タクロリムス;
ビタミンE トコフェロールポリエチレングリコールサクシネート(TPGS);および
オクトキシノール-40、
ここで該組成物は眼組織への局所適用に好適である。 - 下記のものを含んでいる医薬組成物:
シロリムス;
ビタミンE トコフェロールポリエチレングリコールサクシネート(TPGS);および
オクトキシノール-40、
ここで該組成物は眼組織への局所適用に好適である。 - カルシニューリン阻害剤またはmTOR阻害剤が、眼底に到達できる、請求項1、2および4のいずれかに記載の医薬組成物。
- カルシニューリン阻害剤またはmTOR阻害剤が、医薬組成物の全容量の0.01重量パーセントから10重量パーセントの範囲である、請求項1、2および4のいずれかに記載の医薬組成物。
- ビタミンE TPGSが、医薬組成物の全容量の0.01重量パーセントから20重量パーセントの範囲である、請求項1-6および11-14のいずれかに記載の医薬組成物。
- オクトキシノール-40が、該組成物の全容量の0.01重量パーセントから10.0重量パーセントの範囲にある、請求項1-6および11-14のいずれかに記載の医薬組成物。
- 1以上のPVP-K-30、PVP-K-90、HPMC、HEC、およびポリカルボフィルからなる群から選択される生体接着性ポリマーをさらに含んでいる、請求項1-6および11-14のいずれかに記載の医薬組成物。
- 1以上のトレハロース、マンノース、D-ガラクトースおよびラクトースから選択される添加剤をさらに含んでいる、請求項1-6および11-14のいずれかに記載の医薬組成物。
- 眼疾患を処置するための、請求項1-6および11-20のいずれかに記載の医薬組成物。
- 該眼疾患が、ドライアイ症候群(DES)、シェーングレン症候群、ブドウ膜炎、結膜炎(伝染性結膜炎)、角膜炎、角結膜炎、春季角結膜炎(VKC)、アトピー性角結膜炎(AKC)、痕跡性結膜炎などの眼の表面の自己免疫障害、眼瞼炎および強膜炎からなる群から選択される炎症性の眼の表面疾患である、請求項21記載の医薬組成物。
- 眼底症状または障害を処置するための、請求項1-6および11-20のいずれかに記載の医薬組成物。
- 該眼底症状または障害が、糖尿病性網膜症(「DR」)、加齢性黄斑変性症(「AMD」)、糖尿病性黄斑浮腫(「DME」)、後部ブドウ膜炎、およびその組合せからなる群から選択される、請求項23記載の医薬組成物。
Applications Claiming Priority (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US99779607P | 2007-10-08 | 2007-10-08 | |
US60/997,796 | 2007-10-08 | ||
US99220507P | 2007-12-04 | 2007-12-04 | |
US60/992,205 | 2007-12-04 | ||
US3822308P | 2008-03-20 | 2008-03-20 | |
US61/038,223 | 2008-03-20 | ||
US9942008P | 2008-09-23 | 2008-09-23 | |
US61/099,420 | 2008-09-23 | ||
PCT/US2008/079170 WO2009048929A1 (en) | 2007-10-08 | 2008-10-08 | Ophthalmic compositions comprising calcineurin inhibitors or mtor inhibitors |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014243249A Division JP5836473B2 (ja) | 2007-10-08 | 2014-12-01 | 眼科用組成物 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2010540682A JP2010540682A (ja) | 2010-12-24 |
JP2010540682A5 JP2010540682A5 (ja) | 2011-11-24 |
JP5668476B2 true JP5668476B2 (ja) | 2015-02-12 |
Family
ID=40523446
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2010528993A Active JP5668476B2 (ja) | 2007-10-08 | 2008-10-08 | カルシニューリン阻害剤またはmTOR阻害剤を含む眼科用組成物 |
JP2014243249A Active JP5836473B2 (ja) | 2007-10-08 | 2014-12-01 | 眼科用組成物 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014243249A Active JP5836473B2 (ja) | 2007-10-08 | 2014-12-01 | 眼科用組成物 |
Country Status (10)
Country | Link |
---|---|
US (6) | US8435544B2 (ja) |
EP (1) | EP2197461B1 (ja) |
JP (2) | JP5668476B2 (ja) |
CN (1) | CN101918019B (ja) |
AU (1) | AU2008310956B2 (ja) |
CA (2) | CA2701482C (ja) |
ES (1) | ES2667945T3 (ja) |
HK (1) | HK1150771A1 (ja) |
MX (1) | MX2010003364A (ja) |
WO (1) | WO2009048929A1 (ja) |
Families Citing this family (73)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8263102B2 (en) | 2004-09-28 | 2012-09-11 | Atrium Medical Corporation | Drug delivery coating for use with a stent |
US9000040B2 (en) | 2004-09-28 | 2015-04-07 | Atrium Medical Corporation | Cross-linked fatty acid-based biomaterials |
US9801982B2 (en) | 2004-09-28 | 2017-10-31 | Atrium Medical Corporation | Implantable barrier device |
US9801913B2 (en) | 2004-09-28 | 2017-10-31 | Atrium Medical Corporation | Barrier layer |
US9012506B2 (en) | 2004-09-28 | 2015-04-21 | Atrium Medical Corporation | Cross-linked fatty acid-based biomaterials |
US9278161B2 (en) | 2005-09-28 | 2016-03-08 | Atrium Medical Corporation | Tissue-separating fatty acid adhesion barrier |
US9427423B2 (en) | 2009-03-10 | 2016-08-30 | Atrium Medical Corporation | Fatty-acid based particles |
US9492596B2 (en) | 2006-11-06 | 2016-11-15 | Atrium Medical Corporation | Barrier layer with underlying medical device and one or more reinforcing support structures |
WO2008057344A2 (en) | 2006-11-06 | 2008-05-15 | Atrium Medical Corporation | Coated surgical mesh |
US20080207756A1 (en) * | 2007-02-27 | 2008-08-28 | Atrium Medical Corporation | Bio-absorbable oil suspension |
JP5668476B2 (ja) | 2007-10-08 | 2015-02-12 | オーリニア・ファーマシューティカルズ・インコーポレイテッドAurinia Pharmaceuticals Inc. | カルシニューリン阻害剤またはmTOR阻害剤を含む眼科用組成物 |
CA2716185C (en) * | 2008-02-21 | 2017-03-21 | Rutgers, The State University Of New Jersey | Compositions and methods for treating ophthalmic diseases |
CN102238949A (zh) * | 2008-10-09 | 2011-11-09 | 拉姆斯科股份有限公司 | 治疗干眼综合征的组合物和方法 |
CN102458370A (zh) * | 2009-06-09 | 2012-05-16 | 卢克斯生物科技公司 | 用于眼科用途的表面药物递送系统 |
US20110038910A1 (en) | 2009-08-11 | 2011-02-17 | Atrium Medical Corporation | Anti-infective antimicrobial-containing biomaterials |
US20110045050A1 (en) * | 2009-08-24 | 2011-02-24 | Atrium Medical Corporation | Nanoemulsion formulations for direct delivery |
EP2538965B1 (en) * | 2010-02-25 | 2017-04-12 | Schepens Eye Research Institute | Therapeutic compositions for the treatment of dry eye disease |
IT1404931B1 (it) | 2010-06-11 | 2013-12-09 | Medivis S R L | Composizioni oftalmiche per la somministrazione di principi attivi liposolubili . |
WO2011161295A2 (es) * | 2010-06-23 | 2011-12-29 | Fundación Centro Nacional De Investigaciones Cardiovasculares Carlos Iii | Uso de compuestos anticalcineurina para el tratamiento de patologías que cursan con neovascularización ocular |
FR2961694B1 (fr) * | 2010-06-29 | 2013-01-25 | Thea Lab | Systeme de delivrance polymerique d'une solution non visqueuse a base de prostaglandine sans conservateur |
WO2012009707A2 (en) | 2010-07-16 | 2012-01-19 | Atrium Medical Corporation | Composition and methods for altering the rate of hydrolysis of cured oil-based materials |
CN102100665B (zh) * | 2011-01-14 | 2012-05-30 | 华南理工大学 | 一种含维生素e衍生物的滴眼液及其制备方法 |
US20130029919A1 (en) | 2011-07-26 | 2013-01-31 | Allergan, Inc. | Two part formulation system for opthalmic delivery |
US8912215B2 (en) | 2011-12-13 | 2014-12-16 | Everon Biosciences, Inc. | Rapamycin composition |
JP2015511242A (ja) * | 2012-02-23 | 2015-04-16 | インセルム(インスティチュート ナショナル デ ラ サンテ エ デ ラリシェルシェ メディカル) | 病変性前庭障害の治療に使用するカルシニューリン阻害剤 |
FR2988297B1 (fr) * | 2012-03-22 | 2014-03-28 | Thea Lab | Solution ophtalmique aqueuse a base de ciclosporine a sans conservateur |
US9867880B2 (en) | 2012-06-13 | 2018-01-16 | Atrium Medical Corporation | Cured oil-hydrogel biomaterial compositions for controlled drug delivery |
CA3050298A1 (en) | 2012-08-24 | 2014-02-27 | Sun Pharma Global Fze | Ophthalmic formulation of polyoxyl lipid or polyoxyl fatty acid and polyalkoxylated alcohol for use in the treatment of ocular conditions |
ES2797376T3 (es) | 2013-01-24 | 2020-12-02 | Palvella Therapeutics Inc | Composiciones para la administración transdérmica de inhibidores de mTOR |
CN108606951A (zh) * | 2013-01-31 | 2018-10-02 | 千寿制药株式会社 | 稳定的水性液体制剂 |
CN105073112B (zh) | 2013-03-13 | 2017-12-29 | 参天制药株式会社 | 睑板腺功能障碍的治疗剂 |
DE102013006596A1 (de) * | 2013-04-17 | 2014-10-23 | Jaime Guardiola | Verfahren zum Herstellen einer sterilen intraokularen Spül-Lösung und Spül-Lösung |
WO2015162552A2 (en) * | 2014-04-22 | 2015-10-29 | Biodue S.P.A. | Composition for topic use |
KR101587412B1 (ko) * | 2014-10-17 | 2016-01-21 | 주식회사 휴온스 | 사이클로스포린 및 트레할로스를 포함하는 안과용 조성물 |
US9463201B2 (en) | 2014-10-19 | 2016-10-11 | M.G. Therapeutics Ltd | Compositions and methods for the treatment of meibomian gland dysfunction |
CN113230021A (zh) | 2015-01-12 | 2021-08-10 | 科达莱昂治疗公司 | 微滴递送设备和方法 |
US11324800B2 (en) | 2015-01-15 | 2022-05-10 | Wellspring Ophthalmics, Inc. | Aqueous suspensions of cyclosporin |
US20200237859A1 (en) | 2019-01-25 | 2020-07-30 | Newport Research, Inc. | Aqueous suspensions of cyclosporin |
EP3253433A4 (en) | 2015-04-10 | 2018-08-22 | Kedalion Therapeutics, Inc. | Piezoelectric dispenser with replaceable ampoule |
CN108025011A (zh) * | 2015-07-21 | 2018-05-11 | 艾维德洛公司 | 用光敏剂治疗眼睛的系统和方法 |
AU2016332966A1 (en) | 2015-09-28 | 2018-04-26 | Azura Ophthalmics Ltd. | Thiol and disulfide-containing agents for increasing meibomian gland lipid secretion |
US20190231885A1 (en) | 2015-11-10 | 2019-08-01 | Sun Pharma Global Fze | Topical formulations and uses thereof |
CN109843316A (zh) | 2016-02-29 | 2019-06-04 | 太阳制药全球公司 | 含有环孢菌素的局部制剂及其用途 |
MX2018012390A (es) | 2016-04-14 | 2019-07-04 | Azura Ophthalmics Ltd | Composiciones de disulfuro de selenio para usarse en el tratamiento de la disfuncion de las glandulas de meibomio. |
GB2550346B (en) * | 2016-05-13 | 2021-02-24 | Phytoceutical Ltd | Micelles |
JP7108631B2 (ja) | 2017-01-06 | 2022-07-28 | パルヴェラ セラピューティクス、インク. | mTOR阻害剤の無水組成物およびその使用方法 |
CA3039106A1 (en) | 2017-01-20 | 2018-07-26 | Kedalion Therapeutics, Inc. | Piezoelectric fluid dispenser |
US20230190714A1 (en) * | 2017-05-11 | 2023-06-22 | Richard Postrel | Primary methods and processes for life extension in modern-day humans |
US20190224275A1 (en) | 2017-05-12 | 2019-07-25 | Aurinia Pharmaceuticals Inc. | Protocol for treatment of lupus nephritis |
JP6537092B2 (ja) * | 2017-06-16 | 2019-07-03 | 学校法人同志社 | mTORインヒビターを含む、眼の症状、障害または疾患を治療または予防するための医薬およびその応用 |
CN107334734B (zh) * | 2017-07-10 | 2020-03-17 | 浙江大学 | 一种西罗莫司或其衍生物的眼用制剂 |
US20190134051A1 (en) * | 2017-11-06 | 2019-05-09 | Rheostasis, Llc | Composition for treating ocular disorders such as macular degeneration, retinopathy and glaucoma |
WO2019113483A1 (en) | 2017-12-08 | 2019-06-13 | Kedalion Therapeutics, Inc. | Fluid delivery alignment system |
WO2019200121A1 (en) * | 2018-04-12 | 2019-10-17 | Kedalion Therapeutics, Inc. | Topical ocular delivery methods and devices for use in the same |
JP2021530463A (ja) | 2018-07-02 | 2021-11-11 | パルヴェラ セラピューティクス、インク. | mTOR阻害剤の無水組成物および使用方法 |
US20210338770A1 (en) * | 2018-10-15 | 2021-11-04 | Osaka University | Medicament for improving or preventing symptoms relating to retina and/or light reception and method for screening for substance capable of improving or preventing symptoms relating to retina and/or light reception |
US11179334B1 (en) * | 2019-02-04 | 2021-11-23 | Florida A&M University | Targeted carriers for tacrolimus for ocular inflammation |
US12097145B2 (en) | 2019-03-06 | 2024-09-24 | Bausch + Lomb Ireland Limited | Vented multi-dose ocular fluid delivery system |
US11679028B2 (en) | 2019-03-06 | 2023-06-20 | Novartis Ag | Multi-dose ocular fluid delivery system |
WO2021034850A1 (en) * | 2019-08-18 | 2021-02-25 | Iview Therapeutics, Inc. | In-situ gel forming ophthalmic formulations containing difluprednate |
US10799455B1 (en) | 2019-11-11 | 2020-10-13 | King Abdulaziz University | Micellles containing alpha lipoic acid as a transdermal drug delivery system |
US10736843B1 (en) | 2019-11-22 | 2020-08-11 | King Abdulaziz University | In situ gelling composition containing tocopherol-loaded micelles as an intranasal drug delivery system |
AU2020411442A1 (en) | 2019-12-26 | 2022-06-23 | Santen Pharmaceutical Co., Ltd. | Aqueous suspension composition containing sirolimus or salt thereof |
CA3166357A1 (en) | 2020-01-10 | 2021-07-15 | Azura Ophthalmics Ltd. | Instructions for composition and sensitivity |
WO2021212038A1 (en) | 2020-04-17 | 2021-10-21 | Kedalion Therapeutics, Inc. | Hydrodynamically actuated preservative free dispensing system having a collapsible liquid reservoir |
US11925577B2 (en) | 2020-04-17 | 2024-03-12 | Bausch + Lomb Ireland Limted | Hydrodynamically actuated preservative free dispensing system |
US11938057B2 (en) | 2020-04-17 | 2024-03-26 | Bausch + Lomb Ireland Limited | Hydrodynamically actuated preservative free dispensing system |
KR102444571B1 (ko) * | 2020-11-18 | 2022-09-19 | 주식회사태준제약 | 세티리진 및 토코페솔란을 포함하는 안과용 조성물 |
IT202100006839A1 (it) | 2021-03-22 | 2022-09-22 | Omisan Farm S R L | Preparato topico oftalmico idrosolubile contenente luteina e relativo metodo di produzione |
KR102639701B1 (ko) * | 2021-04-05 | 2024-02-26 | 주식회사 디엔엘바이오켐 | 칼시뉴린 억제제 및 맥문동 추출물을 유효성분으로 하는 알러지 질환 예방 또는 치료용 또는 면역억제용 조성물 |
DE102021212692A1 (de) | 2021-11-11 | 2023-05-11 | Ursapharm Arzneimittel Gmbh | Selbstemulgierende öl-in wasser-mikro- oder nanoemulsion so-wie emulgierende zusammensetzung |
CN115246664B (zh) * | 2022-07-04 | 2023-08-29 | 廊坊新奥龙河环保科技有限公司 | 一种高氯有机物液体危废的脱氯方法 |
TW202423434A (zh) * | 2022-10-07 | 2024-06-16 | 瑞士商歐庫利斯營運股份有限公司 | mTOR抑制劑的點眼劑微懸液 |
Family Cites Families (156)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US677304A (en) * | 1900-11-01 | 1901-06-25 | James N Young | Harvester. |
US3244592A (en) | 1962-06-09 | 1966-04-05 | Arai Tadashi | Ascomycin and process for its production |
US4039662A (en) | 1975-12-04 | 1977-08-02 | Alcon Laboratories, Inc. | Ophthalmic solution |
US4117118A (en) | 1976-04-09 | 1978-09-26 | Sandoz Ltd. | Organic compounds |
US4120949A (en) | 1977-10-05 | 1978-10-17 | Cooper Laboratories, Inc. | Ophthalmic solution |
US4409205A (en) | 1979-03-05 | 1983-10-11 | Cooper Laboratories, Inc. | Ophthalmic solution |
US5209927A (en) | 1985-01-23 | 1993-05-11 | Alcon Laboratories, Inc. | Ophthalmic solution |
US4649047A (en) | 1985-03-19 | 1987-03-10 | University Of Georgia Research Foundation, Inc. | Ophthalmic treatment by topical administration of cyclosporin |
US4883658A (en) | 1986-04-28 | 1989-11-28 | Holly Frank J | Ophthalmic solution for treatment of dry-eye syndrome |
US4744980A (en) | 1986-04-28 | 1988-05-17 | Holly Frank J | Ophthalmic solution for treatment of dry eye syndrome |
US4804539A (en) | 1986-07-28 | 1989-02-14 | Liposome Technology, Inc. | Ophthalmic liposomes |
CH668553A5 (de) | 1987-02-02 | 1989-01-13 | Mepha Ag | Arzneimittel mit verzoegerter wirkstofffreisetzung. |
JP2577049B2 (ja) | 1987-06-04 | 1997-01-29 | 三共株式会社 | シクロスポリン製剤 |
US4839342A (en) | 1987-09-03 | 1989-06-13 | University Of Georgia Research Foundation, Inc. | Method of increasing tear production by topical administration of cyclosporin |
KR920003601B1 (ko) | 1987-09-03 | 1992-05-04 | 유니버시티 어브 죠지아 리서취 화운데이션 인코포레이티드 | 점안 싸이클로스포린(cyclosporin)의 조성물 |
US5110493A (en) | 1987-09-11 | 1992-05-05 | Syntex (U.S.A.) Inc. | Ophthalmic NSAID formulations containing a quaternary ammonium preservative and a nonionic surfactant |
US5414011A (en) * | 1987-09-11 | 1995-05-09 | Syntex (U.S.A.) Inc. | Preservative system for ophthalmic formulations |
US5188826A (en) | 1988-02-08 | 1993-02-23 | Insite Vision Incorporated | Topical ophthalmic suspensions |
US4865846A (en) | 1988-06-03 | 1989-09-12 | Kaufman Herbert E | Drug delivery system |
EP0349061B1 (en) | 1988-06-29 | 1995-03-29 | Merck & Co. Inc. | Immunosuppressant agent |
US5607698A (en) | 1988-08-04 | 1997-03-04 | Ciba-Geigy Corporation | Method of preserving ophthalmic solution and compositions therefor |
US6007840A (en) | 1988-09-16 | 1999-12-28 | Novartis Ag | Pharmaceutical compositions comprising cyclosporins |
US5342625A (en) | 1988-09-16 | 1994-08-30 | Sandoz Ltd. | Pharmaceutical compositions comprising cyclosporins |
KR0148748B1 (ko) | 1988-09-16 | 1998-08-17 | 장 크라메르, 한스 루돌프 하우스 | 사이클로스포린을 함유하는 약학조성물 |
US5360611A (en) | 1988-10-03 | 1994-11-01 | Alcon Laboratories, Inc. | Pharmaceutical compositions and methods of treatment of the cornea following ultraviolet laser irradiation |
US5540931A (en) | 1989-03-03 | 1996-07-30 | Charles W. Hewitt | Methods for inducing site-specific immunosuppression and compositions of site specific immunosuppressants |
US5075104A (en) | 1989-03-31 | 1991-12-24 | Alcon Laboratories, Inc. | Ophthalmic carboxy vinyl polymer gel for dry eye syndrome |
FR2657018A1 (fr) | 1990-01-12 | 1991-07-19 | Merck Sharp & Dohme | Composition ophtalmique fluide a base de microparticules lipidiques contenant au moins un principe actif et son procede de preparation. |
US5227372A (en) | 1990-03-07 | 1993-07-13 | Children's Medical Center Corporation | Method for retaining ophthalmological agents in ocular tissues |
US5252318A (en) | 1990-06-15 | 1993-10-12 | Allergan, Inc. | Reversible gelation compositions and methods of use |
US6165500A (en) | 1990-08-24 | 2000-12-26 | Idea Ag | Preparation for the application of agents in mini-droplets |
DE69112350T2 (de) | 1990-11-19 | 1996-02-08 | Nat Starch Chem Invest | Entzweigte Stärken enthaltende kosmetische Mittel. |
TW209174B (ja) | 1991-04-19 | 1993-07-11 | Takeda Pharm Industry Co Ltd | |
ZA924953B (en) | 1991-07-25 | 1993-04-28 | Univ Louisville Res Found | Method of treating ocular inflammation |
US5252246A (en) | 1992-01-10 | 1993-10-12 | Allergan, Inc. | Nonirritating nonionic surfactant compositions |
GB9204466D0 (en) | 1992-03-02 | 1992-04-15 | Sandoz Ltd | Improvements in or relating to organic compounds |
US5830508A (en) | 1992-08-06 | 1998-11-03 | Deo Corporation | Composition for treating dry eye |
NZ247516A (en) | 1993-04-28 | 1995-02-24 | Bernard Charles Sherman | Water dispersible pharmaceutical compositions comprising drug dissolved in solvent system comprising at least one alcohol and at least one surfactant |
CA2125060C (en) | 1993-07-02 | 1999-03-30 | Henry P. Dabrowski | Ophthalmic solution for artificial tears |
US5624893A (en) | 1993-10-14 | 1997-04-29 | Alcon Laboratories, Inc. | Pharmaceutical compositions and methods of treatment of the cornea following laser irradiation |
JP3644543B2 (ja) | 1993-10-22 | 2005-04-27 | ヘクサル・アーゲー | シクロスポリンA及びα−トコフェロールを含有する医薬組成物 |
WO1995030420A1 (en) | 1994-05-06 | 1995-11-16 | Alcon Laboratories, Inc. | Use of vitamin e tocopheryl derivatives in ophthalmic compositions |
GB9409778D0 (en) | 1994-05-16 | 1994-07-06 | Dumex Ltd As | Compositions |
US5474979A (en) | 1994-05-17 | 1995-12-12 | Allergan, Inc. | Nonirritating emulsions for sensitive tissue |
US6309630B1 (en) | 1994-05-24 | 2001-10-30 | Insite Vision Incorporated | Non-steroidal anti-inflammatory ophthalmic suspensions |
GB9412273D0 (en) | 1994-06-18 | 1994-08-10 | Univ Nottingham | Administration means |
IT1273011B (it) | 1994-07-25 | 1997-07-01 | Trhecnopharma S A | Preparato oftalmico per l'uso come lacrima artificiale |
US5698533A (en) | 1994-07-26 | 1997-12-16 | Kang; Meng-Che | Ophthalmic pharmaceutical composition |
ES2094688B1 (es) | 1994-08-08 | 1997-08-01 | Cusi Lab | Manoemulsion del tipo de aceite en agua, util como vehiculo oftalmico y procedimiento para su preparacion. |
US5599534A (en) | 1994-08-09 | 1997-02-04 | University Of Nebraska | Reversible gel-forming composition for sustained delivery of bio-affecting substances, and method of use |
US5603929A (en) | 1994-11-16 | 1997-02-18 | Alcon Laboratories, Inc. | Preserved ophthalmic drug compositions containing polymeric quaternary ammonium compounds |
US5558876A (en) | 1995-03-29 | 1996-09-24 | Alcon Laboratories, Inc. | Topical ophthalmic acidic drug formulations |
US5869079A (en) | 1995-06-02 | 1999-02-09 | Oculex Pharmaceuticals, Inc. | Formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents |
US20060280774A1 (en) | 1995-06-02 | 2006-12-14 | Allergan, Inc. | Compositions and methods for treating glaucoma |
US5773019A (en) | 1995-09-27 | 1998-06-30 | The University Of Kentucky Research Foundation | Implantable controlled release device to deliver drugs directly to an internal portion of the body |
NZ280689A (en) | 1995-12-15 | 1997-08-22 | Bernard Charles Sherma Sherman | Pharmaceutical composition comprising a cyclosporipharmaceutical composition comprising a cyclosporin; a tocol, tocopherol or tocotrienol; and propylen; a tocol, tocopherol or tocotrienol; and propylene carbonate or polyethylene glycol ne carbonate or polyethylene glycol |
US5798333A (en) | 1996-09-17 | 1998-08-25 | Sherman; Bernard C. | Water-soluble concentrates containing cyclosporins |
US5814655A (en) | 1996-11-14 | 1998-09-29 | Insite Vision Incorporated | Non-steroidal ophthalmic mixtures |
US6458373B1 (en) | 1997-01-07 | 2002-10-01 | Sonus Pharmaceuticals, Inc. | Emulsion vehicle for poorly soluble drugs |
MX9701946A (es) | 1997-03-14 | 1998-04-30 | Arturo Jimenez Bayardo | Solucion oftalmica transportadora. |
US6406719B1 (en) | 1998-05-13 | 2002-06-18 | Microbiological Research Authority | Encapsulation of bioactive agents |
GB9810236D0 (en) | 1998-05-13 | 1998-07-08 | Microbiological Res Authority | Improvements relating to encapsulation of bioactive agents |
US6241969B1 (en) * | 1998-06-26 | 2001-06-05 | Elan Corporation Plc | Aqueous compositions containing corticosteroids for nasal and pulmonary delivery |
NZ512599A (en) | 1998-12-30 | 2003-10-31 | Dexcel Ltd | Formulation for cyclosporin administration featuring a hydrophilic solvent and a surfactant with a HLB of less than 5 |
US6267985B1 (en) * | 1999-06-30 | 2001-07-31 | Lipocine Inc. | Clear oil-containing pharmaceutical compositions |
US6294192B1 (en) * | 1999-02-26 | 2001-09-25 | Lipocine, Inc. | Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents |
US6248363B1 (en) | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
US6217895B1 (en) | 1999-03-22 | 2001-04-17 | Control Delivery Systems | Method for treating and/or preventing retinal diseases with sustained release corticosteroids |
US6254860B1 (en) | 1999-04-13 | 2001-07-03 | Allergan Sales, Inc. | Ocular treatment using cyclosporin-A derivatives |
US6309663B1 (en) * | 1999-08-17 | 2001-10-30 | Lipocine Inc. | Triglyceride-free compositions and methods for enhanced absorption of hydrophilic therapeutic agents |
US6531128B1 (en) | 2000-02-08 | 2003-03-11 | Pharmacia Corporation | Methods for treating glaucoma |
US6284235B1 (en) | 2000-02-11 | 2001-09-04 | National Starch And Chemical Company Investment Holding Corporation | Bioadhesive composition |
US20030018044A1 (en) | 2000-02-18 | 2003-01-23 | Peyman Gholam A. | Treatment of ocular disease |
ES2206363T3 (es) | 2000-04-07 | 2004-05-16 | Laboratoire Medidom S.A. | Formulaciones oftalmicas a base de ciclosporina, de acido hialuronico y de polisorbato. |
JP2004521857A (ja) | 2000-06-29 | 2004-07-22 | エミスフェアー・テクノロジーズ・インク | 活性剤の送達のための化合物及び組成物 |
ATE350015T1 (de) | 2000-09-28 | 2007-01-15 | Novartis Vaccines & Diagnostic | Mikropartikelzusammensetzungen und verfahren zu ihrer herstellung |
US6699493B2 (en) | 2000-11-29 | 2004-03-02 | Oculex Pharmaceuticals, Inc. | Method for reducing or preventing transplant rejection in the eye and intraocular implants for use therefor |
US20030072737A1 (en) | 2000-12-29 | 2003-04-17 | Michael Brines | Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs |
US6784156B2 (en) | 2001-03-05 | 2004-08-31 | Enanta Pharmaceuticals, Inc. | Cyclosporins for the treatment of respiratory diseases |
US6713081B2 (en) | 2001-03-15 | 2004-03-30 | The United States Of America As Represented By The Department Of Health And Human Services | Ocular therapeutic agent delivery devices and methods for making and using such devices |
US7923469B2 (en) * | 2001-04-30 | 2011-04-12 | Allergen, Inc. | Compositions including vitamin-based surfactants and methods for using same |
US6872382B1 (en) | 2001-05-21 | 2005-03-29 | Alcon, Inc. | Use of selective PDE IV inhibitors to treat dry eye disorders |
CN1259049C (zh) | 2001-07-06 | 2006-06-14 | 苏坎波公司 | 包含白介素-2抑制剂和抗菌剂的局部给药组合物 |
US6809077B2 (en) | 2001-10-12 | 2004-10-26 | Enanta Pharmaceuticals, Inc. | Cyclosporin analogs for the treatment of autoimmune diseases |
US20030087813A1 (en) | 2001-10-12 | 2003-05-08 | Or Yat Sun | Cyclosporin analogs for the treatment of lung diseases |
JP2005506990A (ja) * | 2001-10-19 | 2005-03-10 | アイソテクニカ インコーポレーテッド | 新規のシクロスポリン類似体のマイクロエマルションプレコンセントレート |
ES2326040T3 (es) | 2001-10-19 | 2009-09-29 | Isotechnika Inc. | Sintesis de analogos de ciclosporina. |
KR100992850B1 (ko) | 2001-10-19 | 2010-11-09 | 이소테크니카 인코포레이티드 | 시클로스포린 유사체 혼합물 및 면역조절제로서 이들의 용도 |
US7001615B1 (en) | 2001-12-07 | 2006-02-21 | Alcon, Inc. | Sustained release ophthalmic, otic and nasal suspension |
MXPA01013257A (es) | 2001-12-18 | 2003-06-25 | Arturo Jimenez Bayardo | Suspension oftalmica de rofecoxib para el tratamiento de la inflamacion y el dolor ocular. |
US20030165545A1 (en) | 2002-01-30 | 2003-09-04 | Allergan, Inc. | Ophthalmic compositions including oil-in-water emulsions, and methods for making and using same |
US7846478B2 (en) | 2002-01-31 | 2010-12-07 | Henkel Ag & Co. Kgaa | Bioadhesive composition |
AU2003221497A1 (en) | 2002-03-13 | 2003-09-22 | Novartis Ag | Pharmaceutical microparticles |
US6828356B2 (en) | 2002-07-29 | 2004-12-07 | Ast Products, Inc. | Preparation of ophthalmic compositions |
US20040110666A1 (en) | 2002-12-04 | 2004-06-10 | Or Yat Sun | Cyclosporins for the treatment of immune disorders |
US8685428B2 (en) * | 2002-12-10 | 2014-04-01 | Advanced Cardiovascular Systems, Inc. | Therapeutic composition and a method of coating implantable medical devices |
MXJL02000046A (es) | 2002-12-13 | 2004-06-24 | Jimenez Bayardo Arturo | Solucion inyectable intravitrea para el tratamiento de hemorragias vitreas. |
US20060177430A1 (en) | 2002-12-20 | 2006-08-10 | Chakshu Research Inc | Treatment of ocular disorders with ophthalmic formulations containing methylsulfonylmethane as a transport enhancer |
US7012065B2 (en) | 2003-02-07 | 2006-03-14 | Enanta Pharmaceuticals, Inc. | Cyclosporins for the treatment of immune disorders |
TW200505946A (en) | 2003-04-08 | 2005-02-16 | Hoffmann La Roche | Process for preparation of cyclosporin a analog |
AU2003228126A1 (en) | 2003-05-02 | 2004-11-23 | Arturo Jimenez Bayardo | Method of preparing an aqueous solution of cyclosporin-a and resulting aqueous solution |
WO2004100993A1 (ja) | 2003-05-15 | 2004-11-25 | Menicon Co., Ltd. | 眼科用組成物 |
CA2527121A1 (en) | 2003-06-13 | 2004-12-29 | Alcon, Inc. | Formulations of non-steroidal anti-inflammatory agents to treat pathologic ocular angiogenesis |
US20040266669A1 (en) | 2003-06-20 | 2004-12-30 | Wu Frank X. H. | Cyclosporin derivatives for the treatment of immune disorders |
WO2005004876A1 (es) | 2003-07-10 | 2005-01-20 | Arturo Jimenez Bayardo | Metodo para preparar una solucion acuosa de meloxicam y solucion acuosa resultante |
US6984628B2 (en) | 2003-07-15 | 2006-01-10 | Allergan, Inc. | Ophthalmic compositions comprising trefoil factor family peptides |
US8871269B2 (en) | 2003-07-15 | 2014-10-28 | Evonik Corporation | Method for the preparation of controlled release formulations |
DK1654002T4 (da) | 2003-08-07 | 2014-02-17 | Allergan Inc | Sammensætninger til fremføring af terapeutiske midler til øjnene |
US20050059583A1 (en) | 2003-09-15 | 2005-03-17 | Allergan, Inc. | Methods of providing therapeutic effects using cyclosporin components |
US7087237B2 (en) | 2003-09-19 | 2006-08-08 | Advanced Ocular Systems Limited | Ocular solutions |
US7083803B2 (en) | 2003-09-19 | 2006-08-01 | Advanced Ocular Systems Limited | Ocular solutions |
US20050181018A1 (en) | 2003-09-19 | 2005-08-18 | Peyman Gholam A. | Ocular drug delivery |
TW200517114A (en) | 2003-10-15 | 2005-06-01 | Combinatorx Inc | Methods and reagents for the treatment of immunoinflammatory disorders |
KR20060123384A (ko) * | 2003-12-24 | 2006-12-01 | 가부시키가이샤 엘티티 바이오파마 | 약물을 함유하는 나노 입자 및 그 제조 방법, 그리고 당해나노 입자로 이루어지는 비경구 투여용 제제 |
EP1759702B1 (en) | 2004-05-26 | 2009-01-07 | Arturo Jimenez Bayardo | Method of preparing a latanoprost ophthalmic solution and solution thus produced |
US20050267423A1 (en) * | 2004-05-27 | 2005-12-01 | Russ Johnson | Ophthalmic surgery preparation system and method |
US8372814B2 (en) | 2004-06-07 | 2013-02-12 | Ista Pharmaceuticals, Inc. | Ophthalmic formulations and uses thereof |
US20050277584A1 (en) | 2004-06-09 | 2005-12-15 | Allergan, Inc. | Pharmaceutical compositions comprising cyclosporins |
WO2006014484A2 (en) | 2004-07-02 | 2006-02-09 | Surmodics, Inc. | Methods and devices for the treatment of ocular conditions |
US20080102099A1 (en) | 2004-09-09 | 2008-05-01 | Arturo Jimenez Bayardo | Implants and Microspheres for the Sustained Release of Drugs for Ophthalmic Use and Preparation Methods Thereof |
ATE533473T1 (de) | 2004-09-24 | 2011-12-15 | Boehringer Ingelheim Pharma | Neue klasse von surfuctantähnlichen materialien mit vitamin-e-tpgs und wasserlöslichem polymer |
WO2006039164A2 (en) | 2004-09-29 | 2006-04-13 | Amr Technology, Inc. | Novel cyclosporin analogues and their pharmaceutical uses |
US7378391B2 (en) | 2004-09-29 | 2008-05-27 | Amr Technology, Inc. | Cyclosporin alkyne analogues and their pharmaceutical uses |
WO2006041631A2 (en) | 2004-10-06 | 2006-04-20 | Amr Technology, Inc. | Novel cyclosporin alkynes and their utility as pharmaceutical agents |
US7214664B2 (en) | 2004-12-03 | 2007-05-08 | The Curators Of The University Of Missouri | Peptidyl prodrugs that resist P-glycoprotein mediated drug efflux |
EP1831389A1 (en) * | 2004-12-23 | 2007-09-12 | Isotechnika Inc. | Method for biotransformation of the clyclosporin compound isa247 |
WO2006073786A2 (en) | 2004-12-30 | 2006-07-13 | Bausch & Lomb Incorporated | Ophthalmic compositions comprising steroid and cyclosporine for dry eye therapy |
US9161905B2 (en) * | 2005-01-12 | 2015-10-20 | Ocular Research Of Boston, Inc. | Dry eye treatment |
ATE458726T1 (de) | 2005-01-14 | 2010-03-15 | Schering Corp | Exo- und diastereoselektive synthese von himbacin-analoga |
US8637070B2 (en) | 2005-02-09 | 2014-01-28 | Santen Pharmaceutical Co., Ltd. | Rapamycin formulations and methods of their use |
US20060204548A1 (en) | 2005-03-01 | 2006-09-14 | Allergan, Inc. | Microimplants for ocular administration |
WO2006102378A2 (en) | 2005-03-21 | 2006-09-28 | Macusight, Inc. | Drug delivery systems for treatment of diseases or conditions |
EP1868661A1 (en) | 2005-04-08 | 2007-12-26 | SurModics, Inc. | Sustained release implants for subretinal delivery |
US7202209B2 (en) | 2005-07-13 | 2007-04-10 | Allergan, Inc. | Cyclosporin compositions |
US7276476B2 (en) | 2005-07-13 | 2007-10-02 | Allergan, Inc. | Cyclosporin compositions |
US7288520B2 (en) | 2005-07-13 | 2007-10-30 | Allergan, Inc. | Cyclosporin compositions |
US20070015691A1 (en) | 2005-07-13 | 2007-01-18 | Allergan, Inc. | Cyclosporin compositions |
US20070015693A1 (en) | 2005-07-13 | 2007-01-18 | Allergan, Inc. | Cyclosporin compositions |
US7297679B2 (en) | 2005-07-13 | 2007-11-20 | Allergan, Inc. | Cyclosporin compositions |
US8288348B2 (en) | 2005-07-13 | 2012-10-16 | Allergan, Inc. | Cyclosporin compositions |
PL1904056T3 (pl) * | 2005-07-18 | 2009-09-30 | Minu Llc | Zastosowanie makrolidu do przywracania czucia rogówkowego |
US7893040B2 (en) | 2005-07-22 | 2011-02-22 | Oculis Ehf | Cyclodextrin nanotechnology for ophthalmic drug delivery |
US7501393B2 (en) | 2005-07-27 | 2009-03-10 | Allergan, Inc. | Pharmaceutical compositions comprising cyclosporins |
US7745400B2 (en) | 2005-10-14 | 2010-06-29 | Gregg Feinerman | Prevention and treatment of ocular side effects with a cyclosporin |
US20070087962A1 (en) | 2005-10-17 | 2007-04-19 | Allergan, Inc. | Pharmaceutical compositions comprising cyclosporins |
EP2218442A1 (en) * | 2005-11-09 | 2010-08-18 | CombinatoRx, Inc. | Methods, compositions, and kits for the treatment of ophthalmic disorders |
US7544371B2 (en) | 2005-12-20 | 2009-06-09 | Bausch + Lomb Incorporated | Drug delivery systems |
WO2007095486A1 (en) | 2006-02-13 | 2007-08-23 | Allergan, Inc. | Methods of treating blepharospasm using cyclosporine components |
US7557082B2 (en) | 2006-03-03 | 2009-07-07 | Allergan, Inc. | Treatment with cyclosporin A |
US20070219127A1 (en) | 2006-03-20 | 2007-09-20 | Walt John G | Cyclosporin a compositions |
WO2008002118A1 (es) | 2006-06-27 | 2008-01-03 | Arturo Jimenez Bayardo | Una formulación oftálmica en suspensión de etabonato de loteprednol y clorhidrato de ciprofloxacina |
US9561178B2 (en) | 2006-07-25 | 2017-02-07 | Allergan, Inc. | Cyclosporin compositions |
US20080146497A1 (en) | 2006-07-25 | 2008-06-19 | Graham Richard S | Cyclosporin Compositions |
JP5668476B2 (ja) | 2007-10-08 | 2015-02-12 | オーリニア・ファーマシューティカルズ・インコーポレイテッドAurinia Pharmaceuticals Inc. | カルシニューリン阻害剤またはmTOR阻害剤を含む眼科用組成物 |
US20090196905A1 (en) | 2008-02-06 | 2009-08-06 | Spada Lon T | Stabilization of mitochondrial membranes in ocular diseases and conditions |
CN102458370A (zh) | 2009-06-09 | 2012-05-16 | 卢克斯生物科技公司 | 用于眼科用途的表面药物递送系统 |
-
2008
- 2008-10-08 JP JP2010528993A patent/JP5668476B2/ja active Active
- 2008-10-08 MX MX2010003364A patent/MX2010003364A/es active IP Right Grant
- 2008-10-08 US US12/247,701 patent/US8435544B2/en active Active
- 2008-10-08 CA CA2701482A patent/CA2701482C/en active Active
- 2008-10-08 CA CA3014633A patent/CA3014633C/en active Active
- 2008-10-08 ES ES08837729.6T patent/ES2667945T3/es active Active
- 2008-10-08 EP EP08837729.6A patent/EP2197461B1/en active Active
- 2008-10-08 CN CN200880110526.8A patent/CN101918019B/zh active Active
- 2008-10-08 AU AU2008310956A patent/AU2008310956B2/en active Active
- 2008-10-08 WO PCT/US2008/079170 patent/WO2009048929A1/en active Application Filing
-
2011
- 2011-05-17 HK HK11104896.4A patent/HK1150771A1/xx unknown
- 2011-08-19 US US13/213,451 patent/US8535694B2/en active Active
-
2013
- 2013-08-23 US US13/974,241 patent/US20130345185A1/en not_active Abandoned
-
2014
- 2014-12-01 JP JP2014243249A patent/JP5836473B2/ja active Active
-
2015
- 2015-02-20 US US14/627,063 patent/US10265375B2/en active Active
-
2019
- 2019-02-08 US US16/270,760 patent/US10973871B2/en active Active
-
2021
- 2021-04-12 US US17/228,480 patent/US20210338769A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
WO2009048929A1 (en) | 2009-04-16 |
MX2010003364A (es) | 2010-07-06 |
US20200009217A1 (en) | 2020-01-09 |
US20090092665A1 (en) | 2009-04-09 |
CN101918019A (zh) | 2010-12-15 |
JP2010540682A (ja) | 2010-12-24 |
CA3014633A1 (en) | 2009-04-16 |
AU2008310956B2 (en) | 2014-08-07 |
EP2197461B1 (en) | 2018-02-21 |
EP2197461A4 (en) | 2013-10-02 |
US20210338769A1 (en) | 2021-11-04 |
CA3014633C (en) | 2022-05-17 |
AU2008310956A1 (en) | 2009-04-16 |
CA2701482C (en) | 2018-10-23 |
EP2197461A1 (en) | 2010-06-23 |
US20130345185A1 (en) | 2013-12-26 |
CN101918019B (zh) | 2014-11-26 |
US8535694B2 (en) | 2013-09-17 |
JP2015086226A (ja) | 2015-05-07 |
CA2701482A1 (en) | 2009-04-16 |
US8435544B2 (en) | 2013-05-07 |
US20150157687A1 (en) | 2015-06-11 |
US10973871B2 (en) | 2021-04-13 |
HK1150771A1 (en) | 2012-01-13 |
JP5836473B2 (ja) | 2015-12-24 |
US10265375B2 (en) | 2019-04-23 |
US20110300195A1 (en) | 2011-12-08 |
ES2667945T3 (es) | 2018-05-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5836473B2 (ja) | 眼科用組成物 | |
US9937225B2 (en) | Topical formulations and uses thereof | |
US11951153B2 (en) | Topical cyclosporine-containing formulations and uses thereof | |
US20200009137A1 (en) | Topical formulations and uses thereof | |
OA19679A (en) | Topical cyclosporine-containing formulations and uses thereof. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20111007 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20111007 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130528 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20130813 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20130820 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20131126 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20140212 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140512 |
|
A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20140922 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20141007 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20140922 |
|
AA92 | Notification that decision to refuse application was cancelled |
Free format text: JAPANESE INTERMEDIATE CODE: A971092 Effective date: 20141104 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20141118 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20141201 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5668476 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |