WO2024085100A1 - Préparation huileuse dispersée de particules solides - Google Patents
Préparation huileuse dispersée de particules solides Download PDFInfo
- Publication number
- WO2024085100A1 WO2024085100A1 PCT/JP2023/037321 JP2023037321W WO2024085100A1 WO 2024085100 A1 WO2024085100 A1 WO 2024085100A1 JP 2023037321 W JP2023037321 W JP 2023037321W WO 2024085100 A1 WO2024085100 A1 WO 2024085100A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- oil
- solid particle
- ophthalmic
- surfactant
- formulation
- Prior art date
Links
- 239000002245 particle Substances 0.000 title claims abstract description 116
- 239000007787 solid Substances 0.000 title claims abstract description 107
- 238000002360 preparation method Methods 0.000 title claims abstract description 59
- 239000004094 surface-active agent Substances 0.000 claims abstract description 46
- 239000013076 target substance Substances 0.000 claims abstract description 40
- 239000003889 eye drop Substances 0.000 claims abstract description 18
- 239000008180 pharmaceutical surfactant Substances 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims description 71
- 238000009472 formulation Methods 0.000 claims description 67
- 150000007523 nucleic acids Chemical class 0.000 claims description 22
- 108020004707 nucleic acids Proteins 0.000 claims description 21
- 102000039446 nucleic acids Human genes 0.000 claims description 21
- 108090000623 proteins and genes Proteins 0.000 claims description 11
- 102000004169 proteins and genes Human genes 0.000 claims description 11
- 229920002545 silicone oil Polymers 0.000 claims description 5
- 230000002459 sustained effect Effects 0.000 claims description 3
- 229940012356 eye drops Drugs 0.000 abstract description 10
- 239000003921 oil Substances 0.000 description 90
- 235000019198 oils Nutrition 0.000 description 90
- -1 ester compound Chemical class 0.000 description 44
- 239000006185 dispersion Substances 0.000 description 40
- 239000003814 drug Substances 0.000 description 26
- 235000014113 dietary fatty acids Nutrition 0.000 description 22
- 239000000194 fatty acid Substances 0.000 description 22
- 229930195729 fatty acid Natural products 0.000 description 22
- 229940079593 drug Drugs 0.000 description 21
- 239000004359 castor oil Substances 0.000 description 19
- 235000019438 castor oil Nutrition 0.000 description 19
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 19
- 229930006000 Sucrose Natural products 0.000 description 13
- 239000005720 sucrose Substances 0.000 description 13
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 12
- 239000000427 antigen Substances 0.000 description 11
- 108091007433 antigens Proteins 0.000 description 11
- 102000036639 antigens Human genes 0.000 description 11
- 238000000034 method Methods 0.000 description 10
- 239000002736 nonionic surfactant Substances 0.000 description 10
- 102000016943 Muramidase Human genes 0.000 description 9
- 108010014251 Muramidase Proteins 0.000 description 9
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 9
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 9
- 230000027455 binding Effects 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 239000012530 fluid Substances 0.000 description 9
- 230000002209 hydrophobic effect Effects 0.000 description 9
- 230000002262 irrigation Effects 0.000 description 9
- 238000003973 irrigation Methods 0.000 description 9
- 229960000274 lysozyme Drugs 0.000 description 9
- 239000004325 lysozyme Substances 0.000 description 9
- 235000010335 lysozyme Nutrition 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000002131 composite material Substances 0.000 description 8
- 238000009826 distribution Methods 0.000 description 8
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 7
- 241000283973 Oryctolagus cuniculus Species 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 210000003161 choroid Anatomy 0.000 description 7
- 210000001508 eye Anatomy 0.000 description 7
- 239000012634 fragment Substances 0.000 description 7
- 125000004430 oxygen atom Chemical group O* 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- GCSPRLPXTPMSTL-IBDNADADSA-N [(2s,3r,4s,5s,6r)-2-[(2s,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)O[C@@]1([C@]2(CO)[C@H]([C@H](O)[C@@H](CO)O2)O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O GCSPRLPXTPMSTL-IBDNADADSA-N 0.000 description 6
- 108010081667 aflibercept Proteins 0.000 description 6
- 210000001525 retina Anatomy 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 229960002833 aflibercept Drugs 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000013268 sustained release Methods 0.000 description 5
- 239000012730 sustained-release form Substances 0.000 description 5
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 4
- 239000004166 Lanolin Substances 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 239000011258 core-shell material Substances 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 235000019388 lanolin Nutrition 0.000 description 4
- 229940039717 lanolin Drugs 0.000 description 4
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 4
- 229920000223 polyglycerol Polymers 0.000 description 4
- 229920001451 polypropylene glycol Polymers 0.000 description 4
- 229940126585 therapeutic drug Drugs 0.000 description 4
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 4
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 4
- 210000004127 vitreous body Anatomy 0.000 description 4
- 108091023037 Aptamer Proteins 0.000 description 3
- DPUOLQHDNGRHBS-UHFFFAOYSA-N Brassidinsaeure Natural products CCCCCCCCC=CCCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-UHFFFAOYSA-N 0.000 description 3
- URXZXNYJPAJJOQ-UHFFFAOYSA-N Erucic acid Natural products CCCCCCC=CCCCCCCCCCCCC(O)=O URXZXNYJPAJJOQ-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 108010076504 Protein Sorting Signals Proteins 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 239000003945 anionic surfactant Substances 0.000 description 3
- 229960000074 biopharmaceutical Drugs 0.000 description 3
- 210000005252 bulbus oculi Anatomy 0.000 description 3
- 239000003093 cationic surfactant Substances 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 239000002563 ionic surfactant Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 3
- 230000037368 penetrate the skin Effects 0.000 description 3
- 235000019271 petrolatum Nutrition 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 229940032094 squalane Drugs 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- DRAWQKGUORNASA-UHFFFAOYSA-N (2-hydroxy-3-octadec-9-enoyloxypropyl) octadec-9-enoate Chemical compound CCCCCCCCC=CCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCC=CCCCCCCCC DRAWQKGUORNASA-UHFFFAOYSA-N 0.000 description 2
- CUNWUEBNSZSNRX-RKGWDQTMSA-N (2r,3r,4r,5s)-hexane-1,2,3,4,5,6-hexol;(z)-octadec-9-enoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O CUNWUEBNSZSNRX-RKGWDQTMSA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 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
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 108700011259 MicroRNAs Proteins 0.000 description 2
- 239000012901 Milli-Q water Substances 0.000 description 2
- 208000022873 Ocular disease Diseases 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- 108091093037 Peptide nucleic acid Proteins 0.000 description 2
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 description 2
- 235000019484 Rapeseed oil Nutrition 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- ZPVGIKNDGJGLCO-VGAMQAOUSA-N [(2s,3r,4s,5s,6r)-2-[(2s,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)O[C@@]1([C@]2(CO)[C@H]([C@H](O)[C@@H](CO)O2)O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O ZPVGIKNDGJGLCO-VGAMQAOUSA-N 0.000 description 2
- SZYSLWCAWVWFLT-UTGHZIEOSA-N [(2s,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)-2-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxolan-2-yl]methyl octadecanoate Chemical compound O([C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@]1(COC(=O)CCCCCCCCCCCCCCCCC)O[C@H](CO)[C@@H](O)[C@@H]1O SZYSLWCAWVWFLT-UTGHZIEOSA-N 0.000 description 2
- SJDMTGSQPOFVLR-UHFFFAOYSA-N [10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] tetradecanoate Chemical compound C12CCC3(C)C(C(C)CCCC(C)C)CCC3C2CC=C2C1(C)CCC(OC(=O)CCCCCCCCCCCCC)C2 SJDMTGSQPOFVLR-UHFFFAOYSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 210000001742 aqueous humor Anatomy 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol group Chemical group [C@@H]1(CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)[C@H](C)CCCC(C)C HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- DPUOLQHDNGRHBS-KTKRTIGZSA-N erucic acid Chemical compound CCCCCCCC\C=C/CCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-KTKRTIGZSA-N 0.000 description 2
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 2
- 150000002433 hydrophilic molecules Chemical class 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- 229940073475 lysozyme hydrochloride Drugs 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 239000002679 microRNA Substances 0.000 description 2
- 229940049964 oleate Drugs 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940099429 polyoxyl 40 stearate Drugs 0.000 description 2
- WBHHMMIMDMUBKC-QJWNTBNXSA-M ricinoleate Chemical compound CCCCCC[C@@H](O)C\C=C/CCCCCCCC([O-])=O WBHHMMIMDMUBKC-QJWNTBNXSA-M 0.000 description 2
- 229940066675 ricinoleate Drugs 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 229960005078 sorbitan sesquioleate Drugs 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- DUXYWXYOBMKGIN-UHFFFAOYSA-N trimyristin Chemical compound CCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCC DUXYWXYOBMKGIN-UHFFFAOYSA-N 0.000 description 2
- PVNIQBQSYATKKL-UHFFFAOYSA-N tripalmitin Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCC PVNIQBQSYATKKL-UHFFFAOYSA-N 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- 239000000341 volatile oil Substances 0.000 description 2
- 239000003871 white petrolatum Substances 0.000 description 2
- 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 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- HBOQXIRUPVQLKX-BBWANDEASA-N 1,2,3-trilinoleoylglycerol Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/C\C=C/CCCCC)COC(=O)CCCCCCC\C=C/C\C=C/CCCCC HBOQXIRUPVQLKX-BBWANDEASA-N 0.000 description 1
- QMMJWQMCMRUYTG-UHFFFAOYSA-N 1,2,4,5-tetrachloro-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=C(Cl)C(Cl)=CC(Cl)=C1Cl QMMJWQMCMRUYTG-UHFFFAOYSA-N 0.000 description 1
- XFOQWQKDSMIPHT-UHFFFAOYSA-N 2,3-dichloro-6-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=C(Cl)C(Cl)=N1 XFOQWQKDSMIPHT-UHFFFAOYSA-N 0.000 description 1
- PIINGYXNCHTJTF-UHFFFAOYSA-N 2-(2-azaniumylethylamino)acetate Chemical compound NCCNCC(O)=O PIINGYXNCHTJTF-UHFFFAOYSA-N 0.000 description 1
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- BGRXBNZMPMGLQI-UHFFFAOYSA-N 2-octyldodecyl tetradecanoate Chemical compound CCCCCCCCCCCCCC(=O)OCC(CCCCCCCC)CCCCCCCCCC BGRXBNZMPMGLQI-UHFFFAOYSA-N 0.000 description 1
- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 208000005590 Choroidal Neovascularization Diseases 0.000 description 1
- 206010060823 Choroidal neovascularisation Diseases 0.000 description 1
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 1
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- 206010012688 Diabetic retinal oedema Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 101100256637 Drosophila melanogaster senju gene Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- SHBUUTHKGIVMJT-UHFFFAOYSA-N Hydroxystearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OO SHBUUTHKGIVMJT-UHFFFAOYSA-N 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 206010022941 Iridocyclitis Diseases 0.000 description 1
- NAACPBBQTFFYQB-UHFFFAOYSA-N Linolsaeure-cholesterylester Natural products C12CCC3(C)C(C(C)CCCC(C)C)CCC3C2CC=C2C1(C)CCC(OC(=O)CCCCCCCC=CCC=CCCCCC)C2 NAACPBBQTFFYQB-UHFFFAOYSA-N 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 101000808007 Mus musculus Vascular endothelial growth factor A Proteins 0.000 description 1
- RJECHNNFRHZQKU-UHFFFAOYSA-N Oelsaeurecholesterylester Natural products C12CCC3(C)C(C(C)CCCC(C)C)CCC3C2CC=C2C1(C)CCC(OC(=O)CCCCCCCC=CCCCCCCCC)C2 RJECHNNFRHZQKU-UHFFFAOYSA-N 0.000 description 1
- 108700039514 Opeguard MA Proteins 0.000 description 1
- 108010058846 Ovalbumin Proteins 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 235000004347 Perilla Nutrition 0.000 description 1
- 244000124853 Perilla frutescens Species 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920002675 Polyoxyl Polymers 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- 229920002690 Polyoxyl 40 HydrogenatedCastorOil Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 108091027967 Small hairpin RNA Proteins 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 1
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 1
- 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 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- BAECOWNUKCLBPZ-HIUWNOOHSA-N Triolein Natural products O([C@H](OCC(=O)CCCCCCC/C=C\CCCCCCCC)COC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CCCCCCC/C=C\CCCCCCCC BAECOWNUKCLBPZ-HIUWNOOHSA-N 0.000 description 1
- PHYFQTYBJUILEZ-UHFFFAOYSA-N Trioleoylglycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCCCCCCCC)COC(=O)CCCCCCCC=CCCCCCCCC PHYFQTYBJUILEZ-UHFFFAOYSA-N 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- AECIIQVDGKYLNI-VUAWYJOHSA-N [(2s,3r,4s,5s,6r)-2-[(2s,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)O[C@@]1([C@]2(CO)[C@H]([C@H](O)[C@@H](CO)O2)O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O AECIIQVDGKYLNI-VUAWYJOHSA-N 0.000 description 1
- UEYVMVXJVDAGBB-ZHBLIPIOSA-N [(2s,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)-2-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxolan-2-yl]methyl tetradecanoate Chemical compound O([C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@]1(COC(=O)CCCCCCCCCCCCC)O[C@H](CO)[C@@H](O)[C@@H]1O UEYVMVXJVDAGBB-ZHBLIPIOSA-N 0.000 description 1
- SUOVMGLZSOAHJY-JREUTYQLSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] icosanoate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)CCCCCCCCCCCCCCCCCCC)C1 SUOVMGLZSOAHJY-JREUTYQLSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 206010064930 age-related macular degeneration Diseases 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 229940050528 albumin Drugs 0.000 description 1
- 208000002205 allergic conjunctivitis Diseases 0.000 description 1
- 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 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 239000002280 amphoteric surfactant Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 201000004612 anterior uveitis Diseases 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 208000024998 atopic conjunctivitis Diseases 0.000 description 1
- 235000015278 beef Nutrition 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 229940093761 bile salts Drugs 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 229950000025 brolucizumab Drugs 0.000 description 1
- 235000001046 cacaotero Nutrition 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- NAACPBBQTFFYQB-XNTGVSEISA-N cholesteryl octadeca-9,12-dienoate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)CCCCCCCC=CCC=CCCCCC)C1 NAACPBBQTFFYQB-XNTGVSEISA-N 0.000 description 1
- RJECHNNFRHZQKU-RMUVNZEASA-N cholesteryl oleate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)C1 RJECHNNFRHZQKU-RMUVNZEASA-N 0.000 description 1
- 210000004240 ciliary body Anatomy 0.000 description 1
- 239000010630 cinnamon oil Substances 0.000 description 1
- 239000001926 citrus aurantium l. subsp. bergamia wright et arn. oil Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 210000000695 crystalline len Anatomy 0.000 description 1
- 208000001309 degenerative myopia Diseases 0.000 description 1
- 230000004340 degenerative myopia Effects 0.000 description 1
- 201000011190 diabetic macular edema Diseases 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 229940031578 diisopropyl adipate Drugs 0.000 description 1
- 229940031569 diisopropyl sebacate Drugs 0.000 description 1
- XFKBBSZEQRFVSL-UHFFFAOYSA-N dipropan-2-yl decanedioate Chemical compound CC(C)OC(=O)CCCCCCCCC(=O)OC(C)C XFKBBSZEQRFVSL-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002296 dynamic light scattering Methods 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 210000003560 epithelium corneal Anatomy 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229940116333 ethyl lactate Drugs 0.000 description 1
- FMMOOAYVCKXGMF-MURFETPASA-N ethyl linoleate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OCC FMMOOAYVCKXGMF-MURFETPASA-N 0.000 description 1
- 229940031016 ethyl linoleate Drugs 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 239000010642 eucalyptus oil Substances 0.000 description 1
- 229940044949 eucalyptus oil Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940051306 eylea Drugs 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000010643 fennel seed oil Substances 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 230000030279 gene silencing Effects 0.000 description 1
- 238000012226 gene silencing method Methods 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- XJNUECKWDBNFJV-UHFFFAOYSA-N hexadecyl 2-ethylhexanoate Chemical compound CCCCCCCCCCCCCCCCOC(=O)C(CC)CCCC XJNUECKWDBNFJV-UHFFFAOYSA-N 0.000 description 1
- QAKXLTNAJLFSQC-UHFFFAOYSA-N hexadecyl tetradecanoate Chemical compound CCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCC QAKXLTNAJLFSQC-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229940072106 hydroxystearate Drugs 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 125000003010 ionic group Chemical group 0.000 description 1
- 210000000554 iris Anatomy 0.000 description 1
- 229940113601 irrigation solution Drugs 0.000 description 1
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- FMMOOAYVCKXGMF-UHFFFAOYSA-N linoleic acid ethyl ester Natural products CCCCCC=CCC=CCCCCCCCC(=O)OCC FMMOOAYVCKXGMF-UHFFFAOYSA-N 0.000 description 1
- HBOQXIRUPVQLKX-UHFFFAOYSA-N linoleic acid triglyceride Natural products CCCCCC=CCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COC(=O)CCCCCCCC=CCC=CCCCCC HBOQXIRUPVQLKX-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 150000002646 long chain fatty acid esters Chemical class 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 1
- 210000005157 neural retina Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 108091027963 non-coding RNA Proteins 0.000 description 1
- 102000042567 non-coding RNA Human genes 0.000 description 1
- 229920004918 nonoxynol-9 Polymers 0.000 description 1
- 229940087419 nonoxynol-9 Drugs 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- KSCKTBJJRVPGKM-UHFFFAOYSA-N octan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-] KSCKTBJJRVPGKM-UHFFFAOYSA-N 0.000 description 1
- 229920004914 octoxynol-40 Polymers 0.000 description 1
- 229940073665 octyldodecyl myristate Drugs 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000002997 ophthalmic solution Substances 0.000 description 1
- 210000001328 optic nerve Anatomy 0.000 description 1
- 229940092253 ovalbumin Drugs 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229940044476 poloxamer 407 Drugs 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- XEIOPEQGDSYOIH-MURFETPASA-N propan-2-yl (9z,12z)-octadeca-9,12-dienoate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OC(C)C XEIOPEQGDSYOIH-MURFETPASA-N 0.000 description 1
- 229960003876 ranibizumab Drugs 0.000 description 1
- 210000003583 retinal pigment epithelium Anatomy 0.000 description 1
- 208000004644 retinal vein occlusion Diseases 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000003786 sclera Anatomy 0.000 description 1
- 239000004055 small Interfering RNA Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000003760 tallow Substances 0.000 description 1
- FBWNMEQMRUMQSO-UHFFFAOYSA-N tergitol NP-9 Chemical compound CCCCCCCCCC1=CC=C(OCCOCCOCCOCCOCCOCCOCCOCCOCCO)C=C1 FBWNMEQMRUMQSO-UHFFFAOYSA-N 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- HYVJNYYVNIYMDK-QSEXIABDSA-N triarachidonin Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)OCC(OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC)COC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC HYVJNYYVNIYMDK-QSEXIABDSA-N 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 229940081852 trilinolein Drugs 0.000 description 1
- 229940113164 trimyristin Drugs 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- 229940117972 triolein Drugs 0.000 description 1
- 229960001947 tripalmitin Drugs 0.000 description 1
- 231100000402 unacceptable toxicity Toxicity 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
-
- 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
Definitions
- the present disclosure relates to solid particle dispersion oil-based formulations.
- Formulations for treating ophthalmic diseases are being developed.
- US2021/145736A, US2017/273901A, US2013/164285A, US2012/258163A, and US2016/0235674A disclose methods for intravitreal administration of drugs.
- WO2021/049529A, EP3950071A, US2019/117777A, JP2018-70535A, EP2298282A, and US2010/298447A disclose dispersions of particles having a core-shell structure as formulations for transdermal administration.
- the present disclosure relates to a solid particle dispersion oil formulation.
- the solid particle dispersion oil formulation includes (i) a solid complex including particles containing a pharma- ceutically acceptable target substance or target molecule (e.g., a nucleic acid or a biopharmaceutical) and a pharma- ceutically acceptable surfactant, and (ii) a pharma- ceutically acceptable oil base.
- a pharma- ceutically acceptable target substance or target molecule e.g., a nucleic acid or a biopharmaceutical
- a pharma- ceutically acceptable surfactant e.g., a pharma- ceutically acceptable surfactant
- a pharma- ceutically acceptable oil base e.g., a pharma- ceutically acceptable oil base.
- the particles are typically coated with the surfactant.
- the target substance or target molecule may be water-soluble.
- the present disclosure also provides a solid particle disper
- the present disclosure further provides a solid particle dispersion oil formulation for ophthalmic or intraocular administration.
- an ophthalmic formulation is provided, the formulation including (i) a solid complex including particles containing a pharma- ceutically acceptable target substance or target molecule and a pharma- ceutically acceptable surfactant, and (ii) a pharma- ceutically acceptable oil base.
- an ophthalmic formulation comprising: (i) a solid complex comprising particles containing a pharma- ceutically acceptable target substance or molecule and a pharma-ceutically acceptable surfactant; and (ii) a pharma-ceutically acceptable oil base.
- An ophthalmic preparation comprising: (i) a solid complex comprising particles containing a pharma- ceutically acceptable target substance or molecule and a pharma-ceutically acceptable surfactant; (ii) a pharma- ceutically acceptable oil base; the particles are coated with the surfactant, The solid complex is dispersed in the oil base.
- Ophthalmic preparations (2) The ophthalmic preparation according to (1) above, which is formulated as an eye drop. (3) The ophthalmic preparation according to (1) above, which is for intravitreal administration or is formulated for intravitreal administration.
- the average hydrodynamic particle size is 80 nm to 200 nm.
- the oily base is silicone oil.
- FIG. 1 shows a schematic diagram of a test system simulating the intravitreal environment.
- FIG. 2A shows the release profile of antibody molecules from a formulation of the present disclosure in a test system simulating the intravitreal environment.
- FIG. 2B shows particle formation and particle size distribution of the particles formed for a formulation of the present disclosure that includes an antibody as a substance or molecule of interest.
- FIG. 3A shows the release behavior of a protein molecule (eg, lysozyme) from a formulation of the present disclosure in a test system simulating the intravitreal environment.
- FIG. 3B shows particle formation and the size distribution of the formed particles in a formulation of the present disclosure that includes a protein molecule (lysozyme) as a target substance or molecule.
- FIG. 1 shows a schematic diagram of a test system simulating the intravitreal environment.
- FIG. 2A shows the release profile of antibody molecules from a formulation of the present disclosure in a test system simulating the intravitreal environment.
- FIG. 4A shows the release profile of an anti-VEGF antibody from a formulation of the present disclosure in a test system simulating the intravitreal environment.
- FIG. 4B shows the transfer of anti-VEGF antibody from a formulation of the present disclosure to the retina and choroid following ocular administration to rabbits.
- FIG. 54 shows the vitreous accumulation of anti-VEGF antibodies from a formulation of the present disclosure administered intravitreally to rabbits.
- FIG. 4D shows the translocation of anti-VEGF antibody from a formulation of the present disclosure to the retina and choroid following intravitreal administration in rabbits.
- FIG. 5 shows the release profile of aflibercept from a formulation of the present disclosure in a test system simulating the intravitreal environment.
- FIG. 6 is a histological section (hematoxylin and eosin stained) of the eye of a mouse to which a formulation of the present disclosure was administered intravitreally.
- a "subject” refers to a mammal, including a human, and preferably a human.
- mammals include, but are not limited to, humans, chimpanzees, and other primates; dogs, cats, rabbits, horses, sheep, goats, cows, pigs, rats (including nude rats), mice (including nude mice and skid mice), guinea pigs, and other livestock animals, pets, and laboratory animals.
- a "solid composite” is a composite made of solids.
- a solid composite may contain water, but is a composite containing solid components.
- a solid composite may be water-free or have a low water content, for example, a water content of 1% by weight or less, 0.9% by weight or less, 0.8% by weight or less, 0.7% by weight or less, 0.6% by weight or less, 0.5% by weight or less, 0.4% by weight or less, 0.3% by weight or less, 0.2% by weight or less, or 0.1% by weight or less, as measured by a known method (e.g., Karl Fischer method).
- a solid composite containing hydrophilic molecules and a surfactant may have a core-shell structure, in which the core contains hydrophilic molecules and the shell contains a surfactant, and the surfactant may have a hydrophilic portion facing the core and a hydrophobic portion facing the outer surface of the solid composite.
- the surfactant preferably covers the surface of the hydrophilic drug and turns the particle surface hydrophobic.
- a "solid particle-dispersed oil preparation” is a preparation that includes a plurality of solid particles and an oil base, and the solid particles are dispersed in the oil base.
- the solid particles include a target substance or target molecule (e.g., a nucleic acid or a biopharmaceutical) and a surfactant.
- the solid particles also contain no water or only a limited amount of water.
- the particle size is typically less than 1 ⁇ m.
- the solid particles can be stably dispersed in the oil base.
- the “solid particle” is also referred to as a "solid complex.”
- the target substance or target molecule may be hydrophilic, and in this case, the solid particle-dispersed oil preparation is a preparation in which a hydrophilic target substance or target molecule is dispersed in an oil base using a surfactant.
- the target substance or target molecule may be, for example, a biomolecule.
- the target substance or target molecule may be, for example, a pharmaceutical active ingredient.
- the target substance or target molecule may be, for example, a therapeutic drug for an ophthalmic disease.
- the solid particle dispersion oil preparation preferably does not contain aggregates formed by aggregation of multiple particles (particularly 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, or 10 or more).
- a biopharmaceutical is a pharmaceutical product that contains an active pharmaceutical ingredient produced by cells.
- a "surfactant” is a molecule that has a relatively hydrophilic portion and a relatively hydrophobic portion in the molecule.
- Surfactants are broadly classified into ionic surfactants and nonionic surfactants.
- Ionic surfactants include cationic surfactants and anionic surfactants.
- an ionic surfactant may have either a cation or an anion and a hydrophobic portion.
- a cationic surfactant may contain a cationic portion and a fatty chain (e.g., a long fatty chain) such as an alkyl, alkenyl, or alkynyl.
- An anionic surfactant may contain an anionic portion and a fatty acid such as a long chain fatty acid, an unsaturated fatty acid (e.g., monovalent or divalent), or a long chain unsaturated fatty acid (e.g., monovalent or divalent).
- a fatty acid such as a long chain fatty acid, an unsaturated fatty acid (e.g., monovalent or divalent), or a long chain unsaturated fatty acid (e.g., monovalent or divalent).
- "Long chain” is a term given to compounds that have 14 to 22 carbon atoms.
- the fatty chain may be a fatty chain with 8 to 22 carbon atoms, i.e., a C 8 to C 22 fatty chain such as a C 8 to C 22 alkyl, C 8 to C 22 alkenyl, or C 8 to C 22 alkynyl.
- the fatty chain may be a long fatty chain.
- Saturated means that the fatty chain has no double or triple bonds
- unsaturated means that the fatty chain has at least one double or triple bond.
- the fatty chain having a double bond may be a cis type or a trans type, and the cis type is preferred from the viewpoint of biocompatibility.
- a nonionic surfactant is a surfactant that does not have an ionic group in the molecule, and has a nonionic hydrophilic portion and a hydrophobic portion.
- the hydrophobic portion may include a fatty chain such as an alkyl, alkenyl, or alkynyl (e.g., a long fatty chain).
- an ester compound made from unsaturated fatty acids such as erucic acid and oleic acid is preferred.
- lipophilic nonionic surfactants include sucrose fatty acid esters (sucrose stearate, sucrose palmitate, sucrose myristic acid, sucrose oleate, sucrose laurate, sucrose erucate, sucrose mixed fatty acid esters) with a high degree of esterification (i.e., a high ratio of di-, tri-, and polyester to monoester), polyglycerol condensed ricinoleate, decaglycerol ester, glycerol fatty acid ester, polyglycerol fatty acid ester, polyoxyethylene glycerol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, and polyoxyethylene castor oil/hydrogenated castor oil.
- the nonionic surfactant is preferably sucrose laurate.
- Surfactants include, for example, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (200) polyoxypropylene (70) glycol, polysorbate 80, macrogol 4000, macrogol 6000, aluminum monostearate, polyethylene glycol monostearate, glyceryl monostearate, nonoxynol-9, octoxynol-40, polyethylene glycol (PEG)/polypropylene glycol (PPG)-4/30 copolymer, poloxamer 188, poloxamer 407, polyoxyl 15 hydroxystearate, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearate, and polysorbate 20.
- polyoxyl 40 stearate polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxy
- a suitable example of a surfactant used to prepare the complex is a lipophilic (hydrophobic) nonionic surfactant with an HLB (Hydrophile-Lipophile Balance) value of 10 or less.
- the HLB of the nonionic surfactant is preferably 8 or less, more preferably 5 or less, and particularly preferably 3 or less.
- antibody refers to an immunoglobulin.
- the antibody may be of various isotypes, e.g., IgG.
- the antibody may preferably be a monoclonal antibody.
- the antibody may be a human chimeric antibody, a humanized antibody, or a human antibody.
- a human chimeric antibody may be produced by replacing the constant region of a non-human antibody with the constant region of a human antibody.
- a humanized antibody may be produced by replacing the six CDRs of a human antibody with the six corresponding CDRs of a non-human antibody.
- a human antibody may be produced using an animal (e.g., a mouse) in which at least the heavy chain variable region of an immunoglobulin has been replaced with the corresponding region of a human locus.
- a human antibody can be obtained by replacing the constant region with the amino acid sequence of a human antibody.
- the antibody may preferably be a humanized antibody.
- the antibody may preferably be a human antibody.
- An antibody has a signal peptide when produced intracellularly, but the signal peptide is removed when secreted extracellularly. Therefore, when administered as a pharmaceutical, the antibody does not require a signal peptide.
- CDR refers to a complementarity determining region present in the heavy and light chain variable regions of an antibody. There are three CDRs in each of the heavy and light chain variable regions, and they are called CDR1, CDR2, and CDR3 from the N-terminus.
- the CDRs can be determined, for example, based on the numbering scheme of Kabat et al. (Kabat, E. A. et al., Sequences of Proteins of Immunological Interest, 5th ed., 1991, Bethesda: US Dept. of Health and Human Services, PHS, NIH.).
- antigen-binding fragment of antibody means a fragment of an antibody that maintains binding to an antigen.
- antigen-binding fragments include Fab, Fab', F(ab') 2 , Fv, scFv (single chain Fv), diabody, and sc(Fv) 2 (single chain (Fv) 2 ).
- Fab can be obtained by digesting an antibody with papain.
- F(ab') 2 can be obtained by digesting an antibody with pepsin, and Fab' can be obtained by further reducing this.
- Antigen-binding fragments of other antibodies can also be prepared by methods well known to those skilled in the art. Such antigen-binding fragments of antibodies can be used in the present invention.
- pharmaceutical acceptable means that when administered to a subject as a medicine, it does not cause unacceptable toxicity.
- intraocular administration refers to invasive administration to the eyeball other than eye drops.
- intraocular administration include intravitreal administration, subconjunctival administration, suprachoroidal administration, and subretinal administration.
- a solid particle dispersion oil formulation comprising: (i) a solid complex comprising particles containing a pharma- ceutically acceptable target substance or molecule and a pharma-ceutically acceptable surfactant; (ii) a pharma- ceutically acceptable oily base.
- the solid particle dispersion oil formulation of the present disclosure may be free of water or have a low water content, for example, the water content may be 1% by mass or less, 0.9% by mass or less, 0.8% by mass or less, 0.7% by mass or less, 0.6% by mass or less, 0.5% by mass or less, 0.4% by mass or less, 0.3% by mass or less, 0.2% by mass or less, or 0.1% by mass or less, as measured by known methods.
- the target substance or target molecule is hydrophilic.
- the target substance or target molecule can be a physiologically active substance, for example, a biomolecule.
- the biomolecule is a molecule found in a living organism or an analog thereof, for example, a protein, a peptide, an antibody or an antigen-binding fragment thereof, a nucleic acid, or other biomolecule.
- the biomolecule may or may not be chemically modified.
- Ophthalmic solutions are the most widely used non-invasive drug administration form for treating anterior ocular diseases due to their non-invasiveness and convenience.
- anterior ocular diseases include glaucoma, allergic conjunctivitis, anterior uveitis, and cataracts.
- hydrophilic active ingredient in eye drops so long as it is a medicinal ingredient that is administered to the eye.
- the antibody may be, but is not limited to, an antibody that has benefits for absorption through the skin or intraocular (intravitreal) administration.
- the antibody include, for example, anti-VEGF antibodies (e.g., ranibizumab, bevacizumab, aflibercept, or brolucizumab).
- Anti-VEGF antibodies have been confirmed to be effective against age-related macular degeneration, diabetic retinopathy (diabetic macular edema), retinal vein occlusion, pathological myopia (choroidal neovascularization), and the like.
- the antibody or antigen-binding fragment thereof does not lose its antigen-binding ability in a solid complex or in a solid particle-dispersed oil formulation, and exhibits antigen-specific binding after administration.
- the protein or peptide does not lose its antigen-binding ability in a solid complex or in a solid particle-dispersed oil formulation, and exerts at least a part of its function after administration. Examples of the protein or peptide include lysozyme, insulin, albumin, ovalbumin, neutrophin 4, and the like.
- the nucleic acid includes one or more selected from the group consisting of DNA, RNA, and modified nucleic acid.
- the nucleic acid may be a single-stranded or double-stranded nucleic acid.
- the nucleic acid may be an antisense oligo.
- the RNA may include artificial RNA for gene silencing, such as siRNA and shRNA, non-coding RNA, such as microRNA (miRNA), aptamers, and natural RNA, such as mRNA.
- the nucleic acid or RNA may include aptamers (e.g., anti-VEGF aptamers). These RNAs may be modified to be stabilized in vivo.
- Modified nucleic acids include, for example, nucleic acids modified with fluorescent dyes, biotinylated nucleic acids, and nucleic acids into which cholesteryl groups have been introduced.
- bases may be modified with 2'-O-methyl, 2'-fluoro, or 2'-methoxyethyl (MOE), and the phosphodiester bonds in the nucleic acid backbone may be replaced with phosphorothioate bonds.
- Artificial nucleic acids include nucleic acids in which the oxygen atom at the 2' position is crosslinked with the carbon atom at the 4' position.
- LNA locked nucleic acid
- ENA in which the oxygen atom at the 2' position and the carbon atom at the 4' position are bridged via ethylene
- BNACOC in which the oxygen atom at the 2' position and the carbon atom at the 4' position are bridged via -CH 2 OCH 2 -
- bridged nucleic acid (BNA) such as BNANC, in which the oxygen atom at the 2' position and the carbon atom at the 4' position are bridged via -NR-CH 2 - (where R is a methyl or hydrogen atom);
- cMOE in which the oxygen atom at the 2' position and the carbon atom at the 4' position are bridged via -CH 2 (OCH 3 ) - ; )-bridged cEt; AmNA in which the 2'- and 4'-carbon
- surfactant can be used without particular restrictions as long as it is medicamentally acceptable.
- surfactants include nonionic surfactants, anionic surfactants, cationic surfactants, amphoteric surfactants, and bile salts.
- Nonionic surfactants include polyglycerol condensed ricinoleate, decaglycerol ester, glycerol fatty acid ester, polyglycerol fatty acid ester, polyoxyethylene glycerol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene castor oil, hydrogenated castor oil, sucrose fatty acid ester (sucrose stearate, sucrose palmitate, sucrose myristate, sucrose oleate, sucrose laurate, sucrose erucate, sucrose mixed fatty acid ester), etc. One of these may be selected for use, or a mixture of two or more may be used.
- ester compounds made from unsaturated fatty acids such as erucic acid and oleic acid are preferred, and more preferred are sucrose erucic acid ester, sucrose oleic acid ester, and sucrose mixed fatty acid ester.
- one or more surfactants selected from the group consisting of glycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, polyoxyethylene sorbit fatty acid ester, polyoxyethylene castor oil, and hydrogenated castor oil can be used.
- the HLB value indicates the degree of hydrophilicity and hydrophobicity of a surfactant.
- a smaller HLB value means a higher hydrophobicity.
- the surfactant is not particularly limited, but it is preferable to use one with high hydrophobicity, with an HLB value of 10 or less. This is because it can easily dissolve or disperse the antigen-containing complex in the oil phase.
- surfactants having an HLB value of 10 or less, 8 or less, 6 or less, 5 or less, 4 or less, or 3 or less may be preferably used. In the present disclosure, the smaller the HLB value, the more preferable.
- a water-soluble target substance or molecule When a water-soluble target substance or molecule is mixed with a surfactant in an oil phase (preferably a volatile oil phase), particles having a core-shell structure are formed, the core containing the water-soluble target substance or molecule and the shell containing the surfactant.
- the particles are dispersed in the oil phase.
- the oil phase used here is a volatile oil phase (e.g., cyclohexane)
- it is easy to subsequently evaporate the solvent and by removing the solvent by drying (e.g., freeze-drying)
- the core-shell particles containing the water-soluble target substance or molecule and the shell containing the surfactant can be obtained as solid particles (also called "solid composites").
- solid particles also called "solid composites"
- the solid particles may have an average hydrodynamic particle size of 50 nm to 200 nm as determined by dynamic light scattering. In some embodiments, the average hydrodynamic particle size may be 100 to 160 nm. In some embodiments, the average hydrodynamic particle size may be 80 to 120 nm.
- the oil base may be any oil that is acceptable for use in pharmaceutical preparations administered to the eye (i.e., ophthalmic preparations such as eye drops or preparations for intravitreal administration).
- the oil base may be preferably an oil that is liquid at room temperature (25°C).
- the oil base may be either natural or synthetic.
- the oil base may be, for example, vegetable oils such as soybean oil, cottonseed oil, rapeseed oil, sesame oil, corn oil, peanut oil, safflower oil, sunflower oil, olive oil, castor oil, rapeseed oil, perilla oil, fennel oil, lanolin, lanolin oil, lanolin alcohol, refined lanolin, mineral oil, cacao oil, cinnamon oil, peppermint oil, eucalyptus oil, and bergamot oil, or animal oils such as beef tallow, lard, and fish oil.
- vegetable oils such as soybean oil, cottonseed oil, rapeseed oil, sesame oil, corn oil, peanut oil, safflower oil, sunflower oil, olive oil, castor oil, rapeseed oil, perilla oil, fennel oil, lanolin, lanolin oil, lanolin alcohol, refined lanolin, mineral oil, cacao oil, cinnamon oil, peppermint oil, eucalyptus oil, and bergamot oil
- the oil base may be a neutral lipid such as glyceride, triolein, trilinolein, tripalmitin, tristearin, trimyristin, triarachidonin, or a synthetic lipid.
- the oil base may be a sterol derivative such as cholesteryl oleate, cholesteryl linoleate, cholesteryl myristate, cholesteryl palmidate, or cholesteryl arachidate, or a long-chain fatty acid ester such as isopropyl myristate, octyldodecyl myristate, cetyl myristate, ethyl oleate, ethyl linoleate, isopropyl linoleate, isopropyl palmitate, or butyl stearate.
- the oil phase may be a carboxylic acid ester such as ethyl lactate, cetyl lactate, triethyl citrate, diisopropyl adipate, diethyl sebacate, diisopropyl sebacate, or cetyl 2-ethylhexanoate, or a hydrocarbon such as petrolatum, white petrolatum, liquid paraffin, squalane, or vegetable squalane, or a silicone oil.
- the oil-based base material may be used alone or in a mixture of two or more.
- Preferred oil-based base materials include squalane oil, castor oil, sesame oil, white petrolatum, and liquid paraffin, and more preferred oil-based base materials include castor oil, isopropyl myristate, and silicone oil.
- the oil base is castor oil
- the surfactant can be any one or more surfactants selected from the group consisting of glyceryl dioleate, polyoxyethylene hydrogenated castor oil 10, sorbitan sesquioleate, and sucrose laurate.
- the solid particle-dispersed oil-based formulation is formulated as an ophthalmic formulation (e.g., eye drops or intraocular formulation).
- an ophthalmic formulation e.g., eye drops or intraocular formulation
- a solid complex comprising particles containing a pharma- ceutically acceptable target substance or molecule and a pharma-ceutically acceptable surfactant
- a pharma- ceutically acceptable oil base is provided.
- the ophthalmic formulation is an eye drop.
- the ophthalmic formulation is an intravitreal formulation.
- the solid particle dispersion oil formulation can release the target substance or target molecule in a sustained manner.
- the solid particle dispersion oil formulation can release the target substance or target molecule in the eye of a living body (e.g., in the vitreous body) for at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 9 hours, 12 hours, 18 hours, 24 hours (2 days), 3 days, 4 days, 5 days, 6 days, 7 days (1 week), or 2 weeks.
- the solid particle dispersion oil formulation of the present disclosure can release the target substance or target molecule in the ocular irrigation solution for at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 9 hours, 12 hours, 18 hours, 24 hours (2 days), 3 days, 4 days, 5 days, 6 days, 7 days (1 week), or 2 weeks.
- the solid particle dispersion oil formulation releases the target substance or target molecule only at or below the sustained release standard value.
- the sustained release standard value is a standard time in which the target substance or target molecule contained in the formulation is released at 50% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, or 5% or less.
- the sustained release standard time can be, for example, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 9 hours, 12 hours, 18 hours, 24 hours (2 days), 3 days, 4 days, 5 days, 6 days, 7 days (1 week), or 2 weeks.
- the sustained release preferably occurs after administration to the vitreous of the subject.
- the solid particle dispersion oil formulation of the present disclosure can deliver the target substance or molecule to one or more of the anterior ocular tissues selected from the group consisting of the cornea, conjunctiva, aqueous humor, iris, ciliary body, and lens, and the posterior ocular tissues selected from the group consisting of the sclera, choroid, retinal pigment epithelium, neural retina, optic nerve, vitreous membrane, and vitreous humor.
- the solid particle dispersion oil formulation of the present disclosure can deliver the target substance or molecule to one or more of the above tissues over an extended period of time.
- the eye drops of the present disclosure are dispersed in an oily base and are less likely to be excreted by tears than hydrophilic substances.
- the eye drops of the present disclosure may also pass through the corneal epithelium, which exhibits hydrophobic properties, and may be suitable for the penetration of drugs into ocular tissues and posterior ocular tissues.
- the eye drops of the present disclosure may have tissue permeability.
- the formulation for intravitreal administration of the present disclosure is dispersed in an oily base and is less likely to be diffused or excreted by vitreous humor than hydrophilic substances. It is believed that the form of the solid particle-dispersed oily formulation may inhibit the active ingredient from diffusing prematurely into body fluids, allowing the active ingredient to be released gradually.
- a method of treating an ophthalmic disease in a subject includes administering to the subject a therapeutic agent for ophthalmic disease of the present disclosure.
- the therapeutic agent for ophthalmic disease may be a solid particle dispersion oily formulation containing the therapeutic agent for ophthalmic disease as a drug.
- the administration may be by eye drops or intraocular administration, preferably intravitreal administration.
- the amount administered may be a therapeutically effective amount.
- the present disclosure provides a method for administering a therapeutic drug for ophthalmic disease to a subject, the therapeutic drug for ophthalmic disease being a solid particle dispersion oil formulation containing the therapeutic drug for ophthalmic disease as a drug.
- a solid particle dispersion oil formulation for use in the method of the present disclosure.
- a solid particle dispersion oil formulation or a target substance or target molecule in the manufacture of a medicament for use in the method of the present disclosure.
- Example 1 Preparation of eye drop preparation and intravitreal preparation
- a preparation in which solid particles formed by coating a drug with a surfactant are dispersed in oil was applied to the eye.
- Drugs used included those from a variety of pharmaceutical modalities, including proteins, antibodies, and nucleic acids.
- An experimental system was constructed to examine the application of solid particle dispersion oil preparations as ophthalmic preparations. Specifically, a stationary jacketed Franz diffusion cell for membrane permeation tests (manufactured by Cosmedy) was divided into the top and bottom by a polycarbonate membrane (pore size: 0.1 ⁇ m, manufactured by Merck), the solid particle dispersion oil preparation was added to the top, and the bottom was filled with ocular irrigation fluid (Opeguard) MA ocular irrigation fluid, manufactured by Senju Pharmaceutical Co., Ltd.). The temperature was maintained at 36°C, which is the eyeball surface temperature. When the obtained solid particle dispersion oil preparation was added to the top, the transfer of the drug to the ocular irrigation fluid in the bottom was confirmed.
- ocular irrigation fluid Opeguard
- Antibody A human total IgG antibody was used as the antibody.
- An aqueous solution containing 1 mg/mL IgG and 0.3 mg mannitol was mixed with a cyclohexane solution containing 25 mg/mL surfactant, and the mixture was stirred for 2 minutes at 26,000 rpm using a homogenizer.
- the surfactant one selected from glyceryl dioleate (DGMO), sorbitan sesquioleate (SO), polyoxyethylene hydrogenated castor oil 10 (HCO), and sucrose laurate (L195) was used.
- DGMO glyceryl dioleate
- SO sorbitan sesquioleate
- HCO polyoxyethylene hydrogenated castor oil 10
- sucrose laurate L195
- the obtained solid particles were dispersed in 1 mL castor oil (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) to obtain a solid particle dispersion oil formulation containing an IgG antibody.
- the particle size distribution of the solid particles in the obtained solid particle dispersion oil formulation was measured using a Zetasizer (Zetasizer Nano ZS, manufactured by Marvern). The particle size distribution results were as shown in FIG. 2B.
- the average hydrodynamic particle size was about 110 to 170 nm.
- the average hydrodynamic particle size of particles with HCO as the surfactant was 120 ⁇ 9 nm, with a PDI of 0.564 to 0.787
- the average hydrodynamic particle size of particles with DGMO as the surfactant was 114 ⁇ 7 nm, with a PDI of 0.307 to 0.399
- the average hydrodynamic particle size of particles with SO as the surfactant was 122 ⁇ 12 nm, with a PDI of 0.345 to 0.693
- the average hydrodynamic particle size of particles with L195 as the surfactant was 163 ⁇ 8 nm, with a PDI of 0.604 to 0.816.
- the obtained solid particles were dispersed in 1 mL castor oil (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) to obtain a solid particle dispersion oil formulation containing lysozyme as an active ingredient.
- the particle size distribution of the solid particles in the obtained solid particle dispersion oil formulation was measured with a Zetasizer (Zetasizer Nano ZS, manufactured by Marvern). The particle size distribution results are shown in FIG. 3B.
- Anti-VEGF antibody A commercially available mouse-derived anti-VEGF antibody (Recombinant Mouse VEGF 164 ) was used as the antibody. 100 ⁇ g of a commercially available antibody lyophilized with trehalose and PBS was dissolved in 500 ⁇ L of Milli-Q water. 50 ⁇ L of an aqueous antibody solution was mixed with 2 mL of a cyclohexane solution containing 4 mg/mL surfactant, and stirred for 2 minutes at 26,000 rpm with a homogenizer. The resulting emulsion was lyophilized for 24 hours to remove the solvent, and solid particles in which the drug was coated with the surfactant were obtained.
- the resulting solid particles were dispersed in 50 ⁇ L of castor oil to obtain a solid particle-dispersed oil formulation containing an anti-VEGF antibody as an active ingredient.
- the particle size distribution of the solid particles in the resulting solid particle-dispersed oil formulation was measured with a Zetasizer (Zetasizer Nano ZS, manufactured by Marvern). The particle size distribution results were as shown in FIG. 4A.
- the kinetics of the drug after administration was confirmed using rabbits.
- the obtained solid particle dispersion oil formulation was administered by eye drop or intravitreally to rabbits so that the antibody amount was 0.4 ⁇ g per single eye.
- the aqueous humor, vitreous body, and retina/choroid of the rabbits were collected 24 hours, 72 hours, and 120 hours after administration, and the amount of antibody contained in each was measured.
- Figure 4B after the obtained solid particle dispersion oil formulation was administered by eye drop, some of the anti-VEGF antibodies were detected in the retina/choroid up to 120 hours after administration.
- Figures 4C and 4D after the obtained solid particle dispersion oil formulation was administered intravitreally, most of the antibodies migrated to the retina/choroid and maintained their concentration for a long period of time.
- the antibody used was aflibercept, an anti-VEGF antibody.
- Aflibercept was purified. Specifically, the product additives of Eylea (registered trademark) intravitreal injection solution were removed using PD-10 (Cytiva) according to the manufacturer's manual, and then mannitol was added to the obtained antibody to a final concentration of 0.1%, and Milli-Q water was added to the obtained antibody to an antibody concentration of 1 mg/mL to obtain an antibody aqueous solution. The antibody aqueous solution was mixed with a cyclohexane solution containing 25 mg/mL surfactant, and stirred at 26,000 rpm for 2 minutes using a homogenizer.
- the obtained emulsion was freeze-dried for 24 hours to remove the solvent, and solid particles in which the drug was coated with the surfactant were obtained.
- the obtained solid particles were dispersed in 1 mL of isopropyl myristate (manufactured by Tokyo Chemical Industry Co., Ltd.) to obtain a solid particle dispersion oil formulation containing an anti-VEGF antibody as an active ingredient.
- Example 2 Toxicity Test Mice were used in the test. Mice (Balb/cJJcl, 10 weeks old, female) were intravitreally injected with 100 ⁇ L of solid particle dispersion oil formulation (see STAR Protocols 1, 100094, September 18, 2020), and the eyeballs were collected after 2 weeks and tissue sections were observed under a microscope. The tissue sections were 20 ⁇ m thick and were subjected to hematoxylin-eosin staining. The toxicity of any of the oil bases, castor oil, isopropyl myristate, or silicone oil (KF96), was evaluated.
- KF96 silicone oil
- the solid particle-dispersed oil formulation was administered by eye drop and intravitreal administration.
- the solid particle-dispersed oil formulation was excellent in long-term sustained release performance of the drug when administered by eye drop and intravitreal administration.
- the solid particle-dispersed oil formulation also had advantages such as high delivery and/or accumulation of the drug to the retina/choroid. It is suggested that the preparation in which solid particles are dispersed in oil (solid particle-dispersed oil formulation) has high tissue permeability and is effective not only in intravitreal administration but also in various intraocular administrations.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dispersion Chemistry (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Ophthalmology & Optometry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
La présente divulgation concerne une préparation huileuse dispersée de particules solides. La présente divulgation concerne également une préparation huileuse dispersée de particules solides appropriée pour des gouttes oculaires ou une administration intraoculaire. La préparation d'huile dispersée de particules solides contient (i) des complexes solides qui contiennent un tensioactif pharmaceutiquement acceptable et des particules contenant une substance cible pharmaceutiquement acceptable ou une molécule cible et (ii) une base huileuse pharmaceutiquement acceptable. Les particules dans la préparation huileuse dispersée de particules solides sont typiquement enrobées avec le tensioactif. De plus, la substance cible ou la molécule cible dans la préparation huileuse dispersée de particules solides peut être soluble dans l'eau.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2022-166209 | 2022-10-17 | ||
JP2022166209 | 2022-10-17 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2024085100A1 true WO2024085100A1 (fr) | 2024-04-25 |
Family
ID=90737568
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2023/037321 WO2024085100A1 (fr) | 2022-10-17 | 2023-10-16 | Préparation huileuse dispersée de particules solides |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2024085100A1 (fr) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011004552A1 (fr) * | 2009-07-09 | 2011-01-13 | 国立大学法人九州大学 | Support de médicament soluble dans l'eau et son procédé de fabrication |
WO2020203809A1 (fr) * | 2019-03-29 | 2020-10-08 | 日産化学株式会社 | Nouveau procédé de production de formulation s/o de lécithine, et formulation associée |
WO2022196748A1 (fr) * | 2021-03-17 | 2022-09-22 | 国立大学法人九州大学 | Agent d'absorption transdermique |
WO2022264184A1 (fr) * | 2021-06-17 | 2022-12-22 | The University Of Jordan | Composition ophtalmique en nano-dispersion, procédé pour sa préparation, et formulation de guérison de plaies épithéliales de la cornée |
-
2023
- 2023-10-16 WO PCT/JP2023/037321 patent/WO2024085100A1/fr unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011004552A1 (fr) * | 2009-07-09 | 2011-01-13 | 国立大学法人九州大学 | Support de médicament soluble dans l'eau et son procédé de fabrication |
WO2020203809A1 (fr) * | 2019-03-29 | 2020-10-08 | 日産化学株式会社 | Nouveau procédé de production de formulation s/o de lécithine, et formulation associée |
WO2022196748A1 (fr) * | 2021-03-17 | 2022-09-22 | 国立大学法人九州大学 | Agent d'absorption transdermique |
WO2022264184A1 (fr) * | 2021-06-17 | 2022-12-22 | The University Of Jordan | Composition ophtalmique en nano-dispersion, procédé pour sa préparation, et formulation de guérison de plaies épithéliales de la cornée |
Non-Patent Citations (2)
Title |
---|
JABER MAI; JABER BAHAA; HAMED SAJA; ALKHATIB HATIM S.: "Preparation and evaluation of ascorbyl glucoside and ascorbic acid solid in oil nanodispersions for corneal epithelial wound healing", INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER, NL, vol. 627, 23 September 2022 (2022-09-23), NL , XP087200549, ISSN: 0378-5173, DOI: 10.1016/j.ijpharm.2022.122227 * |
SRIVIDYA GORANTLA: "Nanocarriers for ocular drug delivery: current status and translational opportunity", RSC ADVANCES, ROYAL SOCIETY OF CHEMISTRY, GB, vol. 10, no. 46, 24 July 2020 (2020-07-24), GB , pages 27835 - 27855, XP093161045, ISSN: 2046-2069, DOI: 10.1039/D0RA04971A * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Souto et al. | Advanced formulation approaches for ocular drug delivery: state-of-the-art and recent patents | |
Souza et al. | Topical delivery of ocular therapeutics: carrier systems and physical methods | |
Li et al. | Nanoparticulate drug delivery to the retina | |
Soni et al. | Design and evaluation of ophthalmic delivery formulations | |
Liu et al. | Highly bioactive, bevacizumab-loaded, sustained-release PLGA/PCADK microspheres for intravitreal therapy in ocular diseases | |
UA111168C2 (uk) | Емульсія типу вода-в-олії для лікування хвороб ока | |
Desai et al. | Ophthalmic and otic drug administration: novel approaches and challenges | |
Formica et al. | Triamcinolone acetonide-loaded lipid nanocapsules for ophthalmic applications | |
CA2809460C (fr) | Emulsion de type eau-dans-l'huile destinee au traitement d'une maladie oculaire | |
JP2009538880A (ja) | 硝子体内注入用のプロドラッグ | |
JP7079250B2 (ja) | リポソーム構築物を用いた黄斑細胞及び網膜細胞への尿素の送達 | |
JP2011522792A (ja) | 生物活性薬の封入 | |
Kim et al. | Intraocular distribution and kinetics of intravitreally injected antibodies and nanoparticles in rabbit eyes | |
US20240207195A1 (en) | Ocular drug delivery | |
JP5920928B2 (ja) | 局所眼科用ペプチド製剤 | |
Eriksen et al. | Multifarious biologic loaded liposomes that stimulate the mammalian target of rapamycin signaling pathway show retina neuroprotection after retina damage | |
Chaw et al. | In vivo fate of liposomes after subconjunctival ocular delivery | |
Pignatello et al. | Nanotechnology in ophthalmic drug delivery: a survey of recent developments and patenting activity | |
WO2024085100A1 (fr) | Préparation huileuse dispersée de particules solides | |
Yordanova Andonova | A new direction in ophthalmic development: Nanoparticle drug delivery systems | |
CN109906075A (zh) | 用于在发炎病灶或区域中局部注射的脂质体皮质类固醇 | |
US20120058187A1 (en) | Water-in-oil type emulsion for treating a disease of the eye | |
JP2011519893A (ja) | 生物活性薬の封入 | |
JP2023541372A (ja) | 神経保護方法及びその使用 | |
Kim et al. | Ocular permeation enhancers |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 23879743 Country of ref document: EP Kind code of ref document: A1 |