WO2006009112A1 - 水性点眼剤 - Google Patents
水性点眼剤 Download PDFInfo
- Publication number
- WO2006009112A1 WO2006009112A1 PCT/JP2005/013157 JP2005013157W WO2006009112A1 WO 2006009112 A1 WO2006009112 A1 WO 2006009112A1 JP 2005013157 W JP2005013157 W JP 2005013157W WO 2006009112 A1 WO2006009112 A1 WO 2006009112A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- eye drop
- eye
- oil
- lecithin
- aqueous
- Prior art date
Links
- 239000003889 eye drop Substances 0.000 title claims abstract description 85
- 229940012356 eye drops Drugs 0.000 title abstract description 25
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims abstract description 34
- 206010013774 Dry eye Diseases 0.000 claims abstract description 34
- 235000019438 castor oil Nutrition 0.000 claims abstract description 29
- 239000004359 castor oil Substances 0.000 claims abstract description 29
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims abstract description 29
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims abstract description 27
- 239000000787 lecithin Substances 0.000 claims abstract description 26
- 235000010445 lecithin Nutrition 0.000 claims abstract description 26
- 229940067606 lecithin Drugs 0.000 claims abstract description 25
- 239000000839 emulsion Substances 0.000 claims description 39
- 230000003204 osmotic effect Effects 0.000 claims description 17
- 150000005846 sugar alcohols Polymers 0.000 claims description 6
- 239000003792 electrolyte Substances 0.000 claims description 5
- 235000000346 sugar Nutrition 0.000 claims description 5
- 239000003921 oil Substances 0.000 abstract description 48
- 230000002265 prevention Effects 0.000 abstract description 9
- 239000006196 drop Substances 0.000 abstract description 2
- 239000002085 irritant Substances 0.000 abstract 1
- 231100000021 irritant Toxicity 0.000 abstract 1
- 235000019198 oils Nutrition 0.000 description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- 239000002245 particle Substances 0.000 description 19
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 18
- 239000002997 ophthalmic solution Substances 0.000 description 16
- 229940054534 ophthalmic solution Drugs 0.000 description 16
- 239000008213 purified water Substances 0.000 description 16
- 230000005068 transpiration Effects 0.000 description 15
- 239000012530 fluid Substances 0.000 description 14
- 235000011187 glycerol Nutrition 0.000 description 9
- -1 polyoxyethylene Polymers 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 8
- 230000008020 evaporation Effects 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 239000004094 surface-active agent Substances 0.000 description 8
- 239000000607 artificial tear Substances 0.000 description 7
- 239000010408 film Substances 0.000 description 6
- 230000008859 change Effects 0.000 description 5
- 210000004087 cornea Anatomy 0.000 description 5
- 238000007865 diluting Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000004945 emulsification Methods 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- 102000015728 Mucins Human genes 0.000 description 4
- 108010063954 Mucins Proteins 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 230000007794 irritation Effects 0.000 description 4
- 229910001415 sodium ion Inorganic materials 0.000 description 4
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical class CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 241000283977 Oryctolagus Species 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 238000005266 casting Methods 0.000 description 3
- 210000000795 conjunctiva Anatomy 0.000 description 3
- 229940099578 hydrogenated soybean lecithin Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229910001414 potassium ion Inorganic materials 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 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
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- 244000068988 Glycine max Species 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 206010047513 Vision blurred Diseases 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 208000003464 asthenopia Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229920001400 block copolymer Polymers 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 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
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 description 1
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 1
- LSIXBBPOJBJQHN-UHFFFAOYSA-N 2,3-Dimethylbicyclo[2.2.1]hept-2-ene Chemical compound C1CC2C(C)=C(C)C1C2 LSIXBBPOJBJQHN-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 206010051625 Conjunctival hyperaemia Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 241000196324 Embryophyta Species 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
- 206010015946 Eye irritation Diseases 0.000 description 1
- 206010052140 Eye pruritus Diseases 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 241000083513 Punctum Species 0.000 description 1
- MJNIWUJSIGSWKK-BBANNHEPSA-N Riboflavin butyrate Chemical compound CCCC(=O)OC[C@@H](OC(=O)CCC)[C@@H](OC(=O)CCC)[C@@H](OC(=O)CCC)CN1C2=CC(C)=C(C)C=C2N=C2C1=NC(=O)NC2=O MJNIWUJSIGSWKK-BBANNHEPSA-N 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 108091006503 SLC26A1 Proteins 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 241000808812 Thrombium 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
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004397 blinking Effects 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940006423 chondroitin sulfate sodium Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001687 destabilization Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 235000013345 egg yolk Nutrition 0.000 description 1
- 210000002969 egg yolk Anatomy 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 231100000013 eye irritation Toxicity 0.000 description 1
- 230000004438 eyesight Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 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
- 210000003097 mucus Anatomy 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229940056692 resinol Drugs 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- WBHHMMIMDMUBKC-XLNAKTSKSA-N ricinelaidic acid Chemical compound CCCCCC[C@@H](O)C\C=C\CCCCCCCC(O)=O WBHHMMIMDMUBKC-XLNAKTSKSA-N 0.000 description 1
- FEUQNCSVHBHROZ-UHFFFAOYSA-N ricinoleic acid Natural products CCCCCCC(O[Si](C)(C)C)CC=CCCCCCCCC(=O)OC FEUQNCSVHBHROZ-UHFFFAOYSA-N 0.000 description 1
- 229960003656 ricinoleic acid Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 230000004488 tear evaporation Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 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
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- 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
-
- 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
Definitions
- the present invention relates to an aqueous eye drop, and more particularly to an aqueous eye drop effective for the prevention or treatment of dry eye associated with increased evaporation of tears.
- dry eye is a state in which the cornea or conjunctiva on the surface of the eye has been damaged due to a decrease in the amount of tears secreted or a qualitative change in tears.
- Tear fluid is composed of three layers: an oil layer, an aqueous layer, and a mucin layer, and the failure of the three-layer structure of tears causes dry eye.
- Commonly used eye drops for dry eye are artificial tears mainly composed of sodium ions and strength thrombium ions for the purpose of replenishing the water layer, chondroitin sulfate sodium and hyaluronic acid.
- these eye drops are effective in preventing or treating tear-reducing dry eye caused by decreased secretion of water or mucin secretion, but are caused by damage to the oil layer.
- an aqueous eye drop in which an oil is dissolved using a surfactant is known.
- oils such as riboflavin butyrate and castor oil, which have high lipid solubility and are insoluble in water, are treated with polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene.
- a surfactant such as ethylene polyoxypropylene block copolymers
- lecithin is a component that is originally present in tear fluid and is safe, and thus an eye drop in which oil is emulsified using lecithin has been known (see Patent Documents 6 and 7).
- Patent Document 8 it is known that aqueous oil-in-water emulsions containing specific phospholipids and nonpolar oils are effective for dry eyes (see Patent Document 8). While casting, castor oil with lecithin Emulsified and provided an aqueous eye drop effective for the prevention or treatment of dry eye.
- Patent Document 1 Japanese Patent Laid-Open No. 10-218760
- Patent Document 2 Japanese Patent Laid-Open No. 2000-159659
- Patent Document 3 JP-A-2-83323
- Patent Document 4 Japanese Patent Laid-Open No. 11 29483
- Patent Document 5 Japanese Unexamined Patent Publication No. 2000-273061
- Patent Document 6 Japanese Patent Laid-Open No. 62-106018
- Patent Document 7 Japanese Patent Laid-Open No. 62-270521
- Patent Document 8 JP-A-4-279525
- An object of the present invention is to prevent or treat dry eye, which can uniformly disperse castor oil on the ocular surface, has a stable presence of oil in the eye drop, and has low irritation. It is to provide an effective aqueous eye drop.
- an aqueous eye drop formulated with castor oil and lecithin can stably retain the oil content in the eye drop, and immediately after the eye drop. It has been found that the oil component is separated and the oil component can be efficiently dispersed on the ocular surface, thereby significantly suppressing the transpiration of water from the ocular surface.
- An embodiment of the present invention completed on the basis of strong knowledge is an aqueous eye drop for preventing or treating dry eye characterized by containing castor oil and lecithin.
- the aspect of the present invention is a method for preventing or treating dry eye using an aqueous eye drop containing castor oil and lecithin, or an aqueous eye drop for preventing or treating dry eye.
- dry eye associated with increased evaporation of tears and fatigue of the eyes, which are the symptoms of the dry eye. It is effective in preventing or treating blurred vision, itchy eyes, itching of the eyes, conjunctival hyperemia, and discomfort when wearing contact lenses, and the oil is stably retained in the eye drops and is safe for the eyes. It became possible to provide a high aqueous eye drop.
- FIG. 1 is a photograph showing a tear film in normal eyes.
- FIG. 2 is a photograph showing a tear film when the eye drop prepared in Example 2 is instilled.
- FIG. 3 A photograph showing the tear film after the tears in the eye surface and conjunctival sac are completely wiped off with filter paper.
- the present invention is unique to the combination of castor oil and lecithin. If other vegetable oils or low molecular weight oil-soluble components are used as the oil, the oil cannot be efficiently dispersed on the ocular surface. This is because castor oil is a polar oil containing 80% or more of a monovalent unsaturated fatty acid called ricinoleic acid having a hydroxyl group, and its molecular weight is as high as 900 or more, so it is efficiently applied to the interface between the tear fluid layer and the tear fluid layer. This is because it is thought that it accumulates and disperses on the surface of the eye, thereby suppressing water evaporation from the surface of the eye.
- castor oil is a polar oil containing 80% or more of a monovalent unsaturated fatty acid called ricinoleic acid having a hydroxyl group, and its molecular weight is as high as 900 or more, so it is efficiently applied to the interface between the tear fluid layer and the tear fluid layer. This is because it is thought
- the compounding (contained) amount of castor oil is 0.001% by mass to 10% by mass in the eye drop, and 0.01% by mass to 1% by mass is preferable. If it exceeds 10% by mass, it may cause stickiness, blurred vision, or irritation, and if it is less than 0.001% by mass, sufficient suppression of water evaporation on the surface of the eye cannot be obtained. .
- lecithin examples include lecithin derived from natural products obtained from diacyl ester-type glycemic phospholipids such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidic acid, and animals and plants such as soybeans and egg yolk, or hydrogens thereof. Additives can be mentioned. Hydrogenated lecithin is preferred because of its excellent acid stability. Hydrogenated soybean lecithin is more preferred. These lecithins can only be used with one species
- Two or more types can be used in combination.
- the amount of lecithin (containing) is 0.001 part by mass or more with respect to 1 part by mass of castor oil, 0.001 to 10 parts by mass being preferred, and 0.01 to 1 part by mass being preferred. More preferred.
- the aqueous eye drop of the present invention is preferably an OZW type emulsion.
- castor oil is emulsified with lecithin and is present in the aqueous eye drop as fine oil droplets. It is an eye drop that forms
- the aqueous eye drop of the present invention is preferably isotonic to relieve irritation during eye drops, and an osmotic pressure regulator may be blended.
- the osmotic pressure adjusting agent include polyhydric alcohols or sugars.
- examples of the polyhydric alcohol include glycerin, sorbitol, mannitol, trenorose, xylitol, propylene glycol, and polyethylene glycol. Glucose is mentioned as sugar. These polyhydric alcohols and sugars can be used in combination of two or more, just by using one.
- the amount (inclusive) of the polyhydric alcohol or sugar is 0.01 to 4% by mass in the eye drop, and the osmotic pressure of the eye drop is 228 to 458 mOsm considering eye irritation. It is preferable to blend in.
- the aqueous eye drop of the present invention contains various additives such as a stabilizer, an antioxidant, a chelating agent, a pH adjuster, and a thickener as long as the effects of the present invention are not impaired. can do.
- a stabilizer such as sodium ion or potassium ion
- the total amount of the electrolyte must be 30 mmolZL or less in the eye drop. If the amount exceeds this, the stability of the emulsion cannot be maintained in the eye drop, and the oils will coalesce or aggregate.
- the average particle diameter of the emulsion in the eye drop is preferably 200 nm or less in order to ensure the transparency of the eye drop.
- the particle diameter can be measured using a laser diffraction / scattering particle size distribution measuring apparatus or the like.
- the aqueous eye drop of the present invention uses a surfactant such as polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene polyoxypropylene block copolymers, and the like.
- a surfactant such as polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene polyoxypropylene block copolymers, and the like.
- castor oil is emulsified with lecithin to form emulsion, and is stably present in the eye drop, but when it comes into contact with tears in the conjunctival sac,
- the formulation is designed so that it reacts with a large amount of electrolytes and proteins present in it, and the emulsion structure collapses.As a result, the oil in the emulsion coalesces or aggregates and disperses efficiently in the tear oil layer. It is a thing.
- the aqueous eye drop of the present invention is prepared by the following method. Hydrogenated soybean lecithin is heated and dissolved in an aqueous solution containing purified water in a polyhydric alcohol such as glycerin to obtain an aqueous phase. Castor oil, which is an oil component, is added to this aqueous phase, and a pre-emulsion obtained using a general stirrer is subjected to a high-pressure emulsification method using a high-pressure homogenizer, an ultrasonic emulsification method using an ultrasonic homogenizer, or a high-speed homogenizer. High energy emulsification is performed by high-speed concentrated shearing emulsification method to obtain fine emulsion.
- This fine emulsion can be diluted with purified water and then sterilized by filtration to give a sterile eye drop. Furthermore, by filling the unit dose, it is possible to provide an eye drop that is stable and safe for a long period of time without the addition of an antiseptic that is undesirable for dry eye patients.
- Glycerin Japanese Pharmacopoeia compatible product 58. 2 g of purified water 19. Og was added and homogenized, then heated to 70 ° C and stirred with hydrogenated soybean soy lecithin (Resinol S-10M (trade name) 2. 2 g was added and dispersed. While heating at 70 ° C., 20 g of castor oil (Japanese Pharmacopoeia compatible product) was added and stirred with a homogenizer (Hiscotron (trade name), manufactured by Hitachi, Ltd.) to obtain a preliminary emulsion.
- a homogenizer Hiscotron (trade name), manufactured by Hitachi, Ltd.
- This emulsion was emulsified at a pressure of lOOMPa using a high-pressure homogenizer (Minilab 830H (trade name), manufactured by Runny) to prepare a fine emulsion.
- the average particle size of the emulsion was measured with a laser diffraction / scattering particle size distribution analyzer (HORIBA LA-920 (trade name)) and found to be 124 nm.
- Example 1 After diluting the emulsion prepared in Production Example 1 200 times with purified water, add an appropriate amount of glycerin to adjust the osmotic pressure, sterilize by filtration, and prepare a total amount of aseptic eyedrops of lOOmL. Filled in todos. At this time, the osmotic pressure was 286 mOsm and the average particle size was 124 nm.
- the emulsion prepared in Production Example 1 was diluted 20 times with purified water, and then sterilized by filtration. A total amount of aseptic ophthalmic solution (10 mL) was prepared and filled in a unit dose. The osmotic pressure at this time was 304 mOsm, and the average particle size was 124 nm.
- Example 8 After diluting the emulsion prepared in Production Example 1 200 times with purified water, add sorbitol to adjust the osmotic pressure, sterilize by filtration, prepare a total amount of aseptic eyedrops lOOmL, and fill the unit dose. did. At this time, the osmotic pressure was 286 mOsm and the average particle size was 124 nm. [0035] Example 8
- the osmotic pressure was 286 mOsm, and the average particle size was 124 nm.
- glycerin was added to adjust the osmotic pressure, sterilization by filtration was carried out, and a total amount of aseptic ophthalmic solution of lOOmL was prepared and filled in a unit dose.
- the osmotic pressure at this time was 286 mOsm.
- taurine 1 The calorie was added so that 0% by mass, 0.3% by mass of sodium chloride and 0.06% by mass of potassium chloride were added. After adding appropriate amounts of glycerin and a pH adjuster (sodium hydroxide), the solution was sterilized by filtration to prepare a total amount of sterile eye drops of 10 mL and filled in a unit dose. The osmotic pressure at this time was 286 mOsm, pH 7.4.
- the amount of water transpiration from the ocular surface was measured using TEWAMETER TM300 (COURAGE + KHAZ AKA electronic GmbH). After fixing a male Japanese white rabbit (Kitayama Labes) weighing approximately 2.5 kg with an Oshida-type fixator, inoculate 50% L of Benokiseal 0.4 mass% ophthalmic solution (trade name, Santen Pharmaceutical Co., Ltd.) and ocular surface anesthesia was given. After 5 minutes, the tears in the ocular surface and conjunctival sac are completely wiped off using filter paper, and 50 L of the instillation sample is applied. After 5 minutes, 10 minutes, 15 minutes, and 30 minutes The amount of water transpiration was measured. The amount of moisture evaporation was calculated from the following formula using the value immediately before instillation as 100%. The number of cases in each group was 6. The results are shown in Table 3.
- the aqueous eye drops prepared by casting castor oil with lecithin rapidly disperse on the surface of the eye due to the unstable emulsion structure on the surface of the eye. It has become clear that even a small amount of oil can effectively suppress moisture evaporation.
- Example 2 To 10 mL of the artificial tears, 10 mL of the aqueous eye drop prepared in Example 2 was added, stored at 37 ° C, and the particle size was measured. The particle size of the eye drop of Example 2 before addition was 124 nm, whereas the particle size after 5 minutes at 37 ° C was 350 nm, showing a rapid increase, and the emulsion became unstable. It was. The ion concentration at this time was 78.5 mmol / L.
- the emulsion ophthalmic solution according to the present invention is unstable in artificial tears mainly composed of sodium ions, potassium ions, etc., which are close to physiological conditions, but the ion concentration is 30 mmolZL or less.
- the present aqueous eye drop was stable. That is, the aqueous ophthalmic solution according to the present invention has an unstable emulsion structure in tears after instillation, and efficiently disperses the oil in the ophthalmic solution on the surface of the eye, whereas it is stable in the ophthalmic solution before instillation. It became clear that the emulsion structure was maintained.
- Test Example 4 Evaluation of the tear oil layer by the tear speckle measurement method
- a dry eye observation apparatus DR-1 (manufactured by Kowa Co., Ltd.) was used for the observation of tear fluid dynamics.
- DR-1 is a device that irradiates the cornea with white light and measures the reflected light with a video camera.
- the tear film has a three-layer structure of a mucus layer, an aqueous layer and an oil layer from the corneal surface.
- This device measures the interference image of the light reflected from the oil layer surface and the oil layer back surface (boundary surface with the water layer). That is, the interference image obtained by this apparatus shows the state of the tear fluid layer.
- the interference image obtained by this apparatus is observed to be uniform gray or white in normal eyes, and in dry eye, the oil layer is not uniform, so an image in which red and blue colors are mixed is observed. In more severe dry eyes, there is no oil layer, so the interference image disappears and the cornea Exposed state (this is the same (see “Atarashi ⁇ B”, 14 (11), 1605-1612, 1997, Am. J. Op hthalmol., 122, 818-824, 1996)).
- a male Japanese white rabbit weighing approximately 2.5 kg was fixed with an Oshida type fixator, then 50 drops of 0.4% by weight of Benokiseal ophthalmic solution was applied, and ocular surface anesthesia was performed. After 5 minutes, the tears in the ocular surface and conjunctival sac were completely wiped off using filter paper, and the eye drop prepared in Example 2 was instilled with 50 L, and 5 minutes later, the state of the tear fluid layer was observed. The tear oil layer in normal eyes was observed before ocular surface anesthesia.
- the present aqueous ophthalmic solution spreads to the tear fluid layer after instillation, maintains the oil layer in a uniform state, and suppresses the amount of transpiration from the eye surface as shown in Test Example 2, It was found to be effective in improving dry eye symptoms.
- the present invention suggests the development of an aqueous eye drop effective for the prevention or treatment of dry eye associated with increased tear evaporation.
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WO2008074885A2 (en) * | 2006-12-21 | 2008-06-26 | Novagali Pharma Sa | Process for manufacturing ophthalmic oil-in-water emulsions |
JP2008273959A (ja) * | 2007-04-04 | 2008-11-13 | Taisho Pharmaceutical Co Ltd | 点眼剤 |
WO2010064636A1 (ja) * | 2008-12-02 | 2010-06-10 | ロート製薬株式会社 | 眼科用組成物 |
JP2014028865A (ja) * | 2013-11-11 | 2014-02-13 | Santen Sas | 眼科用水中油型乳剤を製造する方法 |
CN107614018A (zh) * | 2015-05-28 | 2018-01-19 | 乐敦制药株式会社 | 水性眼科组合物 |
KR20180081597A (ko) | 2015-12-22 | 2018-07-16 | 니치유 가부시키가이샤 | 누액 유층 안정화제 및 이것을 함유하는 점안제 |
EP3500344A4 (en) * | 2016-08-19 | 2020-08-05 | Akrivista, LLC | METHOD OF DIAGNOSIS AND TREATMENT OF DRY EYE SYNDROME AND COMPOSITIONS FOR TREATMENT OF A HUMAN EYE |
RU2772357C2 (ru) * | 2011-12-07 | 2022-05-19 | Аллерган, Инк. | Состав для эффективной доставки липидов в слезную пленку человека с использованием чувствительной к соли эмульсионной системы |
US11622982B2 (en) | 2017-08-18 | 2023-04-11 | Akrivista Llc | Methods of diagnosing and treating dry eye syndrome and compositions for treating a human eye |
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WO2008074885A2 (en) * | 2006-12-21 | 2008-06-26 | Novagali Pharma Sa | Process for manufacturing ophthalmic oil-in-water emulsions |
WO2008074885A3 (en) * | 2006-12-21 | 2008-10-09 | Novagali Pharma Sa | Process for manufacturing ophthalmic oil-in-water emulsions |
US9364461B2 (en) | 2006-12-21 | 2016-06-14 | Santen Sas | Process for manufacturing ophthalmic oil-in-water emulsions |
JP2011506266A (ja) * | 2006-12-21 | 2011-03-03 | ノバガリ・フアルマ・エス・エイ | 眼科用水中油型乳剤を製造する方法 |
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JP5670200B2 (ja) * | 2008-12-02 | 2015-02-18 | ロート製薬株式会社 | 眼科用組成物 |
WO2010064636A1 (ja) * | 2008-12-02 | 2010-06-10 | ロート製薬株式会社 | 眼科用組成物 |
RU2772357C2 (ru) * | 2011-12-07 | 2022-05-19 | Аллерган, Инк. | Состав для эффективной доставки липидов в слезную пленку человека с использованием чувствительной к соли эмульсионной системы |
JP2014028865A (ja) * | 2013-11-11 | 2014-02-13 | Santen Sas | 眼科用水中油型乳剤を製造する方法 |
CN107614018A (zh) * | 2015-05-28 | 2018-01-19 | 乐敦制药株式会社 | 水性眼科组合物 |
KR20180081597A (ko) | 2015-12-22 | 2018-07-16 | 니치유 가부시키가이샤 | 누액 유층 안정화제 및 이것을 함유하는 점안제 |
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US11903986B2 (en) | 2016-08-19 | 2024-02-20 | Akrivista Llc | Methods of diagnosing and treating dry eye syndrome and compositions for treating a human eye |
US11622982B2 (en) | 2017-08-18 | 2023-04-11 | Akrivista Llc | Methods of diagnosing and treating dry eye syndrome and compositions for treating a human eye |
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