WO2018011705A1 - Liposome-based eye drops and use thereof for in vivo evaluation of the drug efficacy of medical and surgical anti-glaucoma therapy - Google Patents
Liposome-based eye drops and use thereof for in vivo evaluation of the drug efficacy of medical and surgical anti-glaucoma therapy Download PDFInfo
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- WO2018011705A1 WO2018011705A1 PCT/IB2017/054164 IB2017054164W WO2018011705A1 WO 2018011705 A1 WO2018011705 A1 WO 2018011705A1 IB 2017054164 W IB2017054164 W IB 2017054164W WO 2018011705 A1 WO2018011705 A1 WO 2018011705A1
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- Prior art keywords
- eye drops
- drug
- liposome
- drops according
- solution
- Prior art date
Links
- 229940079593 drug Drugs 0.000 title claims abstract description 31
- 239000003814 drug Substances 0.000 title claims abstract description 31
- 239000002502 liposome Substances 0.000 title claims abstract description 25
- 239000003889 eye drop Substances 0.000 title claims abstract description 23
- 229940012356 eye drops Drugs 0.000 title claims abstract description 23
- 238000001727 in vivo Methods 0.000 title abstract description 9
- 230000001384 anti-glaucoma Effects 0.000 title abstract description 7
- 238000002560 therapeutic procedure Methods 0.000 title description 8
- 238000011156 evaluation Methods 0.000 title description 7
- 210000001742 aqueous humor Anatomy 0.000 claims abstract description 13
- 230000037361 pathway Effects 0.000 claims abstract description 11
- 239000006185 dispersion Substances 0.000 claims abstract description 10
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229920001287 Chondroitin sulfate Polymers 0.000 claims abstract description 6
- 229920002385 Sodium hyaluronate Polymers 0.000 claims abstract description 6
- 229940059329 chondroitin sulfate Drugs 0.000 claims abstract description 6
- 229940010747 sodium hyaluronate Drugs 0.000 claims abstract description 6
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims abstract description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 229960004657 indocyanine green Drugs 0.000 claims description 9
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 claims description 9
- 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 description 7
- 235000010445 lecithin Nutrition 0.000 claims description 7
- 229940067606 lecithin Drugs 0.000 claims description 7
- 239000000787 lecithin Substances 0.000 claims description 7
- 235000012000 cholesterol Nutrition 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 5
- 230000009467 reduction Effects 0.000 claims description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- SJEYSFABYSGQBG-UHFFFAOYSA-M Patent blue Chemical compound [Na+].C1=CC(N(CC)CC)=CC=C1C(C=1C(=CC(=CC=1)S([O-])(=O)=O)S([O-])(=O)=O)=C1C=CC(=[N+](CC)CC)C=C1 SJEYSFABYSGQBG-UHFFFAOYSA-M 0.000 claims description 3
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 claims description 3
- UDSAIICHUKSCKT-UHFFFAOYSA-N bromophenol blue Chemical compound C1=C(Br)C(O)=C(Br)C=C1C1(C=2C=C(Br)C(O)=C(Br)C=2)C2=CC=CC=C2S(=O)(=O)O1 UDSAIICHUKSCKT-UHFFFAOYSA-N 0.000 claims description 3
- 239000007853 buffer solution Substances 0.000 claims description 3
- NJDNXYGOVLYJHP-UHFFFAOYSA-L disodium;2-(3-oxido-6-oxoxanthen-9-yl)benzoate Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=CC(=O)C=C2OC2=CC([O-])=CC=C21 NJDNXYGOVLYJHP-UHFFFAOYSA-L 0.000 claims description 3
- -1 infracyanine green Chemical compound 0.000 claims description 3
- RWVGQQGBQSJDQV-UHFFFAOYSA-M sodium;3-[[4-[(e)-[4-(4-ethoxyanilino)phenyl]-[4-[ethyl-[(3-sulfonatophenyl)methyl]azaniumylidene]-2-methylcyclohexa-2,5-dien-1-ylidene]methyl]-n-ethyl-3-methylanilino]methyl]benzenesulfonate Chemical compound [Na+].C1=CC(OCC)=CC=C1NC1=CC=C(C(=C2C(=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C)C=2C(=CC(=CC=2)N(CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C)C=C1 RWVGQQGBQSJDQV-UHFFFAOYSA-M 0.000 claims description 3
- 239000002539 nanocarrier Substances 0.000 abstract description 2
- 238000012800 visualization Methods 0.000 abstract 1
- 230000004410 intraocular pressure Effects 0.000 description 16
- 239000000975 dye Substances 0.000 description 12
- 239000008154 viscoelastic solution Substances 0.000 description 7
- 208000010412 Glaucoma Diseases 0.000 description 6
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 5
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 229960001416 pilocarpine Drugs 0.000 description 5
- 210000001585 trabecular meshwork Anatomy 0.000 description 5
- 230000000007 visual effect Effects 0.000 description 5
- 239000000872 buffer Substances 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 230000004509 aqueous humor production Effects 0.000 description 3
- 230000001886 ciliary effect Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000013160 medical therapy Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 150000003180 prostaglandins Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000011200 topical administration Methods 0.000 description 3
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 239000000048 adrenergic agonist Substances 0.000 description 2
- 239000002876 beta blocker Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 229940039231 contrast media Drugs 0.000 description 2
- 239000002872 contrast media Substances 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229960001160 latanoprost Drugs 0.000 description 2
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000003547 miosis Effects 0.000 description 2
- 239000003604 miotic agent Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 210000001525 retina Anatomy 0.000 description 2
- 229960004605 timolol Drugs 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- WLRMANUAADYWEA-NWASOUNVSA-N (S)-timolol maleate Chemical compound OC(=O)\C=C/C(O)=O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 WLRMANUAADYWEA-NWASOUNVSA-N 0.000 description 1
- XYLJNLCSTIOKRM-UHFFFAOYSA-N Alphagan Chemical compound C1=CC2=NC=CN=C2C(Br)=C1NC1=NCCN1 XYLJNLCSTIOKRM-UHFFFAOYSA-N 0.000 description 1
- 201000002862 Angle-Closure Glaucoma Diseases 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 208000024304 Choroidal Effusions 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
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010020852 Hypertonia Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000006550 Mydriasis Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 description 1
- 208000037111 Retinal Hemorrhage Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 206010045178 Tunnel vision Diseases 0.000 description 1
- 206010047555 Visual field defect Diseases 0.000 description 1
- 230000004308 accommodation Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 229940006133 antiglaucoma drug and miotics carbonic anhydrase inhibitors Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 229960003679 brimonidine Drugs 0.000 description 1
- 229960000722 brinzolamide Drugs 0.000 description 1
- HCRKCZRJWPKOAR-JTQLQIEISA-N brinzolamide Chemical compound CCN[C@H]1CN(CCCOC)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 HCRKCZRJWPKOAR-JTQLQIEISA-N 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960004484 carbachol Drugs 0.000 description 1
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 description 1
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- RZWZDIVNLQZHGB-UHFFFAOYSA-N chloroform;methylsulfinylmethane Chemical compound CS(C)=O.ClC(Cl)Cl RZWZDIVNLQZHGB-UHFFFAOYSA-N 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 210000003161 choroid Anatomy 0.000 description 1
- 210000004240 ciliary body Anatomy 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229960003933 dorzolamide Drugs 0.000 description 1
- IAVUPMFITXYVAF-XPUUQOCRSA-N dorzolamide Chemical compound CCN[C@H]1C[C@H](C)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 IAVUPMFITXYVAF-XPUUQOCRSA-N 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000004438 eyesight Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000000642 iatrogenic effect Effects 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002430 laser surgery Methods 0.000 description 1
- 238000002647 laser therapy Methods 0.000 description 1
- 229960000831 levobunolol Drugs 0.000 description 1
- IXHBTMCLRNMKHZ-LBPRGKRZSA-N levobunolol Chemical compound O=C1CCCC2=C1C=CC=C2OC[C@@H](O)CNC(C)(C)C IXHBTMCLRNMKHZ-LBPRGKRZSA-N 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 229960002362 neostigmine Drugs 0.000 description 1
- ALWKGYPQUAPLQC-UHFFFAOYSA-N neostigmine Chemical compound CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 ALWKGYPQUAPLQC-UHFFFAOYSA-N 0.000 description 1
- 210000001328 optic nerve Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229960001697 physostigmine Drugs 0.000 description 1
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 229940127293 prostanoid Drugs 0.000 description 1
- 150000003814 prostanoids Chemical class 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 239000000310 rehydration solution Substances 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 229960005221 timolol maleate Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000003860 topical agent Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229960002368 travoprost Drugs 0.000 description 1
- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000004382 visual function Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
- A61K49/0034—Indocyanine green, i.e. ICG, cardiogreen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0076—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion
- A61K49/0084—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion liposome, i.e. bilayered vesicular structure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
Definitions
- the present invention relates to contrast media, more specifically to contrast media for use in the immediate evaluation of the efficacy of a drug or surgery for treating glaucoma.
- the eye pressure is kept constant by the balance between the continuous formation of aqueous humor by the ciliary body, and the outflow of a same amount of aqueous humor mainly through the iridocorneal trabecular meshwork, Schlemm's canal and the aqueous veins. This balance between production and elimination allows the eye to have its own pressure.
- Medical therapy essentially acts either by reducing the amount of aqueous humor produced per unit of time or by facilitating the outflow thereof from the eye through the conventional trabecular, or unconventional uveo-scleral pathway.
- the main outflow pathway is the trabecular, which is pressure-dependent, which discharges 80%-85% of the aqueous humor, with progressively increasing difficulty moving from the uveal to the cribriform trabecular meshwork, which is less permeable.
- the multiplicity of possible "fractals" in the trabecular meshwork affects the resistance to outflow and is one of the main sites responsible for ocular hypertonia.
- the genetic expression of glaucoma is also surely expressed through this fractal structure of the trabecular meshwork.
- the outflow through this pathway can increase the longitudinal fibers of the ciliary muscle by contraction, with retraction and fan-like opening of trabecular spaces.
- a second pathway is uveo- scleral, which is pressure-independent and uses the relative patency of the ciliary muscle tissue and of the suprachoroidal spaces. It contributes to 15%-20% of the total outflow under normal conditions, taking considerable importance in situations of obstruction of the main pathway.
- IOP intraocular pressure
- Glaucoma patients require periodic check-ups. The disease may in fact worsen without the patient's being aware of that, in which case it may be necessary to change the type of therapy. Once the damage has established, it is not reversible: medication and surgery are used to prevent further damage and to keep the existing visual function. Glaucoma treatment is only effective if the patient observes the therapy prescribed by the doctor. If medical therapy is not effective in controlling intraocular pressure, it may be necessary to resort to laser therapy or surgery. In most cases, the described operations are able to prevent the disease progression to blindness. Therefore, the goal of any anti-glaucoma therapy is to reach the target IOP, i.e. the one which does not worsen the visual field. Each reduced pressure millimeter corresponds to a reduction in the risk of worsening of the visual field by about 19%.
- the patient risks getting worse before he/she has verified whether the therapeutic choice was adequate or not.
- the effectiveness or not of the drug substance or of the selected surgical technique in reducing IOP can only be assessed on the basis of the deterioration or absence of morphological and functional parameters, after a certain period of time.
- Anti-glaucoma drugs can basically be divided into 6 groups:
- Miotics with direct action such as pilocarpine, carbachol
- Miotics in an indirect action cholinesterase inhibitors which are more powerful than the previous ones, but with more side effects (such as neostigmine, physostigmine);
- Beta-adrenergic receptor blocking agents which do not result in alterations of the accommodation and of the size of the pupil, but work by reducing the production of aqueous humor (such as timolol, levobunolol);
- Non-selective adrenergic agonists which cause mydriasis and lower IOP by reducing the aqueous humor production and increasing the outflow thereof (such as adenalin);
- Selective adrenergic agonists which lower IOP by reducing the aqueous humor production and increasing the uveoscleral outflow (such as apralonidine, brimonidine);
- Carbonic anhydrase inhibitors useful as an adjunct therapy to topical agents (such as dorzolamide and brinzolamide);
- Hyperosmotic agents used in acute glaucoma attack such as mannitol and glycerin
- Prostaglandin analogs such as latanoprost and travoprost.
- vital dyes are known in ophthalmology, called vital dyes, which are already used in ocular diagnostics for the angiography of the retina and choroid, for coloring the capsule of lens in capsulorrhexis, and for visualizing the internal limiting membrane in vitreo-retinal surgery.
- indocyanine green infracyanine green
- sodium fluorescein trypan blue
- Patent blue bromophenol blue
- brilliant blue G the most used are: indocyanine green, infracyanine green, sodium fluorescein, trypan blue, Patent blue, bromophenol blue, brilliant blue G.
- the amounts of dye used in surgical practice are, however, such as to induce a toxic effect, both directly and by metabolites thereof.
- the intravitreal injection of the dye to at the required concentrations can in fact alter the osmolarity in the vitreous cavity, thus damaging the neurosensory retina, with the possibility of causing iatrogenic damage on the inner retinal layers, a high incidence of retinal hemorrhage and visual field defects.
- Figure 1 shows how the aqueous humor production and outflow take place.
- Figure 2 (A-D) shows the trabecular outflow by means of injection of a solution containing indocyanine green in Schlemm's canal.
- Eye drops consisting of a visco-elastic dispersion comprising chondroitin sulfate and optionally sodium hyaluronate, a vitreo-retinal dye and an antiglaucoma drug of the above type, conveyed by a liposome-based nano-carrier to be administered topically as eye drops.
- the present invention allows to solve the above problems by providing the physician with a means of investigation which allows the immediate in vivo evaluation of the pharmacological effectiveness of the drug tested.
- eye drops consisting of a dispersion of liposomes in buffer solution, wherein said liposomes contain:
- buffered saline is an aqueous solution having a pH of between 6.8 - 7.5.
- the above solution is a saline and the buffer used is PBS; particularly preferred is a pH value equal to 7.2.
- Liposomes are, as is known, hollow spherical particles whose surface consists of a dual phospholipid layer and normally having a diameter of the order of 100-200 nm, capable of transporting hydrophilic substances in their cavity and lipid substances in the dual phospholipid layer.
- liposomes consist of the binary lecithin/water system or preferably of the ternary lecithin-water-cholesterol system.
- lecithin/cholesterol weight ratio By modulating the lecithin/cholesterol weight ratio, liposomes develop different performances and stability which can be exploited in particular situations.
- the liposomes used according to the invention were prepared using the dehydrated film formation technique and subsequent rehydration with phosphate buffer, using a lecithin to cholesterol weight ratio of 4:1 .
- a viscoelastic solution, a vital dye for ophthalmological use and an anti-glaucoma drug selected from those mentioned above in the prior art discussion are inserted in the liposomes as described above; depending on the nature of these compounds (hydrophilic or lipophilic), they will of course arrange themselves in the cavity or in the part of the liposome.
- the drug is hydrophilic, it is loaded with the rehydration solution of the liposome, if it is hydrophobic it is loaded with a mixed solvent, such as chloroform-dimethylsulfoxide in the solubilization step.
- the viscoelastic solution according to the invention is an aqueous solution preferably consisting of chondroitin sulfate and sodium hyaluronate.
- chondroitin sulfate is present in the solution in an amount of between 4 and 40 mg per imL, sodium hyaluronate in an amount of between 1 .0 and 17 mg per imL
- the vital dye used for the invention is one of those normally used in ophthalmology and is selected for example from: indocyanine green, infracyanine green, sodium fluorescein, trypan blue, Patent blue, bromophenol blue, brilliant blue G.
- the amount of dye depends on the type used; for indocyanine green, the concentration preferably used is between 0.125 ⁇ g (micrograms) to 25 mg (milligrams) per imL; preferably, the amount used is 2.5 micrograms per imL
- the drug to be tested is present at a concentration ranging from 0.001 %, for example for prostaglandin analogs, up to 1 % for pilocarpine.
- the percentages indicated refer to the weight calculated on the total weight of the liposome.
- Liposomes (lecithin/water/cholesterol) 0.5 img/mL;
- the activity of the eye drops was investigated in rabbit eyes.
- Intraocular pressure was measured using a Schiotz tonometer before and after the topical administration with free drug, and with drug in liposomal dispersion. The results showed that administration of the liposomal dispersion prolongs the effect compared to the administration of the free drug.
- the stability of the liposomal preparation studied by measuring the phase transition and the particle size distribution by means of light scattering technique demonstrated that the liposomes with pilocarpine maintained the integrity and the physical-chemical properties for at least 12 months, which makes them suitable for commercial use.
- the main action of the drug is exerted through the contraction of the ciliary muscle, which in turn moves the scleral spur and the trabecular tissues, in such a way as to widen the spaces for the outflow of the aqueous humor (Duke-Elder,
- Liposome-based eye drops for in vivo evaluation of the pharmacological effectiveness of beta-blockers.
- Liposomes (lecithin/water/cholesterol) 0.5 img/mL;
- Intraocular pressure was measured using a Schiotz tonometer before and after the topical administration with free drug, and with drug in liposomal dispersion. Compared with the free drug, the formulation into a liposomal dispersion showed a significant increase in the corneal penetration. Since the primary action of the drug is exerted through the decreased production of aqueous humor, such a case in vivo corresponds to a significant reduction of the clearance of the aqueous humor.
- Liposomes (lecithin/water/cholesterol) 0.5 img/mL;
- Intraocular pressure was measured using a Schiotz tonometer before and after the topical administration with free drug, and with drug in liposomal dispersion. Compared with the free drug, the formulation into a liposomal dispersion showed a significant increase in the corneal penetration. The main action of the drug is exerted through the increase in the uveo-scleral outflow; such a case in vivo corresponds to an increase of the unconventional pathway outflow, with normal trabecular outflow.
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Abstract
Eye drops are described consisting of a visco-elastic dispersion comprising chondroitin sulfate and optionally sodium hyaluronate, a vitreo-retinal dye and an antiglaucoma drug of the above type, conveyed by a liposome-based nano-carrier to be administered topically as eye drops to highlight the drug efficacy in vivo using direct visualization of the conventional aqueous humor outflow pathway.
Description
LIPOSOME-BASED EYE DROPS AND USE THEREOF FOR IN VIVO EVALUATION OF THE DRUG EFFICACY OF MEDICAL AND SURGICAL ANTI- GLAUCOMA THERAPY Field of the invention.
The present invention relates to contrast media, more specifically to contrast media for use in the immediate evaluation of the efficacy of a drug or surgery for treating glaucoma. Prior art
In healthy individuals, the eye pressure is kept constant by the balance between the continuous formation of aqueous humor by the ciliary body, and the outflow of a same amount of aqueous humor mainly through the iridocorneal trabecular meshwork, Schlemm's canal and the aqueous veins. This balance between production and elimination allows the eye to have its own pressure.
The lack of or poor outflow of such a liquid through Schlemm's canal can lead to an increase in eye pressure which can be mitigated by medical therapy, parasurgical therapy and surgical therapy.
Medical therapy essentially acts either by reducing the amount of aqueous humor produced per unit of time or by facilitating the outflow thereof from the eye through the conventional trabecular, or unconventional uveo-scleral pathway.
The main outflow pathway is the trabecular, which is pressure-dependent, which discharges 80%-85% of the aqueous humor, with progressively increasing difficulty moving from the uveal to the cribriform trabecular meshwork, which is less permeable.
The multiplicity of possible "fractals" in the trabecular meshwork affects the resistance to outflow and is one of the main sites responsible for ocular hypertonia. The genetic expression of glaucoma is also surely expressed through this fractal structure of the trabecular meshwork. The outflow through this pathway can increase the longitudinal fibers of the ciliary muscle by contraction, with retraction and fan-like opening of trabecular spaces. A second pathway is uveo- scleral, which is pressure-independent and uses the relative patency of the ciliary
muscle tissue and of the suprachoroidal spaces. It contributes to 15%-20% of the total outflow under normal conditions, taking considerable importance in situations of obstruction of the main pathway.
A high eye pressure leads to a decrease in the patient's visual capacity by progressively narrowing his/her field of vision up to cause a tubular vision. IOP (intraocular pressure) is the only modifiable risk factor, for which reason decreasing the IOP decreases the risk of damage to the optic nerve and preserves the visual field. Moreover, the earlier and more consistent the reduction of IOP, the better the prognosis.
Glaucoma patients require periodic check-ups. The disease may in fact worsen without the patient's being aware of that, in which case it may be necessary to change the type of therapy. Once the damage has established, it is not reversible: medication and surgery are used to prevent further damage and to keep the existing visual function. Glaucoma treatment is only effective if the patient observes the therapy prescribed by the doctor. If medical therapy is not effective in controlling intraocular pressure, it may be necessary to resort to laser therapy or surgery. In most cases, the described operations are able to prevent the disease progression to blindness. Therefore, the goal of any anti-glaucoma therapy is to reach the target IOP, i.e. the one which does not worsen the visual field. Each reduced pressure millimeter corresponds to a reduction in the risk of worsening of the visual field by about 19%.
Unfortunately, one of the limits of the treatment of glaucoma is that the therapeutic effectiveness of the approach (whatever it is) can be verified only in retrospect.
The patient risks getting worse before he/she has verified whether the therapeutic choice was adequate or not. In other words, the effectiveness or not of the drug substance or of the selected surgical technique in reducing IOP can only be assessed on the basis of the deterioration or absence of morphological and functional parameters, after a certain period of time.
Anti-glaucoma drugs can basically be divided into 6 groups:
1 . Miotics with direct action (such as pilocarpine, carbachol)
2. Miotics in an indirect action, cholinesterase inhibitors which are more powerful than the previous ones, but with more side effects (such as neostigmine, physostigmine);
3. Beta-adrenergic receptor blocking agents which do not result in alterations of the accommodation and of the size of the pupil, but work by reducing the production of aqueous humor (such as timolol, levobunolol);
4. Non-selective adrenergic agonists which cause mydriasis and lower IOP by reducing the aqueous humor production and increasing the outflow thereof (such as adenalin);
5. Selective adrenergic agonists which lower IOP by reducing the aqueous humor production and increasing the uveoscleral outflow (such as apralonidine, brimonidine);
6. Carbonic anhydrase inhibitors, useful as an adjunct therapy to topical agents (such as dorzolamide and brinzolamide);
7. Hyperosmotic agents used in acute glaucoma attack (such as mannitol and glycerin);
8. Prostaglandin analogs (such as latanoprost and travoprost).
The prior verification of the treatment effectiveness would be extremely useful, and especially of great advantage for the patient.
This can be done through an in vivo imaging technique, capable of highlighting the aqueous humor outflow pathways.
Various dyes are known in ophthalmology, called vital dyes, which are already used in ocular diagnostics for the angiography of the retina and choroid, for coloring the capsule of lens in capsulorrhexis, and for visualizing the internal limiting membrane in vitreo-retinal surgery.
Among these, the most used are: indocyanine green, infracyanine green, sodium fluorescein, trypan blue, Patent blue, bromophenol blue, brilliant blue G.
The amounts of dye used in surgical practice are, however, such as to induce a toxic effect, both directly and by metabolites thereof.
The intravitreal injection of the dye to at the required concentrations can in fact alter the osmolarity in the vitreous cavity, thus damaging the neurosensory retina,
with the possibility of causing iatrogenic damage on the inner retinal layers, a high incidence of retinal hemorrhage and visual field defects.
Visual field disturbances have however been reported after vitrectomy with the use of indocyanine green in the removal of the internal limiting membrane.
In the light of the foregoing, it is clear that it is important to have a carrier capable of using the above dyes in a safe manner, together with every drug approved for the medical treatment of glaucoma in order to verify the effectiveness thereof and thus allow to decide whether to continue treatment with it or instead use a different drug.
Brief description of the figures
Figure 1 shows how the aqueous humor production and outflow take place.
Figure 2 (A-D) shows the trabecular outflow by means of injection of a solution containing indocyanine green in Schlemm's canal.
Summary of the invention
Eye drops are described consisting of a visco-elastic dispersion comprising chondroitin sulfate and optionally sodium hyaluronate, a vitreo-retinal dye and an antiglaucoma drug of the above type, conveyed by a liposome-based nano-carrier to be administered topically as eye drops.
Detailed description of the invention
The present invention allows to solve the above problems by providing the physician with a means of investigation which allows the immediate in vivo evaluation of the pharmacological effectiveness of the drug tested.
It was in fact found that eye drops consisting of a dispersion of liposomes in buffer solution, wherein said liposomes contain:
1 ) a viscoelastic aqueous solution;
2) a vital dye used in ophthalmology;
3) a drug for the reduction of IOP
allows to highlight the therapeutic efficacy of said drug by viewing the effect on the trabecular or conventional aqueous humor outflow pathway.
According to the invention, buffered saline is an aqueous solution having a pH of between 6.8 - 7.5.
Preferably, the above solution is a saline and the buffer used is PBS; particularly preferred is a pH value equal to 7.2.
Liposomes are, as is known, hollow spherical particles whose surface consists of a dual phospholipid layer and normally having a diameter of the order of 100-200 nm, capable of transporting hydrophilic substances in their cavity and lipid substances in the dual phospholipid layer.
In particular, according to the invention, liposomes consist of the binary lecithin/water system or preferably of the ternary lecithin-water-cholesterol system. By modulating the lecithin/cholesterol weight ratio, liposomes develop different performances and stability which can be exploited in particular situations.
The liposomes used according to the invention were prepared using the dehydrated film formation technique and subsequent rehydration with phosphate buffer, using a lecithin to cholesterol weight ratio of 4:1 .
A viscoelastic solution, a vital dye for ophthalmological use and an anti-glaucoma drug selected from those mentioned above in the prior art discussion are inserted in the liposomes as described above; depending on the nature of these compounds (hydrophilic or lipophilic), they will of course arrange themselves in the cavity or in the part of the liposome.
For example, if the drug is hydrophilic, it is loaded with the rehydration solution of the liposome, if it is hydrophobic it is loaded with a mixed solvent, such as chloroform-dimethylsulfoxide in the solubilization step.
The viscoelastic solution according to the invention is an aqueous solution preferably consisting of chondroitin sulfate and sodium hyaluronate.
Preferably, according to the invention, chondroitin sulfate is present in the solution in an amount of between 4 and 40 mg per imL, sodium hyaluronate in an amount of between 1 .0 and 17 mg per imL
The vital dye used for the invention is one of those normally used in ophthalmology and is selected for example from: indocyanine green, infracyanine green, sodium fluorescein, trypan blue, Patent blue, bromophenol blue, brilliant blue G.
The amount of dye depends on the type used; for indocyanine green, the concentration preferably used is between 0.125 μg (micrograms) to 25 mg (milligrams) per imL; preferably, the amount used is 2.5 micrograms per imL
The drug to be tested is present at a concentration ranging from 0.001 %, for example for prostaglandin analogs, up to 1 % for pilocarpine. The percentages indicated refer to the weight calculated on the total weight of the liposome.
Once prepared, the solution is ready to be instilled as extemporaneous eye drops. Experimental part Examplel
Liposome-based eye drops for in vivo evaluation of the pharmacological effectiveness of pilocarpine.
Eye drops were used, consisting of:
Buffer aqueous solution pH 7.2 3 imL;
Liposomes (lecithin/water/cholesterol) 0.5 img/mL;
Viscoelastic solution and indocyanine green 52.5 img/mL;
Pilocarpine 10 μg/mL.
The activity of the eye drops was investigated in rabbit eyes.
Intraocular pressure (IOP) was measured using a Schiotz tonometer before and after the topical administration with free drug, and with drug in liposomal dispersion. The results showed that administration of the liposomal dispersion prolongs the effect compared to the administration of the free drug. The stability of the liposomal preparation studied by measuring the phase transition and the particle size distribution by means of light scattering technique demonstrated that the liposomes with pilocarpine maintained the integrity and the physical-chemical properties for at least 12 months, which makes them suitable for commercial use.
Both the dye and the viscoelastic solution were added to this preparation.
The main action of the drug is exerted through the contraction of the ciliary muscle, which in turn moves the scleral spur and the trabecular tissues, in such a way as to widen the spaces for the outflow of the aqueous humor (Duke-Elder,
1958). In vivo, such a case corresponds to a significant increase in the conventional outflow of the aqueous humor if the pathways downstream of the
trabecular meshwork (Schlemm's canal, collector channels, episcleral veins) are functioning.
Example 2:
Liposome-based eye drops for in vivo evaluation of the pharmacological effectiveness of beta-blockers.
Eye drops were used, consisting of:
Buffer aqueous solution pH 7.2 3 imL;
Liposomes (lecithin/water/cholesterol) 0.5 img/mL;
Viscoelastic solution and indocyanine green 52.5 img/mL;
Timolol 50 μg/mL.
Liposomes loaded with timolol maleate were prepared. Both the dye and the viscoelastic solution were added to this preparation. Intraocular pressure (IOP) was measured using a Schiotz tonometer before and after the topical administration with free drug, and with drug in liposomal dispersion. Compared with the free drug, the formulation into a liposomal dispersion showed a significant increase in the corneal penetration. Since the primary action of the drug is exerted through the decreased production of aqueous humor, such a case in vivo corresponds to a significant reduction of the clearance of the aqueous humor.
Example 3:
Liposome-based eye drops for in vivo evaluation of the pharmacological effectiveness of prostaglandin analogs and prostanoids
Eye drops were used, consisting of:
Buffer aqueous solution pH 7.2 3 imL;
Liposomes (lecithin/water/cholesterol) 0.5 img/mL;
Viscoelastic solution and indocyanine green 52.5 img/mL;
Latanoprost 50 μg/mL.
Intraocular pressure (IOP) was measured using a Schiotz tonometer before and after the topical administration with free drug, and with drug in liposomal dispersion. Compared with the free drug, the formulation into a liposomal dispersion showed a significant increase in the corneal penetration. The main
action of the drug is exerted through the increase in the uveo-scleral outflow; such a case in vivo corresponds to an increase of the unconventional pathway outflow, with normal trabecular outflow.
Claims
1 . Eye drops consisting of a dispersion of liposomes in buffer solution, wherein said liposomes contain:
a viscoelastic aqueous solution;
a vital dye used in ophthalmology;
a drug for the reduction of IOP.
2. Eye drops according to claim 1 , wherein the buffer solution is a physiological solution at pH of between 6.8-7.5, preferably 7.2.
3. Eye drops according to claim 1 , wherein said viscoelastic aqueous solution is an aqueous solution containing sodium hyaluronate and chondroitin sulfate.
4. Eye drops according to claims 1 and 2, wherein said liposomes consist of lecithin and cholesterol in a weight ratio of 4:1 .
5. Eye drops according to claims 1 -4, wherein chondroitin sulfate is present in the solution in an amount of between 4 and 40 mg per imL and sodium hyaluronate in an amount of between 1 .0 and 17 mg per imL
6. Eye drops according to claim 1 , wherein the vital dye is selected from: indocyanine green, infracyanine green, sodium fluorescein, trypan blue, Patent blue, bromophenol blue, brilliant blue G.
7. Eye drops according to claims 1 -6, wherein the drug is present in a concentration of between 0.001 % and 1 % by weight, calculated on the total weight of the liposome.
8. Use of the eye drops according to claims 1 -7 to highlight the therapeutic efficacy of said drug by viewing the effect on the trabecular or conventional aqueous humor outflow pathway.
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---|---|---|---|---|
CN110559261A (en) * | 2018-06-06 | 2019-12-13 | 常州药物研究所有限公司 | Liposome microemulsion containing nano cross-linked hyaluronic acid and preparation method and application thereof |
WO2022008703A1 (en) * | 2020-07-10 | 2022-01-13 | Universiteit Gent | Dyes for use in a method of photoporation of the inner limiting membrane |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0522226A1 (en) * | 1991-07-12 | 1993-01-13 | Ciro Costagliola | Eyedrop solution for the treatment of ocular hypertension containing ketauserin |
-
2016
- 2016-07-11 IT IT102016000072000A patent/IT201600072000A1/en unknown
-
2017
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0522226A1 (en) * | 1991-07-12 | 1993-01-13 | Ciro Costagliola | Eyedrop solution for the treatment of ocular hypertension containing ketauserin |
Non-Patent Citations (5)
Title |
---|
A.SOLTAN MONEM ET AL: "Prolonged effect of liposomes encapsulating pilocarpine HCl in normal and glaucomatous rabbits", INTERNATIONAL JOURNAL OF PHARMACEUTICS, 1 January 2000 (2000-01-01), NETHERLANDS, pages 29 - 38, XP055359960, Retrieved from the Internet <URL:http://www.sciencedirect.com/science/article/pii/S0378517399003488/pdfft?md5=a3fb89b8b8940256fc0f104b2e3be517&pid=1-s2.0-S0378517399003488-main.pdf> DOI: 10.1016/S0378-5173(99)00348-8 * |
LUIGI AMBROSONE ET AL: "Corneal Epithelial Wound Healing Promoted by Verbascoside-Based Liposomal Eyedrops", BIOMED RESEARCH INTERNATIONAL, vol. 2014, 1 January 2014 (2014-01-01), pages 1 - 8, XP055360437, ISSN: 2314-6133, DOI: 10.1155/2014/471642 * |
NAKAMURA SHIGERU ET AL: "Development of a rabbit model of tear film instability and evaluation of viscosity of artificial tear preparations", vol. 23, no. 4, 1 May 2004 (2004-05-01), pages 390 - 397, XP008184072, ISSN: 0277-3740, Retrieved from the Internet <URL:http://journals.lww.com/corneajrnl/Abstract/2004/05000/Development_of_a_Rabbit_Model_of_Tear_Film.15.aspx> * |
RANIA M. HATHOUT ET AL: "Liposomes as an ocular delivery system for acetazolamide: In vitro and in vivo studies", AAPS PHARMSCITECH, vol. 8, no. 1, 1 March 2007 (2007-03-01), pages E1 - E12, XP055360402, DOI: 10.1208/pt0801001 * |
TINA T. WONG ET AL: "Nanomedicine for glaucoma: sustained release latanoprost offers a new therapeutic option with substantial benefits over eyedrops", DRUG DELIVERY AND TRANSLATIONAL RESEARCH, vol. 4, no. 4, 31 March 2014 (2014-03-31), Germany, pages 303 - 309, XP055359873, ISSN: 2190-393X, DOI: 10.1007/s13346-014-0196-9 * |
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CN110559261A (en) * | 2018-06-06 | 2019-12-13 | 常州药物研究所有限公司 | Liposome microemulsion containing nano cross-linked hyaluronic acid and preparation method and application thereof |
WO2022008703A1 (en) * | 2020-07-10 | 2022-01-13 | Universiteit Gent | Dyes for use in a method of photoporation of the inner limiting membrane |
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