JP2007517885A - 眼に投与するためのメマンチンおよびポリアニオン性ポリマーを含む組成物 - Google Patents
眼に投与するためのメマンチンおよびポリアニオン性ポリマーを含む組成物 Download PDFInfo
- Publication number
- JP2007517885A JP2007517885A JP2006549374A JP2006549374A JP2007517885A JP 2007517885 A JP2007517885 A JP 2007517885A JP 2006549374 A JP2006549374 A JP 2006549374A JP 2006549374 A JP2006549374 A JP 2006549374A JP 2007517885 A JP2007517885 A JP 2007517885A
- Authority
- JP
- Japan
- Prior art keywords
- component
- composition
- eye
- adamantane
- neuroprotective
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 187
- 229920000447 polyanionic polymer Polymers 0.000 title claims abstract description 26
- 229960004640 memantine Drugs 0.000 title claims description 102
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 title claims 6
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 claims abstract description 160
- 230000000324 neuroprotective effect Effects 0.000 claims abstract description 96
- 238000000034 method Methods 0.000 claims abstract description 58
- 230000000694 effects Effects 0.000 claims abstract description 46
- 241001465754 Metazoa Species 0.000 claims abstract description 24
- 150000001412 amines Chemical class 0.000 claims abstract description 18
- 231100000252 nontoxic Toxicity 0.000 claims abstract description 10
- 230000003000 nontoxic effect Effects 0.000 claims abstract description 10
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 59
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 55
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 53
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 53
- 210000001525 retina Anatomy 0.000 claims description 21
- 238000011200 topical administration Methods 0.000 claims description 16
- 230000001154 acute effect Effects 0.000 claims description 13
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 11
- 235000010443 alginic acid Nutrition 0.000 claims description 11
- 229920000615 alginic acid Polymers 0.000 claims description 11
- 230000007794 irritation Effects 0.000 claims description 11
- 239000000783 alginic acid Substances 0.000 claims description 10
- 229960001126 alginic acid Drugs 0.000 claims description 10
- 150000004781 alginic acids Chemical class 0.000 claims description 10
- 239000008365 aqueous carrier Substances 0.000 claims description 10
- 229920002845 Poly(methacrylic acid) Polymers 0.000 claims description 9
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 229920002125 Sokalan® Polymers 0.000 claims description 7
- 239000004584 polyacrylic acid Substances 0.000 claims description 7
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 claims description 6
- 229960003805 amantadine Drugs 0.000 claims description 6
- 229920006321 anionic cellulose Polymers 0.000 claims description 6
- 229960000888 rimantadine Drugs 0.000 claims description 6
- 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 class 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 claims description 5
- 208000003098 Ganglion Cysts Diseases 0.000 claims description 5
- 108010010803 Gelatin Proteins 0.000 claims description 5
- 229920000805 Polyaspartic acid Polymers 0.000 claims description 5
- 208000005400 Synovial Cyst Diseases 0.000 claims description 5
- 229920006320 anionic starch Chemical class 0.000 claims description 5
- 230000006727 cell loss Effects 0.000 claims description 5
- 229920000159 gelatin Polymers 0.000 claims description 5
- 239000008273 gelatin Substances 0.000 claims description 5
- 229940014259 gelatin Drugs 0.000 claims description 5
- 235000019322 gelatine Nutrition 0.000 claims description 5
- 235000011852 gelatine desserts Nutrition 0.000 claims description 5
- 229920002674 hyaluronan Polymers 0.000 claims description 5
- 229960003160 hyaluronic acid Drugs 0.000 claims description 5
- 235000019426 modified starch Nutrition 0.000 claims description 5
- 230000004770 neurodegeneration Effects 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 108010064470 polyaspartate Proteins 0.000 claims description 4
- 229920003169 water-soluble polymer Polymers 0.000 claims description 4
- 125000005647 linker group Chemical group 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- 208000002193 Pain Diseases 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
- 230000001681 protective effect Effects 0.000 claims description 2
- 241000282412 Homo Species 0.000 claims 2
- 210000005036 nerve Anatomy 0.000 claims 1
- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical compound Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 description 110
- 210000001508 eye Anatomy 0.000 description 61
- 238000009472 formulation Methods 0.000 description 38
- 239000004615 ingredient Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 208000010412 Glaucoma Diseases 0.000 description 16
- 239000003755 preservative agent Substances 0.000 description 16
- 230000000699 topical effect Effects 0.000 description 16
- 230000002207 retinal effect Effects 0.000 description 14
- 230000002335 preservative effect Effects 0.000 description 12
- 241000283973 Oryctolagus cuniculus Species 0.000 description 11
- 238000000502 dialysis Methods 0.000 description 11
- 239000004090 neuroprotective agent Substances 0.000 description 11
- 239000000902 placebo Substances 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 10
- 229940068196 placebo Drugs 0.000 description 10
- 229960000686 benzalkonium chloride Drugs 0.000 description 9
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 9
- 230000006378 damage Effects 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 229920000642 polymer Polymers 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- 201000010099 disease Diseases 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 239000000872 buffer Substances 0.000 description 7
- 125000002091 cationic group Chemical group 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 208000014674 injury Diseases 0.000 description 7
- 230000035699 permeability Effects 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 206010057430 Retinal injury Diseases 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 6
- -1 adamantane amines Chemical class 0.000 description 6
- 210000001742 aqueous humor Anatomy 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 6
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 5
- 208000027418 Wounds and injury Diseases 0.000 description 5
- 230000002411 adverse Effects 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 5
- 229940024606 amino acid Drugs 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 229930195712 glutamate Natural products 0.000 description 5
- 230000003204 osmotic effect Effects 0.000 description 5
- 230000009885 systemic effect Effects 0.000 description 5
- 201000002862 Angle-Closure Glaucoma Diseases 0.000 description 4
- 201000004569 Blindness Diseases 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 229920006318 anionic polymer Polymers 0.000 description 4
- 210000002159 anterior chamber Anatomy 0.000 description 4
- 230000004410 intraocular pressure Effects 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 210000003583 retinal pigment epithelium Anatomy 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 101000623895 Bos taurus Mucin-15 Proteins 0.000 description 3
- 206010051625 Conjunctival hyperaemia Diseases 0.000 description 3
- 206010010726 Conjunctival oedema Diseases 0.000 description 3
- 206010012689 Diabetic retinopathy Diseases 0.000 description 3
- 206010020565 Hyperaemia Diseases 0.000 description 3
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 3
- 206010038848 Retinal detachment Diseases 0.000 description 3
- 201000001326 acute closed-angle glaucoma Diseases 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 230000004264 retinal detachment Effects 0.000 description 3
- 208000004644 retinal vein occlusion Diseases 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 231100000041 toxicology testing Toxicity 0.000 description 3
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- 208000002177 Cataract Diseases 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical class OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
- 102000018899 Glutamate Receptors Human genes 0.000 description 2
- 108010027915 Glutamate Receptors Proteins 0.000 description 2
- 229940122459 Glutamate antagonist Drugs 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 102000004310 Ion Channels Human genes 0.000 description 2
- 206010023644 Lacrimation increased Diseases 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 2
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 2
- 206010038903 Retinal vascular occlusion Diseases 0.000 description 2
- 206010046851 Uveitis Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 206010064930 age-related macular degeneration Diseases 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000003194 amino acid receptor blocking agent Substances 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000000376 autoradiography Methods 0.000 description 2
- 210000005252 bulbus oculi Anatomy 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 201000005667 central retinal vein occlusion Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 210000003161 choroid Anatomy 0.000 description 2
- 201000005682 chronic closed-angle glaucoma Diseases 0.000 description 2
- OSVXSBDYLRYLIG-UHFFFAOYSA-N dioxidochlorine(.) Chemical compound O=Cl=O OSVXSBDYLRYLIG-UHFFFAOYSA-N 0.000 description 2
- 208000002173 dizziness Diseases 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 229940009662 edetate Drugs 0.000 description 2
- 208000030533 eye disease Diseases 0.000 description 2
- 230000023747 glial cell migration Effects 0.000 description 2
- 230000004317 lacrimation Effects 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 208000002780 macular degeneration Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229960000967 memantine hydrochloride Drugs 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 210000004498 neuroglial cell Anatomy 0.000 description 2
- 231100000344 non-irritating Toxicity 0.000 description 2
- 210000001328 optic nerve Anatomy 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 150000003141 primary amines Chemical group 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 210000001747 pupil Anatomy 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 210000003994 retinal ganglion cell Anatomy 0.000 description 2
- 210000003786 sclera Anatomy 0.000 description 2
- 150000003335 secondary amines Chemical group 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 150000003512 tertiary amines Chemical group 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- 210000004127 vitreous body Anatomy 0.000 description 2
- JCIIKRHCWVHVFF-UHFFFAOYSA-N 1,2,4-thiadiazol-5-amine;hydrochloride Chemical compound Cl.NC1=NC=NS1 JCIIKRHCWVHVFF-UHFFFAOYSA-N 0.000 description 1
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 239000004155 Chlorine dioxide Substances 0.000 description 1
- 208000005590 Choroidal Neovascularization Diseases 0.000 description 1
- 206010060823 Choroidal neovascularisation Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010018325 Congenital glaucomas Diseases 0.000 description 1
- 206010058202 Cystoid macular oedema Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 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
- 206010012565 Developmental glaucoma Diseases 0.000 description 1
- 206010012688 Diabetic retinal oedema Diseases 0.000 description 1
- QZKRHPLGUJDVAR-UHFFFAOYSA-K EDTA trisodium salt Chemical compound [Na+].[Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O QZKRHPLGUJDVAR-UHFFFAOYSA-K 0.000 description 1
- 208000001351 Epiretinal Membrane Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 206010022945 Iris adhesions Diseases 0.000 description 1
- 208000001344 Macular Edema Diseases 0.000 description 1
- 208000031471 Macular fibrosis Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- BWUKUMPSMJYAJP-HVDRVSQOSA-N N[C@@H](CCC(=O)O)C(=O)O.C12CC3CC(CC(C1)C3)C2 Chemical compound N[C@@H](CCC(=O)O)C(=O)O.C12CC3CC(CC(C1)C3)C2 BWUKUMPSMJYAJP-HVDRVSQOSA-N 0.000 description 1
- 206010068960 Narrow anterior chamber angle Diseases 0.000 description 1
- 206010029216 Nervousness Diseases 0.000 description 1
- 206010052143 Ocular discomfort Diseases 0.000 description 1
- 206010061323 Optic neuropathy Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 description 1
- 206010064714 Radiation retinopathy Diseases 0.000 description 1
- 201000007527 Retinal artery occlusion Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 208000007014 Retinitis pigmentosa Diseases 0.000 description 1
- 206010038934 Retinopathy proliferative Diseases 0.000 description 1
- RXDLGFMMQFNVLI-UHFFFAOYSA-N [Na].[Na].[Ca] Chemical compound [Na].[Na].[Ca] RXDLGFMMQFNVLI-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 210000003484 anatomy Anatomy 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 229920001400 block copolymer Polymers 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
- 239000007853 buffer solution Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 235000019398 chlorine dioxide Nutrition 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 201000010206 cystoid macular edema Diseases 0.000 description 1
- 201000011190 diabetic macular edema Diseases 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- 229940048820 edetates Drugs 0.000 description 1
- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000000416 exudates and transudate Anatomy 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000012374 filter flush Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 229960004716 idoxuridine Drugs 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000013532 laser treatment Methods 0.000 description 1
- 238000011068 loading method Methods 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
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 150000002734 metacrylic acid derivatives Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 208000021971 neovascular inflammatory vitreoretinopathy Diseases 0.000 description 1
- 208000020911 optic nerve disease Diseases 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 238000002103 osmometry Methods 0.000 description 1
- 125000005430 oxychloro group Chemical group 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229940096826 phenylmercuric acetate Drugs 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000000649 photocoagulation Effects 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 210000003488 posterior eye segment Anatomy 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 201000007914 proliferative diabetic retinopathy Diseases 0.000 description 1
- 230000006785 proliferative vitreoretinopathy Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004283 retinal dysfunction Effects 0.000 description 1
- 231100000161 signs of toxicity Toxicity 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 229940100613 topical solution Drugs 0.000 description 1
- 210000001585 trabecular meshwork Anatomy 0.000 description 1
- 229960005066 trisodium edetate Drugs 0.000 description 1
- 230000004393 visual impairment Effects 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
- A61K31/13—Amines
-
- 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
- A61P27/06—Antiglaucoma agents or miotics
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Ophthalmology & Optometry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/752,125 US20050147584A1 (en) | 2004-01-05 | 2004-01-05 | Compositions and methods comprising memantine and polyanionic polymers |
| US10/941,272 US20050031652A1 (en) | 2003-02-25 | 2004-09-14 | Compositions and methods comprising memantine and polyanionic polymers |
| PCT/US2005/000249 WO2005067891A1 (en) | 2004-01-05 | 2005-01-04 | Compositions comprosing memantine and polyanionic polymers for administration to the eye |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2007517885A true JP2007517885A (ja) | 2007-07-05 |
| JP2007517885A5 JP2007517885A5 (https=) | 2008-02-21 |
Family
ID=34798997
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2006549374A Withdrawn JP2007517885A (ja) | 2004-01-05 | 2005-01-04 | 眼に投与するためのメマンチンおよびポリアニオン性ポリマーを含む組成物 |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US20050031652A1 (https=) |
| EP (1) | EP1701700A1 (https=) |
| JP (1) | JP2007517885A (https=) |
| AU (1) | AU2005204365A1 (https=) |
| BR (1) | BRPI0506689A (https=) |
| CA (1) | CA2552521A1 (https=) |
| WO (1) | WO2005067891A1 (https=) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050009884A1 (en) * | 1997-06-30 | 2005-01-13 | Dreyer Evan B. | Calcium blockers to treat proliferative retinal diseases |
| JP2002182418A (ja) * | 2000-12-11 | 2002-06-26 | Konica Corp | 画像形成方法、画像形成装置 |
| US20080033053A1 (en) * | 2004-07-22 | 2008-02-07 | Wolfgang Curt D | Cross-Reference To Related Applications |
| EP1776097A1 (en) * | 2004-07-26 | 2007-04-25 | Allergan, Inc. | Methods of treating ophthalmic conditions |
| US20070167527A1 (en) * | 2006-01-13 | 2007-07-19 | Burke James A | Memantine for the normalization of visual acuity deficits |
| JP5373613B2 (ja) | 2006-10-16 | 2013-12-18 | バイオノミクス リミテッド | 新規な抗不安薬化合物 |
| US10954231B2 (en) | 2006-10-16 | 2021-03-23 | Bionomics Limited | Anxiolytic compounds |
| WO2008098027A2 (en) * | 2007-02-06 | 2008-08-14 | Allergan, Inc. | Treatment of ischemic retinal conditions with memantine |
| EP2509596B1 (en) | 2009-12-08 | 2019-08-28 | Case Western Reserve University | Gamma aminoacids for treating ocular disorders |
| CA2828780A1 (en) | 2011-03-02 | 2012-09-07 | Bionomics Limited | Novel small-molecules as therapeutics |
| EP2707367B1 (en) | 2011-05-12 | 2019-10-09 | Bionomics Limited | Methods for preparing naphthyridines |
Family Cites Families (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5554367A (en) * | 1984-10-31 | 1996-09-10 | Alcon Laboratories, Inc. | Compositions for treatment of glaucoma |
| US4911920A (en) * | 1986-07-30 | 1990-03-27 | Alcon Laboratories, Inc. | Sustained release, comfort formulation for glaucoma therapy |
| US4738851A (en) * | 1985-09-27 | 1988-04-19 | University Of Iowa Research Foundation, Inc. | Controlled release ophthalmic gel formulation |
| US5008242A (en) * | 1986-12-24 | 1991-04-16 | John Lezdey | Treatment of inflammation using 1-antichymotrypsin |
| US5221696A (en) * | 1989-03-29 | 1993-06-22 | Alcon Laboratories, Inc. | Use of monoacyl phosphoglycerides to enhance the corneal penetration of ophthalmic drugs |
| US5318780A (en) * | 1991-10-30 | 1994-06-07 | Mediventures Inc. | Medical uses of in situ formed gels |
| ES2079994B1 (es) * | 1992-10-07 | 1996-08-01 | Cusi Lab | Formulacion farmaceutica a base de polimixina-trimetoprim y un agente antiinflamatorio para su utilizacion topica oftalmica y otica. |
| US5922773A (en) * | 1992-12-04 | 1999-07-13 | The Children's Medical Center Corp. | Glaucoma treatment |
| US5691316A (en) * | 1994-06-01 | 1997-11-25 | Hybridon, Inc. | Cyclodextrin cellular delivery system for oligonucleotides |
| US5891885A (en) * | 1996-10-09 | 1999-04-06 | Algos Pharmaceutical Corporation | Method for treating migraine |
| EP0994709A4 (en) * | 1997-06-30 | 2006-02-01 | Allergan Inc | CALCIUM BLOCKER FOR THE TREATMENT OF PROLIFERATIVE VITREORETINOPATHY |
| US6509355B1 (en) * | 1998-10-27 | 2003-01-21 | Alcon Laboratories, Inc. | Treatment of disorders of the outer retina |
| US6258350B1 (en) * | 1999-01-20 | 2001-07-10 | Alcon Manufacturing, Ltd. | Sustained release ophthalmic formulation |
| HK1040184A1 (zh) * | 1999-03-12 | 2002-05-31 | Alcon Laboratories, Inc. | 治療青光眼之組合療法 |
| US6482854B1 (en) * | 1999-03-25 | 2002-11-19 | Massachusetts Eye And Ear Infirmary | Glaucoma treatment |
| SK282717B6 (sk) * | 2000-03-10 | 2002-11-06 | �Stav Experiment�Lnej Farmakol�Gie Sav | Spôsob prípravy ultravysokomolekulových hyalurónanov |
| US6572849B2 (en) * | 2000-09-20 | 2003-06-03 | Lee Shahinian, Jr. | Self-preserved antibacterial nasal, inhalable, and topical ophthalmic preparations and medications |
| US6761694B2 (en) * | 2001-12-13 | 2004-07-13 | Allergan, Inc. | Methods for measuring retinal damage |
| US6982079B2 (en) * | 2002-04-26 | 2006-01-03 | Allergan, Inc. | Compositions for treating hyperemia |
| CA2534484A1 (en) * | 2003-08-07 | 2005-02-17 | Allergan, Inc. | Compositions for delivery of therapeutics into the eyes and methods for making and using same |
-
2004
- 2004-09-14 US US10/941,272 patent/US20050031652A1/en not_active Abandoned
-
2005
- 2005-01-04 CA CA002552521A patent/CA2552521A1/en not_active Abandoned
- 2005-01-04 JP JP2006549374A patent/JP2007517885A/ja not_active Withdrawn
- 2005-01-04 WO PCT/US2005/000249 patent/WO2005067891A1/en not_active Ceased
- 2005-01-04 AU AU2005204365A patent/AU2005204365A1/en not_active Abandoned
- 2005-01-04 BR BRPI0506689-1A patent/BRPI0506689A/pt not_active IP Right Cessation
- 2005-01-04 EP EP05705052A patent/EP1701700A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| EP1701700A1 (en) | 2006-09-20 |
| BRPI0506689A (pt) | 2007-05-02 |
| US20050031652A1 (en) | 2005-02-10 |
| AU2005204365A1 (en) | 2005-07-28 |
| WO2005067891A1 (en) | 2005-07-28 |
| CA2552521A1 (en) | 2005-07-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Fraunfelder et al. | Ocular toxicity of antineoplastic agents | |
| EP2262476B1 (en) | Drug delivery to the anterior and posterior segments of the eye using eye drops. | |
| WO2010125416A1 (en) | Drug delivery to the anterior and posterior segments of the eye | |
| RS63136B9 (sr) | Lekoviti sastav koji sadrži tivozanib | |
| CN109996814B (zh) | 多激酶抑制剂及在眼部纤维化中的用途 | |
| WO1989010757A1 (en) | New ophthalmic preparation for treating glaucoma | |
| US5212168A (en) | Method of and solution for treating glaucoma | |
| JP2007517885A (ja) | 眼に投与するためのメマンチンおよびポリアニオン性ポリマーを含む組成物 | |
| JP2005533087A (ja) | 神経損傷の処置にリアノジン拮抗剤を用いる方法 | |
| AU673533B2 (en) | Pharmaceutical composition | |
| JP2009519962A (ja) | 眼投与用局所メカミルアミン製剤およびその使用 | |
| CN103977011B (zh) | 含有曲伏前列素和噻吗洛尔的眼用凝胶剂及其制备方法 | |
| WO2019024433A1 (zh) | 氨基金刚烷胺单硝酸酯类化合物眼用组合物及其制剂和应用 | |
| CA2453442A1 (en) | Compositions and methods of administering tubulin binding agents for the treatment of ocular diseases | |
| EP4087533B1 (en) | Soluble melatonin tripartate adduct for the prevention and treatment of rare and severe eye sight-threatening conditions and neuro-ophthalmic disorders | |
| JP4838968B2 (ja) | 薬物−ポリエチレングリコール結合体を含有する眼組織内注入剤 | |
| JP7114668B2 (ja) | エピナスチン又はその塩を含有する花粉破裂抑制剤 | |
| WO2002040028A1 (fr) | Gouttes pour les yeux en gel antibacterien | |
| US20050277698A1 (en) | Memantine delivery to the back of the eye | |
| US20050147584A1 (en) | Compositions and methods comprising memantine and polyanionic polymers | |
| JPS63502270A (ja) | 散瞳作用を有する眼科用医薬組成物 | |
| JPH04247036A (ja) | 縮瞳をおこすことなく眼圧を下げる治療方法 | |
| CN1633308A (zh) | 使用脲和脲衍生物治疗眼病 | |
| AU2024217271A1 (en) | Alpha-2-adrenergic agonists for improving vision | |
| JP2002356431A (ja) | ステロイドを有効成分とする網脈絡膜疾患治療剤 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20071227 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20071227 |
|
| A761 | Written withdrawal of application |
Free format text: JAPANESE INTERMEDIATE CODE: A761 Effective date: 20090122 |