WO2020197816A1 - Anesthetic composition and method of anesthetizing the eye - Google Patents
Anesthetic composition and method of anesthetizing the eye Download PDFInfo
- Publication number
- WO2020197816A1 WO2020197816A1 PCT/US2020/022915 US2020022915W WO2020197816A1 WO 2020197816 A1 WO2020197816 A1 WO 2020197816A1 US 2020022915 W US2020022915 W US 2020022915W WO 2020197816 A1 WO2020197816 A1 WO 2020197816A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- articaine
- mannitol
- buffer
- complex
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 281
- 230000003444 anaesthetic effect Effects 0.000 title claims abstract description 108
- 238000000034 method Methods 0.000 title claims description 37
- QTGIAADRBBLJGA-UHFFFAOYSA-N Articaine Chemical compound CCCNC(C)C(=O)NC=1C(C)=CSC=1C(=O)OC QTGIAADRBBLJGA-UHFFFAOYSA-N 0.000 claims abstract description 202
- 229960003831 articaine Drugs 0.000 claims abstract description 201
- 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 claims abstract description 97
- 239000000872 buffer Substances 0.000 claims abstract description 77
- 235000010355 mannitol Nutrition 0.000 claims abstract description 68
- 239000000594 mannitol Substances 0.000 claims abstract description 44
- 229930195725 Mannitol Natural products 0.000 claims abstract description 41
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims abstract description 41
- 239000004327 boric acid Substances 0.000 claims abstract description 40
- 238000009472 formulation Methods 0.000 claims abstract description 28
- 206010002091 Anaesthesia Diseases 0.000 claims abstract description 19
- 230000037005 anaesthesia Effects 0.000 claims abstract description 19
- 150000001642 boronic acid derivatives Chemical group 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 52
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 34
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- 235000017281 sodium acetate Nutrition 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 15
- 150000005846 sugar alcohols Chemical class 0.000 claims description 14
- 239000001632 sodium acetate Substances 0.000 claims description 13
- 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 claims description 11
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 6
- 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 claims description 6
- 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 claims description 6
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 6
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 6
- 239000000600 sorbitol Substances 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 5
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims description 5
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 3
- OPGYRRGJRBEUFK-UHFFFAOYSA-L disodium;diacetate Chemical compound [Na+].[Na+].CC([O-])=O.CC([O-])=O OPGYRRGJRBEUFK-UHFFFAOYSA-L 0.000 claims description 2
- 235000017454 sodium diacetate Nutrition 0.000 claims description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims 2
- 230000000699 topical effect Effects 0.000 abstract description 94
- 239000003963 antioxidant agent Substances 0.000 abstract description 6
- 239000000654 additive Substances 0.000 abstract description 3
- 238000010494 dissociation reaction Methods 0.000 abstract description 2
- 230000005593 dissociations Effects 0.000 abstract description 2
- 229920000609 methyl cellulose Polymers 0.000 abstract description 2
- 239000001923 methylcellulose Substances 0.000 abstract description 2
- 239000002674 ointment Substances 0.000 abstract description 2
- 239000007864 aqueous solution Substances 0.000 abstract 1
- 235000010338 boric acid Nutrition 0.000 description 32
- 239000007924 injection Substances 0.000 description 30
- 238000002347 injection Methods 0.000 description 30
- LUPKINKNYDFRIB-UHFFFAOYSA-N 4-methyl-3-[2-(propylazaniumyl)propanoylamino]thiophene-2-carboxylate Chemical compound CCCNC(C)C(=O)NC=1C(C)=CSC=1C(O)=O LUPKINKNYDFRIB-UHFFFAOYSA-N 0.000 description 16
- 229960000583 acetic acid Drugs 0.000 description 14
- 239000006196 drop Substances 0.000 description 14
- 239000000546 pharmaceutical excipient Substances 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 11
- 210000000795 conjunctiva Anatomy 0.000 description 10
- 238000003860 storage Methods 0.000 description 10
- 235000011054 acetic acid Nutrition 0.000 description 9
- 210000004087 cornea Anatomy 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 241000283973 Oryctolagus cuniculus Species 0.000 description 8
- 239000003193 general anesthetic agent Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 6
- 230000007774 longterm Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000003381 stabilizer Substances 0.000 description 6
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 5
- 229930182837 (R)-adrenaline Natural products 0.000 description 5
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 5
- 229940035674 anesthetics Drugs 0.000 description 5
- 235000006708 antioxidants Nutrition 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- 229960005139 epinephrine Drugs 0.000 description 5
- 239000003889 eye drop Substances 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 230000007794 irritation Effects 0.000 description 5
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 5
- 238000001356 surgical procedure Methods 0.000 description 5
- 238000011200 topical administration Methods 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 210000003161 choroid Anatomy 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000003589 local anesthetic agent Substances 0.000 description 4
- 230000036407 pain Effects 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 230000000087 stabilizing effect Effects 0.000 description 4
- -1 D-manniiol Chemical class 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 210000001742 aqueous humor Anatomy 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 239000002997 ophthalmic solution Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 210000001525 retina Anatomy 0.000 description 3
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- PBKADZMAZVCJMR-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid;dihydrate Chemical compound O.O.OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O PBKADZMAZVCJMR-UHFFFAOYSA-N 0.000 description 2
- 206010015150 Erythema Diseases 0.000 description 2
- 108090000371 Esterases Proteins 0.000 description 2
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 2
- 239000002033 PVDF binder Substances 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000002146 bilateral effect Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 229940061607 dibasic sodium phosphate Drugs 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 229940126534 drug product Drugs 0.000 description 2
- 206010014801 endophthalmitis Diseases 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 210000004561 lacrimal apparatus Anatomy 0.000 description 2
- 229960004194 lidocaine Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229940054534 ophthalmic solution Drugs 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000002831 pharmacologic agent Substances 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 229940080150 systane Drugs 0.000 description 2
- 239000005526 vasoconstrictor agent Substances 0.000 description 2
- 239000004034 viscosity adjusting agent Substances 0.000 description 2
- QGBLCIBATKETJC-UHFFFAOYSA-N 3,7-dioxido-2,4,6,8,9-pentaoxa-1,3,5,7-tetraborabicyclo[3.3.1]nonane;manganese(2+) Chemical compound [Mn+2].O1B([O-])OB2OB([O-])OB1O2 QGBLCIBATKETJC-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010002199 Anaphylactic shock Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- 108010061951 Methemoglobin Proteins 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- KCLANYCVBBTKTO-UHFFFAOYSA-N Proparacaine Chemical compound CCCOC1=CC=C(C(=O)OCCN(CC)CC)C=C1N KCLANYCVBBTKTO-UHFFFAOYSA-N 0.000 description 1
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 102000016913 Voltage-Gated Sodium Channels Human genes 0.000 description 1
- 108010053752 Voltage-Gated Sodium Channels Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000003732 agents acting on the eye Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 229960002279 articaine hydrochloride Drugs 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 210000000695 crystalline len Anatomy 0.000 description 1
- URSLCTBXQMKCFE-UHFFFAOYSA-N dihydrogenborate Chemical compound OB(O)[O-] URSLCTBXQMKCFE-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 210000000744 eyelid Anatomy 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 239000013022 formulation composition Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- ODLHGICHYURWBS-FOSILIAISA-N molport-023-220-444 Chemical compound CC(O)COC[C@@H]([C@@H]([C@H]([C@@H]1O)O)O[C@@H]2O[C@H]([C@H](O[C@@H]3O[C@@H](COCC(C)O)[C@@H]([C@H]([C@@H]3O)O)O[C@@H]3O[C@@H](COCC(C)O)[C@@H]([C@H]([C@@H]3O)O)O[C@@H]3O[C@@H](COCC(C)O)[C@@H]([C@H]([C@@H]3O)O)O[C@@H]3O[C@@H](COCC(C)O)[C@@H]([C@H]([C@@H]3O)O)O3)[C@@H](O)[C@@H]2O)COCC(O)C)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O)[C@H]3O[C@H]1COCC(C)O ODLHGICHYURWBS-FOSILIAISA-N 0.000 description 1
- 229940045641 monobasic sodium phosphate Drugs 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 230000007830 nerve conduction Effects 0.000 description 1
- 229940125702 ophthalmic agent Drugs 0.000 description 1
- 210000001328 optic nerve Anatomy 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000004260 plant-type cell wall biogenesis Effects 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 238000011176 pooling Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 229930010796 primary metabolite Natural products 0.000 description 1
- 238000011165 process development Methods 0.000 description 1
- 229960003981 proparacaine Drugs 0.000 description 1
- 125000006308 propyl amino group Chemical group 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 239000003860 topical agent Substances 0.000 description 1
- 229940100613 topical solution Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VLCLHFYFMCKBRP-UHFFFAOYSA-N tricalcium;diborate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]B([O-])[O-].[O-]B([O-])[O-] VLCLHFYFMCKBRP-UHFFFAOYSA-N 0.000 description 1
- NFMWFGXCDDYTEG-UHFFFAOYSA-N trimagnesium;diborate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]B([O-])[O-].[O-]B([O-])[O-] NFMWFGXCDDYTEG-UHFFFAOYSA-N 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 230000002568 urticarial effect Effects 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 210000004127 vitreous body Anatomy 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
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
Definitions
- exemplary embodiments of the present disclosure relate to an anesthetic composition and a method of administering the anesthetic composition to a patient, and particularly for anesthetizing at least a portion of the eye.
- the disclosure relates to a topical anesthetic composition or formulation that can be applied topically to the surface of the eye.
- Exemplary implementations of certain embodiments of the disclosure provide methods for topically applying a topical anesthetic formulation, for example a drop, to achieve a high level of pars plana anesthesia, sufficient to permit intravitreal injection without undue discomfort to the patient.
- Exemplary implementations of certain embodiments of the present disclosure provide methods for applying a topical solution comprising articaine to achieve anesthesia of the surface of the eye as well as the internal aspect of eye wall.
- Articaine formulations containing not more than 4% articaine and a vasoconstrictor, which is commonly epinephrine, are known for use as an injectable anesthetic that is formulated for injection into the tissue in the patient. Such formulations are commonly used in dentistry to perform dental procedures. The prior compositions are generally not suitable or effective for topical administration or applications in the eye.
- Exemplary embodiments of the present disclosure provide an anesthetic composition containing articaine.
- the anesthetic composition is suitable for topical ophthalmic use by topical application to the surface of the eye to achieve a level of anesthesia sufficient for intravitreal injections and other medical procedures.
- the anesthetic composition can be administered in an amount sufficient to permit intravitreal injection in the eye without undue discomfort to the patient.
- the topical ophthalmic composition includes articaine in a sufficiently high concentration to induce anesthesia to the eye by topical administration prior to performing various medical procedures, including surgical procedures.
- the composition is particularly suitable for providing anesthesia to the eye to enable an injection in or through the pars plana of the eye with minimal or no pain to the patient.
- Exemplary embodiments of the present disclosure include formulations, and/or modification and/or use thereof, comprising articaine, which can be an intermediate potency, short acting amide local anesthetic.
- articaine can be an intermediate potency, short acting amide local anesthetic.
- the metabolism of articaine can be rapid due to the presence of an ester group in molecular structure.
- Articaine has been previously administered by injection for peripheral nerve, spinal, epidural, periocular, or regional nerve block.
- a topical ophthalmic anesthetic composition includes articaine in an mount effective to provide an anesthetic effect to the eye of the patient without the need for repeated application or injection of an anesthetic into the eye.
- Articaine can be included in the topical anesthetic composition in mounts and concentrations to provide the desired anesthetic properties by a controlled dosage.
- the composition can include articaine in mounts of up to about 13% w/v based on the total volume of the composition.
- the composition can include articaine in amounts of about 4% w/v to about 12% w/v based on the total volume of the composition.
- the higher concentration of articaine in the ophthalmic composition can be administered at smaller dosages while providing the desired anesthetic effects to the eye.
- the topical ophthalmic anesthetic composition is an aqueous composition that contains about 7.0% w/v to about 8.5% w/v articaine and a buffer that is not reactive with articaine or/and does not promote decomposition of articaine.
- the buffer in an embodiment can provide a pH of about pH 3.5 to about pH 7.0 and an osmolality of about 280 to about 320 mOsm/kg.
- the ophthalmic anesthetic composition has pH of about pH 4.5 to about pH 5.0.
- the buffer in one embodiment is a complex obtained from an acid and a sugar alcohol.
- the acid can be selected from the group consisting of boric acid, citric acid, and mixtures thereof.
- the acid is boric acid.
- the sugar alcohol can be D-mannitol, sorbitol, and mixtures thereof.
- a particularly suitable buffer is a borate/mannitol complex obtained from boric acid or a borate salt and D-mannitol.
- the buffer can be a complex obtained from about 13 wt% to about 17 wt% boric acid and about 83 wt% to about 88 wt% D-mannitol, based on the total weight of the boric acid and D-mannitol.
- the anesthetic composition in the embodiment can include sodium acetate trihydrate, acetic acid, and disodium edetate dihydrate.
- the anesthetic composition can have a pH range of about pH 4.5 to about pH 7.0.
- the topical ophthalmic anesthetic composition in one embodiment is an aqueous mixture of at least about 7.5% w/v articaine, a buffer including a complex formed from boric acid and D-mannitol, sodium acetate, acetic acid, disodium edetate, and the balance water where the composition has a pH of pH 4.5 to about pH 5.0.
- a pH of less than about pH 5.0 has been found to improve long term stability of the articaine composition.
- the topical ophthalmic anesthetic composition is a stable aqueous composition containing articaine in an amount of at least about 8% w/v, at a pH of about pH 4.5 to about pH 5.5, a buffer and excipients that are not reactive with articaine and do not promote decomposition of the articaine in the aqueous composition.
- the composition can include articaine as the only anesthetic agent or compound and is typically in the absence of a vasoconstrictor, such as epinephrine.
- the composition is in the absence of sodium metabisulfite and/or sodium bisulfite.
- the buffer in this embodiment is a borate/mannitol complex.
- the features of the aqueous topical ophthalmic anesthetic composition comprise about 4.0% w/v to about 12.0% w/v articaine, and a buffer in an amount to provide a pH of about pH 3.5 to about pH 7.0, where the buffer is non-reactive with and stabilizes the articaine.
- the buffer can be a complex obtained from boric acid and D-mannitol.
- the aqueous ophthalmic anesthetic composition comprises about 4% w/v articaine, a buffer comprising NaOH and HC1, a pH of about pH 5.5, a pKa of about 7.8, a viscosity of about 20-25 cp, an osmolality of about 275 to 1171 mOsm/kg, and a tonicity of about 0.5 to 5.0%.
- the aqueous topical anesthetic composition comprises 80 mg/g articaine HC1, 1.373 mg/g sodium phosphate monobasic monohydrate, 1.413 mg/g sodium phosphate dibasic anhydrous, 8.1 mg/g hydroxypropylmethyl cellulose, 4 mg/g PEG400, and where said composition has a pH of pH 6.0 to pH 7.0, a viscosity of 743-803 cp, and an osmolality of 517 mOsm/kg.
- Another feature of this disclosure provides a method for inhibiting pain and/or discomfort to the eye of a patient during various surgical procedures in the eye and/or an injection in the eye by a needle.
- the method introduces a topical anesthetic composition to the eye in an amount to induce anesthesia to the eye where the anesthetic composition contains an effective amount of articaine to treat the surface of the eye and the tissue below the surface including the pars plana.
- the method is particularly suitable for procedures for injecting a substance or medication into the eye where the surface of the eye is treated with the topical composition containing at least 4.0% w/v articaine and a non-reactive buffer to provide a pH about pH 4.5 to about pH 7.0 and generally about pH 4.5 to about pH 5.5, In other embodiments, the topical composition has a pH 4.5 to about pH 5.0.
- compositions of the present disclosure provide methodologies employing a topical anesthetic composition or formulation containing articaine with improved anesthetizing effect of the eye and with reduced risk of infection in the eye.
- composition and formula are used interchangeably to refer to the mixture or combination of compounds, including active compounds and excipients.
- the composition is a aqueous mixture containing articaine, buffers and other excipients to obtain a stable composition with a suitable pH, osmolality and articaine concentration for topical application to the eye.
- the topical ophthalmic anesthetic composition is an anesthetic composition containing art effective amount of the anesthetic agent to anesthetize the surface and internal aspects of the eye of a patient by topical administration for performing various medical procedures, such as an intravitreal injection.
- the topical ophthalmic anesthetic composition is prepared as a topical composition and applied directly to the surface of the eye to anesthetize the surface of the eye and the internal aspect of the eye.
- the topical ophthalmic anesthetic composition contains articaine in an amount effective to provide the anesthetic effect to the eye to reduce or inhibit pain and/or discomfort to the patient during a medical procedure in the eye, such as an intravitreal injection or other surgical procedure.
- the topical ophthalmic anesthetic composition containing articaine can have various ranges of pH and various amounts of articaine depending on the buffer and stabilizing agents included in the anesthetic composition.
- the buffers and stabilizing agents provide an effective topical anesthetic composition where the buffers and stabilizing agents enable different ranges of pH to stabilize the composition and maintain a suitable osmolality for the composition.
- the topical ophthalmic anesthetic composition in various embodiments contain about 4.0% w/v to about 13% w/v articaine at a pH to stabilize the articaine and at a pH to minimize discomfort to the patient. Suitable anesthetic compositions can also be prepared containing at least 6% w/v articaine.
- the composition in the embodiments described is an aqueous ophthalmic anesthetic composition.
- the topical ophthalmic anesthetic composition contains articaine in an amount of at least about 7.0 % w/v and generally at least about 8.0% w/v articaine based on the total volume of the composition.
- the topical ophthalmic anesthetic composition contains articaine in an amount of at least about 8.5% w/v articaine.
- w/v refers to grams per 100ml of the composition.
- the ophthalmic composition generally includes at least about 4% w/v articaine and up to about 8.5% w/v articaine.
- the topical composition includes at least about 7.0% and generally at least about 8.0% w/v articaine.
- the articaine as used in the topical compositions is typically prepared from the hydrochloride salt.
- the topical ophthalmic composition in an embodiment includes articaine in an amount of at least about 4% w/v and a buffer to control the pH in the desired range.
- the topical composition has a pH in the range of pH 4.5 to pH 7.0.
- Other embodiments can have a pH of about pH 6.0 to about pH 7.0.
- the topical composition can have a pH less than pH 5.0.
- the buffer is non-reactive with the articaine at pH 4.0 to pH 7.0 to inhibit degradation of the articaine and provide a storage stable composition.
- the topical ophthalmic composition can include articaine in an amount greater than about 4.0% w/v and a buffer to provide a stable mixture at a pH of about pH 6.0 or below where the buffer is not reactive with the articaine.
- the pH of the topical ophthalmic composition is generally adjusted to maintain a desired long term stability of articaine and minimize discomfort to the patient when applied topically to the surface of the eye.
- the pH is generally in the range of about pH 4.5 to about pH 7.0.
- a particularly suitable pH of an articaine composition is about pH 4.5 to about pH 5.5 for compositions containing amounts of articaine greater than about 4,0% and typically greater than about 6.0% w/v.
- One suitable composition containing at least 7.0% w/v or higher has a pH range of about pH 4.5 to about pH 5.5 and found to exhibit long term storage of the articaine in the composition for several months at room temperature.
- the compositions having a pH 5.0 or below provide long-term storage of the articaine to inhibit decomposition of articaine during storage.
- Compositions having about pH 4.5 to about pH 5.0 provide excellent long-term storage without discomfort to the patient when topically applied.
- the topical ophthalmic anesthetic composition containing articaine includes a buffer to adjust, modify, and/or maintain the pH and osmolality within a desired range to stabilize articaine without interacting with articaine or causing degradation of the articaine in the composition during storage.
- the buffer and other excipients in the topical ophthalmic anesthetic composition enable higher concentrations of articaine of 7.5% w/v and up to 8.5% w/v or higher without decomposition of the articaine while maintaining the articaine in solution or suspension with minimal discomfort to the patient when the composition is administered topically to the surface of the eye.
- the buffer according the embodiments of the composition provides a stable composition at higher concentrations of articaine that are not present in the prior compositions.
- Articaine is able to inhibit the growth of certain bacteria, such as Pseudomonas aeruginosa, Proteus mirabilis, Staphylococcus aureus, and Escherichia coli.
- the mechanism of antibacterial action is understood as being mediated by inhibition of cell wall synthesis or distortion of cytoplasmic membrane.
- the topical ophthalmic anesthetic composition as described is a stable composition that car» be applied topically to the surface of the eye without adverse effects.
- the topical ophthalmic anesthetic composition can be applied in drop form directly to the surface of the eye.
- the topical ophthalmic anesthetic composition contains an amount of articaine that is able to provide an anesthetic effect to the eye by a single dosage to the surface of the eye.
- the dosage is selected based on the final concentration of articaine and other buffers, pH adjusting agents and other excipients in the composition to provide the desired anesthetic effect.
- the topical composition is applied as a single dosage of a single drop of about 2 ml to about 30 ml at an articaine concentration of about 8.0 mg/g of the anesthetic composition.
- a drop size is about 15 ml.
- a suitable dosage is about 0.5 ml for the ophthalmic composition containing about 8% w/v of articaine.
- the articaine composition can be administered by about 3-5 drops to the surface of the eye to provide a dosage of about 20 ml or units to about 100 ml.
- the topical ophthalmic anesthetic composition is applied at a dosage of 3-8 drops, typically about 3-5 drops to the surface of the eye, to provide a dosage of about 40 mI to about 80 ml of the composition containing about 8% w/v articaine.
- the composition is an aqueous mixture containing a buffer and has a pH range of about pH 3.5 to about pH 7.0.
- the composition can have a dissolved oxygen content of less than 2 ppm to stabilize the composition and to inhibit oxidation of articaine and/or other compounds in the composition.
- a particularly suitable pH range is about pH 4.5 to about pH 5.0 and an osmolality of about 580 to about 630 mOsm/kg.
- a suitable articaine amount in the composition is about 7.0% to about 8.5% w/v articaine.
- the buffer in this embodiment can be a complex obtained from a mixture of boric acid and D-mannitol.
- the borate/mannitol complex formed from boric acid and D-mannitol has been found to stabilize articaine and provide long storage stability of articaine in the composition at articaine concentrations greater than about 4% w/v and greater than 7% w/v with a pH in the range of pH 4.5 to pH 5.0 without irritation to the eye when applied topically to the surface of the eye.
- the borate component of the borate/marmitol complex is understood as providing a suitable stabilizing effect to the articaine that enables a stable articaine concentration of at least 7% w/v at a pH less than about pH 5.5.
- the buffer provides a stable pH range of about pH 4.5 to about pH 5.0 for articaine enabling concentrations of articaine greater than 4% w/v without irritation to the eye.
- the buffer can be obtained from another source of a borate anion, such as a borate salt.
- borate salts include sodium borate, calcium borate, magnesium borate, manganese borate and others.
- the buffer complex can be obtained from the reaction mixture of boric acid, citric acid, or mixtures thereof, and a sugar alcohol, such as D- mannitol, sorbitol, and mixtures thereof.
- the borate/mannitol complex has been found to be particularly suitable for stabilizing high concentrations of articaine, such as 8% w/v articaine or higher.
- a borate salt and/or a citrate salt can be used as a source of borate and/or citrate to the reaction mixture to form the borate/mannitol complex, a citrate/mannitol complex and/or
- the anesthetic composition in one embodiment includes the buffer complex obtained from boric acid and a sugar alcohol, such as D-manniiol, where the buffer complex is a
- the buffer can be obtained from a mixture of boric acid in an amount of about 13 wt% to about 15 wt% and D-mannitol in an amount of about 85 wt% to about 87 wt% based on the total weight of the boric acid and D-mannitol mixture.
- the buffer in one embodiment can be obtained from a mixture of about 14 wt% boric acid and about 86 wt% D- mannitol based on the combined weight of the boric acid and D-mannitol.
- Boric acid in the topical ophthalmic anesthetic composition forming the borate/mannitol complex can be in amount of about 0.08% w/v to about 0.10% w/v and D-mannitol included in an amount of 0.50% w/v to about 0.60% w/v based on the total volume of the topical ophthalmic anesthetic composition.
- the amount of the borate/mannitol complex included in the topical ophthalmic anesthetic composition is based on the amount of articaine in the final composition to stabilize the articaine and provide the long term storage of the ophthalmic composition.
- the amount of the borate/mannitol complex can be about 0.4% w/v to about 0.75% w/v based on the total volume of the ophthalmic composition.
- the amount of the borate/mannitol complex can be about 0.5% w/v to about 0.75% w/v based on the total volume of the ophthalmic composition.
- the borate/mannitol complex is included in the final ophthalmic composition is an amount of about 6.5 parts by weight to about 7.5 parts by weight based on 100 parts by weight of articaine in the ophthalmic composition.
- the buffer complex is produced from an acid, such as boric acid, citric acid, and mixtures thereof and a sugar alcohol, such as mannitol, sorbitol and mixtures thereof where the ratio of the acid to sugar alcohol can range from about 1 :10 to 10:1.
- the amount of the sugar alcohol is greater than the amount of the acid, i.e., an acid to sugar alcohol in the range of 1 :3 to 1 : 10.
- a boric acid to mannitol ratio can be about 1 :3 to about 1 :7 by weight.
- the ratio of the boric acid to mannitol can be about 1 :4 to about 1 :6 by weight.
- a further example of a suitable boric acid to mannitol ratio can be about 1 :4.5 to about 1 :5.5 by weight.
- Another example of a suitable buffer complex is a borate/citrate/mannitol complex obtained from a mixture of boric acid, citric acid and mannitol.
- buffer and antioxidant components in the embodiment can be included in addition to boric acid and D-mannitol.
- An example of an additional buffer and/or antioxidant compound include an acetate anion, such as sodium acetate trihydrate.
- the additional buffer and/or antioxidant compound can be included in an amount of about 0.3% to about 0.5% w/v based on the total volume of the topical ophthalmic anesthetic composition.
- sodium acetate trihydrate is included in an amount of 0.33% w/v based on the total volume of the topical ophthalmic anesthetic composition.
- Sodium acetate can be included in combination with a complex from boric acid and D-mannitol in an amount of about 33 wt% to about 35 wt% and typically about 34 wt% based on the combined weight of the buffer including boric acid, D-mannitol, and sodium acetate.
- excipients in the topical ophthalmic anesthetic composition include pH adjusting agents or antiseptic compounds.
- Acetic acid such as glacial acetic acid
- Acetic acid typically added as glacial acetic acid, is included in an amount of about 0.05% w/v to about 0.07% w/v based on the total volume of the anesthetic composition.
- Other excipients can include a chelating agent, such as disodium edetate dihydrate.
- the topical ophthalmic anesthetic composition in one embodiment includes articaine in amounts of about 4.5% to about 8.5% w/v, a complex formed from boric acid and D-mannitol as a buffer, sodium acetate, acetic acid, disodium edetate, and the balance water.
- the topical ophthalmic anesthetic composition contains about 7.5% to about 8.5% w/v articaine, a complex obtained from about 0.08% w/v to about 0.10% w/v boric acid and about 0.5% w/v to about 0.6% w/v D-mannitol, about 0.30 to 0.36% w/v sodium acetate, about 0.05% w/v to about 0.07% w/v glacial acetic acid, about 0.05% w/v to about 0.07% w/v disodium edetate dihydrate, based on the total volume of the composition.
- the topical composition can have an osmolality of about 580 to 630 mOsm/kg.
- the composition consists essentially of articaine, a buffer obtained from boric acid and p-mannitol, sodium diacetate, acetic acid, disodium edetate, and water.
- Another suitable example of a suitable topical ophthalmic composition includes about
- composition 7,5% to about 8.5% w/v articaine based on the total volume of the composition, a borate/mannitol complex buffer, and an articaine stabilizer compound, where the composition has a pH of about pH 4.5 to pH.7.0, an osmolality of about 500 to 700 mOsm/kg, and viscosity of about 700 to 850 cp.
- the topical ophthalmic anesthetic composition is an aqueous composition containing at least 4% w/v articaine, and a buffer that is non-reactive with articaine to provide a stable composition without degradation of the articaine and with minimal irritation to the eye.
- the topical ophthalmic anesthetic composition contains articaine in amounts of about 5.0% to 8.5% w/v based on the total volume of the composition.
- the topical ophthalmic anesthetic composition contains articaine in an amount of at least about 8.0% w/v based on the total volume of the composition.
- the buffer is selected to be compatible with articaine to avoid reactions with articaine, inhibit decomposition of articaine during storage, and provide a pH to stabilize the articaine and provide the desired concentration of articaine in the composition with minimal irritation to the eye.
- the buffer stabilizes the articaine by stabilizing the reactive groups, such as the amino group.
- Stabilizers include compounds that inhibit oxidation of the reactive groups on articaine by oxygen and/or oxo radicals.
- Sodium sulfite is an example of a stabilizer to inhibit oxidation in certain embodiments.
- Other antioxidants include sodium EDTA, sodium metasulfite, and ascorbic acid.
- the topical ophthalmic anesthetic composition in an embodiment has a pH of about pH 4.5 to about pH 7.0 and an osmolality of 280 to 320 mOsm/kg.
- the buffer contains compounds to maintain a pH in the topical ophthalmic anesthetic composition of about pH 5.0 to pH 7.0.
- the buffer can also produce a composition having about pH.4.7 to about pH 5.5 depending on the composition and the buffer.
- the topical ophthalmic anesthetic composition can have a pH of at least a pH 5.4. The pH can depend on the buffers and the concentration of articaine in the topical ophthalmic anesthetic composition.
- the topical ophthalmic anesthetic composition can be prepared by methods or procedures to obtain the composition suitable for topical application to the eye.
- the complex is generally prepared before mixing or combining with the articaine to provide the stabilizing effect to the articaine.
- a process for producing the composition in one embodiment prepares the complex in an aqueous medium first by adding the acid component to water to form an acid solution.
- the acid compound can be boric acid, citric acid, or mixtures thereof.
- the sugar alcohol, such as mannitol, sorbitol, or mixtures thereof is then added to the acid solution and allowed to react for sufficient time to form the complex, such as a borate/mannitol complex.
- excipients then are added to the solution of the borate/mannitol complex to obtain the desired pH and final composition.
- excipients include the addition sodium acetate trihydrate to the solution of the borate/mannitol complex until dissolved.
- Acetic acid such as glacial acetic acid, is added to acidify the solution.
- EDTA dihydrate then is added to obtain the desired pH.
- the articaine HCl salt is added and dissolved to obtain the articaine eomposition to obtain the ophthalmic composition having the desired articaine concentration.
- aqueous topical anesthetic composition is administered directly to the surface of the eye in an effective amount to provide sufficient anesthesia to the eye.
- a topical ophthalmic anesthetic composition containing 7% w/v or more can be administered drop-wise to the surface of the eye to provide sufficient anesthesia to the eye.
- a suitable dosage is typically about 30 ml for a composition containing at least about 7% w/v articaine.
- Compositions containing less than 7% w/v articaine may require a larger dosage or repeated dosages to administer an effective amount of articaine to the surface of the eye to achieve the desired anesthetic effect.
- the buffer can be borate/mannitol (pH 6.0), citrate (pH 5.5), acetate (pH 5.5), or phosphate (pH 6.5, 7.0, 7.5).
- the buffer can be included in an amount of not greater than 25mM and can provide a pH less than pH 7.0 and generally less than pH 5.5.
- the buffer can include a mixture of sodium hydroxide and hydrochloric acid.
- Other suitable buffers include monobasic sodium phosphate and dibasic sodium phosphate.
- the topical anesthetic composition can also include optional lubricants and viscosity modifiers.
- additional additives and excipients can include polyethylene glycol, glycerol, sodium sulfite, sodium metasulfite, cetyl alcohol, hydroxypropyl B-cyclodextrin, polaxmer, ty!oxapol, and ascorbate.
- Exemplary embodiments of the present disclosure provide a topical ophthalmic anesthetic comprising a unique formulation with the desired articaine concentration, pH, viscosity, dissociation constant, and additives such as antioxidants, buffers, viscosifiers, such as methylceilulose, to achieve efficacy and safety.
- Exemplary implementations the present disclosure include formulations comprising a liquid, gel, ointment, or in an encapsulated form.
- methylcellulose may be added to increase viscosity and thereby increase contact time with the external ocular surface, increasing the efficacy of articaine.
- Suitable viscosity modifying agents do not negatively interact with or destabilize articaine.
- Other viscosity modifiers include polyvinyl alcohols and hydroxypropyl methyl cellulose.
- topical ophthalmic anesthetic composition includes articaine in an amount of about 4% to about 8.0% w/v supplied with epinephrine 1:100,000 as a sterile composition for topical application by an ophthalmic drop.
- the composition can be applied topically to treat the eye in preparation for an intravitreal injection.
- the topical composition can be applied as a single drop or by several applications to provide the desired anesthetic effect in the eye.
- the topical ophthalmic composition can be applied as a drop by 3 to 6 applications with a time of 3-5 minutes between applications.
- the topical composition can be applied or administered as a single drop and reapplied after 2-5 minutes 3-5 times.
- a topical ophthalmic anesthetic composition comprising articaine as a topical ophthalmic anesthetic including 4% to 8.0% w/v articaine having a pH of about pH 4.5 to about pH 5.5, and a pKa of about 7.0 to about 8.5.
- An example of the aqueous anesthetic composition includes about 4% w/v to about 5 w/v articaine having a pH 5.5, a pKa 7.8, a viscosity of 20 -25 cp (centipoise), osmolality of 275-1171mOsms/kg, tonicity of 0.5% - 5.0%, NaOH buffer, and HC1 buffer.
- a further example of a suitable aqueous topical ophthalmic composition includes about 4%w/w to about 13% w/v articaine and generally at least about 7% w/v articaine, sodium phosphate monobasic monohydrate, dibasic sodium phosphate, a viscosity enhancer, such as
- anesthetic composition includes 80 mg/g articaine HCl, 1.373 mg/g sodium phosphate monobasic monohydrate, 1.413 mg/g sodium phosphate dibasic anhydrous, 8.1 mg/g hydroxypropylmethyl cellulose, 4 mg/g PEG400, and where the composition has a pH of pH 6.0 to pH 7.0, a viscosity of 743-803 cp, and an osmolality of 517 mOsm/kg.
- the topical composition containing 4% w/v articaine applied in one or two doses did not provide a complete anesthetic effect. However, it was observed that 3 or more doses of one drop per application at intervals of 3-5 minutes resulted in effective anesthesia. In addition, patients did not complain of burning, itching, redness, or other manifestations of ocular surface irritation, which are commonly experienced with currently used topical ophthalmic anesthetics.
- a feature of the disclosure is a method of providing anesthesia to the eye by topical application or delivery to the eye by the topical anesthetic ophthalmic composition.
- the anesthetic is administered topically prior to surgery, such as prior to intraocular injections, pars plana vitrectomy, and the like.
- a physician administers an injectable anesthetic to anesthetize the eye, then must wait a suitable period of time for the anesthetic to take effect before beginning a procedure.
- a benefit of a topical approach according to exemplary implementations of the present disclosure is the ease of administering the anesthetic by applying the composition topically without the need to inject an anesthetic into the eye.
- Articaine HC1 has the molecular formula 4- methyl-3 (2- [propylamino] proprioamido)-2-thiophenecarboxylic acid, methyl ester hydrochloride with a molecular weight of 320.84 g/mol, highly protein bound, and has a pKa of 7.8.
- Articaine is an amide- containing anesthetic that contains a thiophene ring and an additional ester group. The thiophene ring provides an increase in the lipid solubility of articaine compared to other amide-containing anesthetics.
- Articaine is highly diffusible and penetrates tissue and bone effectively when administered by injection.
- the presence of the amide group and the ester linkage minimizes a toxic reaction as the biotransformation occurs both in plasma (hydrolysis by plasma esterase) and hepatically (microsomal enzymes).
- the metabolism is initiated by hydrolysis of the ester groups to generate free carboxyl group.
- Articainic acid is the primary metabolite. Additional inactive metabolites have been detected in small amounts. Five to ten percent is renally excreted unchanged and 89% is excreted as the metabolites.
- An injectable form of articaine is commonly used as an anesthetic in dentistry.
- Articaine acts by inhibiting nerve conduction through the blockade of sodium channels in tissue. Articaine acts by reversibly binding to the alpha subunit of the voltage gated sodium channels within the nerve. This reduces sodium influx so that the threshold potential of the nerve will not be reached, halting impulse conduction. Articaine is a short acting, rapid onset of action, tissue penetrating local anesthetic. Articaine has been used in combination with epinephrine in injectable compositions to cause local vasoconstriction, increasing the absorption, and increasing the duration of action. In injectable applications, articaine is typically used at a 4% w/v concentration. Commercially available injectable formulations include articaine hydrochloride (4%) with epinephrine in an amount of 1 :1000,000 (0.01 mgZmi).
- aqueous humor, conjunctivas (palpebral and bulbar), lens, cornea, vitreous humor, iris-ciliary body [ICB], optic nerve, lacrimal gland, retina, and choroid were collected.
- Plasma, aqueous humor, conjunctivas (palpebral and bulbar ), lens, cornea, ICB, choroid, and lacrimal gland tissues were analyzed for concentrations of articaine (active parent) and articainic acid (inactive metabolite), and the remaining tissues stored frozen for possible future analysis.
- Articaine concentrations displayed a typical profile following topical ocular administration of the 8% formulation; highest at the earliest time point (0.167 hours) examined and then decreasing at the later time points (1, 4, and 8 hours).
- Articainic acid displayed a typical profile following topical ocular administration of the 8% formulation; highest at the earliest time point (0.167 hours) examined and then decreasing at the later time points (1, 4, and 8 hours).
- Cmax for articaine was highest in the iris-ciliary body (294,000 ng/g) followed by the palpebral conjunctiva (131,000 ng/g), choroid (103,000 ng/g), bulbar conjunctiva (94,000 ng/g) and cornea (53,500 ng/g)
- Plasma Cmax was 457 ng/mL, the lowest of all matrices examined.
- AUC values denoting exposure of the matrices to articaine generally followed the same order of highest (i.e., iris-ciliary body) to lowest (i.e., plasma) as seen in the Cmax values.
- Tl/2 (half-life) of articaine in the ocular matrices ranged from 1.95 to 3.83 hours with the exception of the palpebral conjunctiva with Tl/2 of 6.31 hours, likely related to the topical dose pooling in the lower eyelid following dosing.
- Tl/2 of articaine in the plasma was approximately 0.5 hours.
- Cmax for articainic acid was highest in the palpebral conjunctiva (71,100 ng/g), cornea (53,500 ng/g), bulbar conjunctiva (29,100 ng/g), and iris-ciliary body (12,600 ng/g). Plasma Cmax was 217 ng/mL, the lowest of all matrices examined.
- AUC values denoting exposure of the matrices to articainic acid generally followed the same order from high to low as articaine but were substantially less than those for articaine with the exception of the cornea and plasma.
- the ratio of AUCO-last articainic acid over AUCO-last articaine the ratio was approximately 2 for both cornea and plasma, indicating greater exposure to articainic acid than to articaine in these two matrices. In all other matrices the ratio was ⁇ 0.7.
- Tl/2 (half-life) of articainic acid in most of the ocular matrices ranged from 1.70 to 3.29 hours.
- Tl/2 of articainic acid in the plasma was approximately 1.5 hours.
- topical ocular administration of articaine provided an anesthetic effect out to 20 minutes postdose with no notable tolerability issues.
- Articaine and articainic acid were detected in all ocular matrices examined with the highest exposure found in the iris-ciliary body, the bulbar and palpebral conjunctiva, and cornea. Rapid metabolism of articaine to articainic acid is expected given the presence of esterase activity in the ocular tissues. Systemic exposure, as indicated by plasma AUC, was minimal.
- the objectives of this study were to determine the tolerability of placebo and Articaine HCI ophthalmic solutions at concentrations of 4, 8, and 12% (w/v) following topical eye drop administration, and to determine the ocular pharmacokinetics and biodistribution of articaine and articainic acid following topical eye drop administration of 8% Articaine HCI ophthalmic solution.
- the rabbit is a standard non-rodent species used in preclinical pharmacokinetic studies, including ocular pharmacokinetics, of new chemical entities and different test article formulations.
- the number of animals is considered an appropriate number necessary to properly perform this tolerability and ocular biodistribution study and accounts for variability among animals as well as allows for the generation of descriptive statistical analysis.
- the topical route was selected as this is the intended route of administration in humans.
- the ocular formulation dose levels selected by the Sponsor were designed to achieve therapeutic ocular tissue concentrations of the test article.
- the single dose of the test article is common for determination of pharmacokinetics.
- a topical ophthalmic anesthetic composition was prepared containing the articaine HCI at a concentration of 8.0% w/v as shown in Table 1.
- the composition was prepared by adding the boric acid to a mixing vessel containing a volume of water until dissolved. Mannitol was then added and mixed until dissolved and stirred to form the borate/mannitol buffer complex. The sodium acetate trihydrate was then added and stirred until dissolved followed by the addition of glacial acetic acid. The EDTA dihydrate was added to obtain a pH of about pH 4.5 to pH 5.2. The articaine HCI was added and stirred until dissolved. The resulting composition had a pH of pH 4.7 to pH 4.9, and an osmolality of 580 to 630 mOsm/kg.
- compositions were prepared having the compositions shown in Table 2 below.
- Systane and Systane + 8% Articaine HCI are included here solely because they were used as viscosity comparatives, but are not otherwise part of the formulation study.
- formulations C and F were evaluated for the stability of the formulations over a period of 8 weeks in containers stored at 5°C, 25°C, and 45°C.
- the composition consisted of 35mM acetate, pH 4.8, with 15mM borate-mannitol complex, and 0.055% EpTA (disodium, dehydrate salt).
- the acetate can be obtained from acetic acid, sodium acetate or mixtures thereof.
- This formulation exhibited a stable pH, and also demonstrated a low hydrolysis rate of ⁇ 0.04% articainic acid formed per week, over a 4-week period at 40°C (1.53% total over 8 weeks), and hydrolysis at a rate of 0.061% / week at 25°C (0.49% total; over 8 weeks). This is over 4 times slower than previously known formulation.
- borate-mannitol complex which is much more acidic than boric acid (pKa 9.14) alone, forms readi ly when these two excipients are combined in the absence of other excipients or buffers, resulting in a pH of around 4.2. In terms of order of addition, these two excipients are added first and the formulation allowed to mix to allow the complex to fully form.
- a suitable molar ratio of sodium acetate to acetic acid is 70:30 (24.5 mM to 10.5 mM), in order to avoid the need for any pH adjustment after dissolution of the Articaine HC1.
- this ratio is used, the final pH after addition of 90.2 mgZmL of Articaine HC1 (equal to 80 mg/mL of Articaine as free base) was reproducibly around pH 4.80 ⁇ 0.05.
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA3134531A CA3134531A1 (en) | 2019-03-26 | 2020-03-16 | Anesthetic composition and method of anesthetizing the eye |
KR1020217034148A KR20210143254A (en) | 2019-03-26 | 2020-03-16 | Anesthetic compositions and methods of anesthesia of the eye |
AU2020245203A AU2020245203A1 (en) | 2019-03-26 | 2020-03-16 | Anesthetic composition and method of anesthetizing the eye |
EP20776365.7A EP3946311A4 (en) | 2019-03-26 | 2020-03-16 | Anesthetic composition and method of anesthetizing the eye |
MX2021011589A MX2021011589A (en) | 2019-03-26 | 2020-03-16 | Anesthetic composition and method of anesthetizing the eye. |
SG11202110423UA SG11202110423UA (en) | 2019-03-26 | 2020-03-16 | Anesthetic composition and method of anesthetizing the eye |
CN202080033483.9A CN114072139A (en) | 2019-03-26 | 2020-03-16 | Anesthetic composition and method of anesthetizing an eye |
JP2021560140A JP2022527621A (en) | 2019-03-26 | 2020-03-16 | Anesthetic composition and how to anesthetize the eye |
IL286624A IL286624A (en) | 2019-03-26 | 2021-09-23 | Anesthetic composition and method of anesthetizing the eye |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201962824207P | 2019-03-26 | 2019-03-26 | |
US62/824,207 | 2019-03-26 | ||
USPCT/US2019/024239 | 2019-03-27 | ||
PCT/US2019/024239 WO2019191200A1 (en) | 2018-03-27 | 2019-03-27 | Method and formulation for producing anesthesia of internal aspect of eye wall by topical application |
US16/811,798 | 2020-03-06 | ||
US16/811,798 US11096922B2 (en) | 2018-03-27 | 2020-03-06 | Anesthetic composition and method of anesthetizing the eye |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2020197816A1 true WO2020197816A1 (en) | 2020-10-01 |
Family
ID=72609654
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2020/022915 WO2020197816A1 (en) | 2019-03-26 | 2020-03-16 | Anesthetic composition and method of anesthetizing the eye |
Country Status (10)
Country | Link |
---|---|
EP (1) | EP3946311A4 (en) |
JP (1) | JP2022527621A (en) |
KR (1) | KR20210143254A (en) |
CN (1) | CN114072139A (en) |
AU (1) | AU2020245203A1 (en) |
CA (1) | CA3134531A1 (en) |
IL (1) | IL286624A (en) |
MX (1) | MX2021011589A (en) |
SG (1) | SG11202110423UA (en) |
WO (1) | WO2020197816A1 (en) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5342620A (en) * | 1992-05-06 | 1994-08-30 | Alcon Laboratories, Inc. | Use of borate-polyol complexes in ophthalmic compositions |
US20030133986A1 (en) * | 2001-11-21 | 2003-07-17 | Fu-Pao Tsao | Compositions for stabilizing poly (carboxylic acids) |
US20130274224A1 (en) * | 2010-12-17 | 2013-10-17 | Anteis S.A. | Sterile injectable aqueous formulation used in ophthalmology |
US20180250313A1 (en) * | 2015-09-08 | 2018-09-06 | Viewpoint Therapeutics, Inc. | Compounds and formulations for treating ophthalmic diseases |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101695488B (en) * | 2009-11-05 | 2012-05-02 | 蚌埠丰原涂山制药有限公司 | Compound articaine freeze-drying preparation for injection and preparation method thereof |
CN101721407B (en) * | 2009-11-23 | 2013-04-10 | 蚌埠丰原涂山制药有限公司 | Compound articaine hydrochloride injection and preparation method thereof |
FR3036035B1 (en) * | 2015-05-11 | 2018-10-05 | Laboratoires Vivacy | COMPOSITIONS COMPRISING AT LEAST ONE POLYOL AND AT LEAST ONE ANESTHETIC |
WO2018220283A1 (en) * | 2017-05-29 | 2018-12-06 | Kh Medtech Sarl | Sterile injectable composition containing cross-linked hyaluronic acid and articaine |
-
2020
- 2020-03-16 JP JP2021560140A patent/JP2022527621A/en active Pending
- 2020-03-16 EP EP20776365.7A patent/EP3946311A4/en active Pending
- 2020-03-16 AU AU2020245203A patent/AU2020245203A1/en active Pending
- 2020-03-16 KR KR1020217034148A patent/KR20210143254A/en unknown
- 2020-03-16 CA CA3134531A patent/CA3134531A1/en active Pending
- 2020-03-16 WO PCT/US2020/022915 patent/WO2020197816A1/en active Application Filing
- 2020-03-16 MX MX2021011589A patent/MX2021011589A/en unknown
- 2020-03-16 SG SG11202110423UA patent/SG11202110423UA/en unknown
- 2020-03-16 CN CN202080033483.9A patent/CN114072139A/en active Pending
-
2021
- 2021-09-23 IL IL286624A patent/IL286624A/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5342620A (en) * | 1992-05-06 | 1994-08-30 | Alcon Laboratories, Inc. | Use of borate-polyol complexes in ophthalmic compositions |
US20030133986A1 (en) * | 2001-11-21 | 2003-07-17 | Fu-Pao Tsao | Compositions for stabilizing poly (carboxylic acids) |
US20130274224A1 (en) * | 2010-12-17 | 2013-10-17 | Anteis S.A. | Sterile injectable aqueous formulation used in ophthalmology |
US20180250313A1 (en) * | 2015-09-08 | 2018-09-06 | Viewpoint Therapeutics, Inc. | Compounds and formulations for treating ophthalmic diseases |
Non-Patent Citations (4)
Title |
---|
ANONYMOUS: "Acetic acid", WIKIPEDIA, 22 July 2015 (2015-07-22), pages 1 - 18, XP055849193, Retrieved from the Internet <URL:https://en.wikipedia.org/wiki/Acetic_acid> * |
ANONYMOUS: "Acid dissociation constant", WIKIPEDIA, 4 April 2018 (2018-04-04), pages 1 - 27, XP055849173, Retrieved from the Internet <URL:https://en.wikipedia.org/wiki/Acid_dissociation_constant> * |
ANONYMOUS: "Articane", WIKIPEDIA, 2 April 2016 (2016-04-02), pages 1 - 6, XP055849189, Retrieved from the Internet <URL:https://en.wikipedia.org/wiki/Articaine> * |
See also references of EP3946311A4 * |
Also Published As
Publication number | Publication date |
---|---|
IL286624A (en) | 2021-10-31 |
EP3946311A4 (en) | 2022-12-28 |
SG11202110423UA (en) | 2021-10-28 |
EP3946311A1 (en) | 2022-02-09 |
CN114072139A (en) | 2022-02-18 |
CA3134531A1 (en) | 2020-10-01 |
KR20210143254A (en) | 2021-11-26 |
JP2022527621A (en) | 2022-06-02 |
AU2020245203A1 (en) | 2021-11-11 |
MX2021011589A (en) | 2021-12-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2563125C2 (en) | Aqueous pharmaceutical compositions, containing borate-polyol complexes | |
US20120034307A1 (en) | Aqueous gel formulation and method for inducing topical anesthesia | |
EP2257275B1 (en) | Ketorolac tromethamine compositions for treating or preventing ocular pain | |
Shah et al. | A novel lidocaine hydrochloride ophthalmic gel for topical ocular anesthesia | |
CN103747786A (en) | Fixed dose combination of bimatoprost and brimonidine | |
AU2021221401B2 (en) | Stable peptide compositions | |
ES2685023T3 (en) | Pharmaceutical composition of ibuprofen and tramadol for ophthalmic use | |
US11850213B2 (en) | Ophthalmic compositions of rifamycins and uses thereof | |
US20240041824A1 (en) | Anesthetic composition and method of anesthetizing the eye | |
US20050080043A1 (en) | Self-preserved antibacterial nasal, inhalable, and topical ophthalmic preparations and medications | |
JP3502574B2 (en) | Eye ointment for treatment of eye infections | |
BR112021000240A2 (en) | OPHTHALMIC COMPOSITIONS CONTAINING A PROSTAMIDE THAT RELEASES NITRIC OXIDE | |
US20240058320A1 (en) | Mydriatic compositions and methods for fabricating thereof | |
WO2020197816A1 (en) | Anesthetic composition and method of anesthetizing the eye | |
RU2812900C2 (en) | Anesthetic composition and method of eye anesthetization | |
KR20120058588A (en) | Ketorolac tromethamine compositions for treating or preventing ocular pain | |
Bellucci et al. | Comparative efficacy of topical tetracaine solution versus lidocaine gel in cataract surgery | |
CA3088185C (en) | Suspension compositions of multi-target inhibitors | |
US20210369648A1 (en) | Cysteamine zinc complex and method of using a cysteamine zinc complex | |
WO2021224815A1 (en) | Stable aqueous parenteral solutions of nonsteroidal anti-inflammatory drug (nsaid) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 20776365 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 3134531 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2021560140 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112021019039 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 20217034148 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2020776365 Country of ref document: EP Effective date: 20211026 |
|
ENP | Entry into the national phase |
Ref document number: 2020245203 Country of ref document: AU Date of ref document: 20200316 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 112021019039 Country of ref document: BR Kind code of ref document: A2 Effective date: 20210923 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 521430393 Country of ref document: SA |