JP4436131B2 - ヒアルロン酸を安定化させる組成物 - Google Patents
ヒアルロン酸を安定化させる組成物 Download PDFInfo
- Publication number
- JP4436131B2 JP4436131B2 JP2003545338A JP2003545338A JP4436131B2 JP 4436131 B2 JP4436131 B2 JP 4436131B2 JP 2003545338 A JP2003545338 A JP 2003545338A JP 2003545338 A JP2003545338 A JP 2003545338A JP 4436131 B2 JP4436131 B2 JP 4436131B2
- Authority
- JP
- Japan
- Prior art keywords
- ophthalmic composition
- composition according
- hydrochloride
- hyaluronic acid
- atropine
- 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.)
- Expired - Fee Related
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- 239000000203 mixture Substances 0.000 title claims abstract description 69
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 45
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 45
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 45
- 230000000087 stabilizing effect Effects 0.000 title claims description 7
- 238000000034 method Methods 0.000 claims abstract description 15
- -1 poly(carboxylic acids) Polymers 0.000 claims abstract description 11
- DUYCTCQXNHFCSJ-UHFFFAOYSA-N dtpmp Chemical compound OP(=O)(O)CN(CP(O)(O)=O)CCN(CP(O)(=O)O)CCN(CP(O)(O)=O)CP(O)(O)=O DUYCTCQXNHFCSJ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910021645 metal ion Inorganic materials 0.000 claims description 14
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 12
- 239000013543 active substance Substances 0.000 claims description 11
- 230000015556 catabolic process Effects 0.000 claims description 11
- 238000006731 degradation reaction Methods 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical group C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 claims description 8
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical group CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 claims description 7
- 229960004194 lidocaine Drugs 0.000 claims description 7
- 229930003347 Atropine Natural products 0.000 claims description 6
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 claims description 6
- 229940035674 anesthetics Drugs 0.000 claims description 6
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical group O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 claims description 6
- 229960000396 atropine Drugs 0.000 claims description 6
- 230000003197 catalytic effect Effects 0.000 claims description 6
- 239000003193 general anesthetic agent Substances 0.000 claims description 6
- 239000003604 miotic agent Substances 0.000 claims description 6
- 230000002911 mydriatic effect Effects 0.000 claims description 6
- STECJAGHUSJQJN-VJQRDGCPSA-N chembl3084722 Chemical compound C1([C@@H](CO)C(=O)O[C@@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-VJQRDGCPSA-N 0.000 claims description 5
- 229960002646 scopolamine Drugs 0.000 claims description 5
- GIKNHHRFLCDOEU-UHFFFAOYSA-N 4-(2-aminopropyl)phenol Chemical compound CC(N)CC1=CC=C(O)C=C1 GIKNHHRFLCDOEU-UHFFFAOYSA-N 0.000 claims description 4
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 claims description 4
- KCLANYCVBBTKTO-UHFFFAOYSA-N Proparacaine Chemical compound CCCOC1=CC=C(C(=O)OCCN(CC)CC)C=C1N KCLANYCVBBTKTO-UHFFFAOYSA-N 0.000 claims description 4
- BGDKAVGWHJFAGW-UHFFFAOYSA-N Tropicamide Chemical compound C=1C=CC=CC=1C(CO)C(=O)N(CC)CC1=CC=NC=C1 BGDKAVGWHJFAGW-UHFFFAOYSA-N 0.000 claims description 4
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 claims description 4
- 230000003547 miosis Effects 0.000 claims description 4
- 239000002637 mydriatic agent Substances 0.000 claims description 4
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 claims description 4
- 229960001697 physostigmine Drugs 0.000 claims description 4
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 claims description 4
- 229960001416 pilocarpine Drugs 0.000 claims description 4
- 229960003981 proparacaine Drugs 0.000 claims description 4
- 229960002372 tetracaine Drugs 0.000 claims description 4
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 claims description 4
- 229960004791 tropicamide Drugs 0.000 claims description 4
- QNIUOGIMJWORNZ-UHFFFAOYSA-N 2-(diethylamino)ethyl 4-butoxybenzoate Chemical compound CCCCOC1=CC=C(C(=O)OCCN(CC)CC)C=C1 QNIUOGIMJWORNZ-UHFFFAOYSA-N 0.000 claims description 3
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 3
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 claims description 3
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 claims description 3
- 230000003444 anaesthetic effect Effects 0.000 claims description 3
- 229960002463 butoxycaine Drugs 0.000 claims description 3
- WTGQALLALWYDJH-MOUKNHLCSA-N scopolamine hydrobromide (anhydrous) Chemical compound Br.C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 WTGQALLALWYDJH-MOUKNHLCSA-N 0.000 claims description 3
- RNAICSBVACLLGM-KXNXZCPBSA-N (3r,4r)-3-ethyl-4-[(3-methylimidazol-4-yl)methyl]oxolan-2-one;hydrochloride Chemical compound Cl.C1OC(=O)[C@H](CC)[C@H]1CC1=CN=CN1C RNAICSBVACLLGM-KXNXZCPBSA-N 0.000 claims description 2
- PRZXEPJJHQYOGF-KXNXZCPBSA-N (3r,4r)-3-ethyl-4-[(3-methylimidazol-4-yl)methyl]oxolan-2-one;nitric acid Chemical compound O[N+]([O-])=O.C1OC(=O)[C@H](CC)[C@H]1CC1=CN=CN1C PRZXEPJJHQYOGF-KXNXZCPBSA-N 0.000 claims description 2
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 claims description 2
- YKFROQCFVXOUPW-UHFFFAOYSA-N 4-(methylthio) aniline Chemical compound CSC1=CC=C(N)C=C1 YKFROQCFVXOUPW-UHFFFAOYSA-N 0.000 claims description 2
- HQFWVSGBVLEQGA-UHFFFAOYSA-N 4-aminobenzoic acid 3-(dibutylamino)propyl ester Chemical compound CCCCN(CCCC)CCCOC(=O)C1=CC=C(N)C=C1 HQFWVSGBVLEQGA-UHFFFAOYSA-N 0.000 claims description 2
- ZTVIKZXZYLEVOL-MCOXGKPRSA-N Homatropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(O)C1=CC=CC=C1 ZTVIKZXZYLEVOL-MCOXGKPRSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- GSYQNAMOFFWAPF-IILNCVEESA-N LSM-1606 Chemical compound C1([C@@H](CO)C(=O)OC2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)([O-])C)=CC=CC=C1 GSYQNAMOFFWAPF-IILNCVEESA-N 0.000 claims description 2
- PPVPUWFOCLLNKS-UHFFFAOYSA-N N-(1-phenylpropan-2-yl)hydroxylamine hydroiodide Chemical compound I.ONC(C)CC1=CC=CC=C1 PPVPUWFOCLLNKS-UHFFFAOYSA-N 0.000 claims description 2
- JQIPVEBSCXNGIG-UHFFFAOYSA-N N-ethyl-3-hydroxy-2-phenyl-N-(pyridin-4-ylmethyl)propanamide hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(CO)C(=O)N(CC)CC1=CC=NC=C1 JQIPVEBSCXNGIG-UHFFFAOYSA-N 0.000 claims description 2
- VNQABZCSYCTZMS-UHFFFAOYSA-N Orthoform Chemical compound COC(=O)C1=CC=C(O)C(N)=C1 VNQABZCSYCTZMS-UHFFFAOYSA-N 0.000 claims description 2
- YQKAVWCGQQXBGW-UHFFFAOYSA-N Piperocaine Chemical compound CC1CCCCN1CCCOC(=O)C1=CC=CC=C1 YQKAVWCGQQXBGW-UHFFFAOYSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 2
- FRMDDIJBLQNNTC-MOTQWOLNSA-N [(1r,5s)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl] 2-hydroxy-2-phenylacetate;hydrochloride Chemical compound Cl.C([C@H]1CC[C@@H](C2)N1C)C2OC(=O)C(O)C1=CC=CC=C1 FRMDDIJBLQNNTC-MOTQWOLNSA-N 0.000 claims description 2
- HOBWAPHTEJGALG-JKCMADFCSA-N [(1r,5s)-8-methyl-8-azoniabicyclo[3.2.1]octan-3-yl] 3-hydroxy-2-phenylpropanoate;sulfate Chemical compound [O-]S([O-])(=O)=O.C([C@H]1CC[C@@H](C2)[NH+]1C)C2OC(=O)C(CO)C1=CC=CC=C1.C([C@H]1CC[C@@H](C2)[NH+]1C)C2OC(=O)C(CO)C1=CC=CC=C1 HOBWAPHTEJGALG-JKCMADFCSA-N 0.000 claims description 2
- YYBNDIVPHIWTPK-KYJQVDHRSA-N [(3as,8bs)-3,4,8b-trimethyl-1,2,3,3a-tetrahydropyrrolo[2,3-b]indol-3-ium-7-yl] n-methylcarbamate;sulfate Chemical compound [O-]S([O-])(=O)=O.C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CC[NH+]2C.C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CC[NH+]2C YYBNDIVPHIWTPK-KYJQVDHRSA-N 0.000 claims description 2
- JUGOREOARAHOCO-UHFFFAOYSA-M acetylcholine chloride Chemical compound [Cl-].CC(=O)OCC[N+](C)(C)C JUGOREOARAHOCO-UHFFFAOYSA-M 0.000 claims description 2
- 229960004266 acetylcholine chloride Drugs 0.000 claims description 2
- 229950010917 atropine oxyde Drugs 0.000 claims description 2
- HGWPFSBHDACWNL-LZYIFBDPSA-N atropine oxyde Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)[N+]2([O-])C)C(=O)C(CO)C1=CC=CC=C1 HGWPFSBHDACWNL-LZYIFBDPSA-N 0.000 claims description 2
- 229960002028 atropine sulfate Drugs 0.000 claims description 2
- 239000006172 buffering agent Substances 0.000 claims description 2
- 229960003150 bupivacaine Drugs 0.000 claims description 2
- 229960003369 butacaine Drugs 0.000 claims description 2
- 229960004484 carbachol Drugs 0.000 claims description 2
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 claims description 2
- DWSGTFTVBLXELC-RDYJJYPNSA-N chembl1319362 Chemical compound Br.O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(O)C1=CC=CC=C1 DWSGTFTVBLXELC-RDYJJYPNSA-N 0.000 claims description 2
- XMLNCADGRIEXPK-KUMOIWDRSA-M chembl2146143 Chemical compound [Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N+]2(C)C)C(=O)C(CO)C1=CC=CC=C1 XMLNCADGRIEXPK-KUMOIWDRSA-M 0.000 claims description 2
- BSQIVYOSLFLSGE-OZVSTBQFSA-N cid_657297 Chemical compound [O-][N+]([O-])=O.C1([C@@H](CO)C(=O)OC2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)C)=CC=CC=C1 BSQIVYOSLFLSGE-OZVSTBQFSA-N 0.000 claims description 2
- 229960001747 cinchocaine Drugs 0.000 claims description 2
- PUFQVTATUTYEAL-UHFFFAOYSA-N cinchocaine Chemical compound C1=CC=CC2=NC(OCCCC)=CC(C(=O)NCCN(CC)CC)=C21 PUFQVTATUTYEAL-UHFFFAOYSA-N 0.000 claims description 2
- 229960003920 cocaine Drugs 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 229960000857 homatropine Drugs 0.000 claims description 2
- 229960002106 homatropine hydrobromide Drugs 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 229950005360 hydroxyamfetamine Drugs 0.000 claims description 2
- 229960005096 methylatropine Drugs 0.000 claims description 2
- PIPAJLPNWZMYQA-YVSFHVDLSA-N methylatropine Chemical compound C[N+]1(C)[C@@H]2CC[C@H]1C[C@@H](C2)OC(=O)[C@@H](CO)c3ccccc3 PIPAJLPNWZMYQA-YVSFHVDLSA-N 0.000 claims description 2
- ALRZZAHTTYSVRF-UHFFFAOYSA-N n-(1-phenylpropan-2-yl)hydroxylamine;hydrochloride Chemical compound Cl.ONC(C)CC1=CC=CC=C1 ALRZZAHTTYSVRF-UHFFFAOYSA-N 0.000 claims description 2
- HKOURKRGAFKVFP-UHFFFAOYSA-N octacaine Chemical compound CCN(CC)C(C)CC(=O)NC1=CC=CC=C1 HKOURKRGAFKVFP-UHFFFAOYSA-N 0.000 claims description 2
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- OCYSGIYOVXAGKQ-FVGYRXGTSA-N phenylephrine hydrochloride Chemical compound [H+].[Cl-].CNC[C@H](O)C1=CC=CC(O)=C1 OCYSGIYOVXAGKQ-FVGYRXGTSA-N 0.000 claims description 2
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- RNAICSBVACLLGM-GNAZCLTHSA-N pilocarpine hydrochloride Chemical compound Cl.C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C RNAICSBVACLLGM-GNAZCLTHSA-N 0.000 claims description 2
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- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 claims description 2
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- RZCJLMTXBMNRAD-UHFFFAOYSA-N 4-(2-aminopropyl)phenol;hydrobromide Chemical compound Br.CC(N)CC1=CC=C(O)C=C1 RZCJLMTXBMNRAD-UHFFFAOYSA-N 0.000 claims 1
- VPRGXNLHFBBDFS-UHFFFAOYSA-N [3-(diethylamino)-1-phenylpropyl] benzoate Chemical compound C=1C=CC=CC=1C(CCN(CC)CC)OC(=O)C1=CC=CC=C1 VPRGXNLHFBBDFS-UHFFFAOYSA-N 0.000 claims 1
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- DKPHLYCEFBDQKM-UHFFFAOYSA-H hexapotassium;1-phosphonato-n,n-bis(phosphonatomethyl)methanamine Chemical compound [K+].[K+].[K+].[K+].[K+].[K+].[O-]P([O-])(=O)CN(CP([O-])([O-])=O)CP([O-])([O-])=O DKPHLYCEFBDQKM-UHFFFAOYSA-H 0.000 description 1
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- FUFVKLQESJNNAN-UHFFFAOYSA-M homatropine methylbromide Chemical compound [Br-].C[N+]1(C)C(C2)CCC1CC2OC(=O)C(O)C1=CC=CC=C1 FUFVKLQESJNNAN-UHFFFAOYSA-M 0.000 description 1
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- 150000003893 lactate salts Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- LZCOQTDXKCNBEE-IKIFYQGPSA-N methscopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)C)=CC=CC=C1 LZCOQTDXKCNBEE-IKIFYQGPSA-N 0.000 description 1
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- 238000002156 mixing Methods 0.000 description 1
- 229940111688 monobasic potassium phosphate Drugs 0.000 description 1
- 229940045641 monobasic sodium phosphate Drugs 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
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- 229920001282 polysaccharide Polymers 0.000 description 1
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- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- STHAHFPLLHRRRO-UHFFFAOYSA-N propipocaine Chemical compound C1=CC(OCCC)=CC=C1C(=O)CCN1CCCCC1 STHAHFPLLHRRRO-UHFFFAOYSA-N 0.000 description 1
- 229950011219 propipocaine Drugs 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 229950000332 pyrrocaine Drugs 0.000 description 1
- OYCGKECKIVYHTN-UHFFFAOYSA-N pyrrocaine Chemical compound CC1=CC=CC(C)=C1NC(=O)CN1CCCC1 OYCGKECKIVYHTN-UHFFFAOYSA-N 0.000 description 1
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- 229960001549 ropivacaine Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
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- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
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- 239000008223 sterile water Substances 0.000 description 1
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- UDKICLZCJWQTLS-UHFFFAOYSA-N tolycaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C(=O)OC UDKICLZCJWQTLS-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/04—Artificial tears; Irrigation solutions
-
- 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
-
- 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
- A61P27/08—Mydriatics or cycloplegics
Landscapes
- Health & Medical Sciences (AREA)
- Ophthalmology & Optometry (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Cosmetics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
発明の分野
本発明は、広義には、濃度が0.3%を超えるポリ(カルボン酸)またはそれらの塩を安定化させるための組成物および方法に関する。好ましい実施態様では、本発明は、眼科用組成物におけるヒアルロン酸ナトリウムの安定化に関する。
ポリ(カルボン酸)およびそれらの塩は、ドライアイ症候群を治療するための点眼薬に有用であることが知られている。例えば、ヒアルロン酸は、この目的のための眼科用液剤または混合物に使用される。市販されているヒアルロン酸ナトリウムの一例は、Fermentechから市販のBS5111である。
a.HEALON(登録商標)−HEALON各1mlは、ヒアルロン酸ナトリウム10mg、塩化ナトリウム8.5mg、リン酸二水素二ナトリウム二水和物0.28mg、リン酸二水素ナトリウム水和物0.04mg、およびUSP注射用水q.s.を含む。
b.AMVISC(登録商標)−AMVISC各1mlは、約40,000センチストークスになるように調節したヒアルロン酸ナトリウム10mg、塩化ナトリウム9.0mg、およびUSP注射用の滅菌水q.s.を含む。
c.VISCOAT(登録商標)−VISCOAT各1ml溶液は、コンドロイチン硫酸ナトリウム40mg以下、ヒアルロン酸ナトリウム30mg、リン酸二水素ナトリウム水和物0.45mg、リン酸水素二ナトリウム2.00mg、塩化ナトリウム4.3mgを含む(USP注射等級の水q.s.を含む)。
本発明の一実施態様は、濃度が0.3%を超える少なくとも1種のポリ(カルボン酸)またはそれらの塩、および痕跡量の遊離触媒金属イオンと錯体形成できる、少なくとも1種の強力なキレート化剤(例えばホスホン酸含有キレート化剤)を含む安定化された、緩衝された組成物である。キレート化剤は、痕跡量の金属イオンと錯体形成し、それによって遊離金属イオン濃度を下げると考えられる。この遊離金属イオン濃度の低下により、ポリ(カルボン酸)の分解速度が低下する。これらの、眼科の分野で特に有用な組成物は、貯蔵寿命の増進を示す。
(a)約0.3重量%を超える、ポリ(カルボン酸)およびそれらの塩並びにそれらの混合物からなる群から選択される少なくとも1種のポリマー、
(b)0.0001〜0.1重量%の量の、少なくとも1個のホスホン酸基を有する少なくとも1種の強力かつ安定なキレート化剤、および
(c)水
を含む安定化された溶液に関する。
本発明の溶液は、0.3%を超える濃度のポリ(カルボン酸)、緩衝剤、および安定剤を含む。好ましくは、ポリ(カルボン酸)の濃度は0.8%を超える。好ましい溶液の群は、眼科的に許容される溶液、すなわち眼、眼の組織、または周囲の液体と接触した時に実質的な刺激または損傷を与えない溶液である。好ましい眼科用液剤は水性のものである。
・非治癒皮膚潰瘍における損なわれた組織の再生
・関節結合組織の関節変性
・眼科手術
が得られることを示している。
(a)約1重量%を超えるヒアルロン酸、および
(b)約0.0001〜0.1重量%の、少なくとも1つのホスホン酸基を有するキレート化剤
を含む緩衝された生理食塩水である。
BS5111ヒアルロン酸ナトリウム(Fermentech Medical Limited, Lot #4916)を精製水に、1%ヒアルロン酸ナトリウム溶液を製造するのに十分な量で加えることにより、溶液を調製した。この溶液のpHは7.384であった。
例1と同様にして、ただし180ppmのDEQUEST 2060と共に、溶液を調製した。この溶液のpHは7.451であった。
BS5111ヒアルロン酸ナトリウムを精製水に、0.8%ヒアルロン酸ナトリウム溶液を製造するのに十分な量で加えることにより、溶液を調製した。この溶液のpHは7.190であった。
例3と同様にして、ただし120ppmのDEQUEST 2060と共に、溶液を調製した。この溶液のpHは7.289であった。
すべての溶液に関して、ヒアルロン酸ナトリウム溶液の粘度を最初に、および約100℃の温度に約4時間曝露した後に測定し、加熱後のヒアルロン酸ナトリウムの相対的な回復を計算した。安定性試験を促進するために、高温を使用した。結果を下記の表1に示し、ヒアルロン酸ナトリウムの安定化におけるDEQUESTの効果を立証する。
Claims (17)
- (a)0.3重量%を超える、ヒアルロン酸およびその塩並びにそれらの混合物、および
(b)ジエチレントリアミンペンタ(メチレンホスホン酸)、および
(c)水
を少なくとも含む安定化された眼科用組成物。 - 前記組成物が、過酸化水素および過酸化水素の供給源を含まない、請求項1記載の眼科用組成物。
- ジエチレントリアミンペンタ(メチレンホスホン酸)の濃度が0.0001〜0.1重量%である、請求項1又は2記載の眼科用組成物。
- ヒアルロン酸の濃度が、少なくとも0.8%である、請求項1〜3いずれか1項記載の眼科用組成物。
- ヒアルロン酸の濃度が、少なくとも1%である、請求項1〜4いずれか1項記載の眼科用組成物。
- 2重量%までの緩衝剤をさらに含む、請求項1〜5いずれか1項記載の眼科用組成物。
- 前記ヒアルロン酸が、少なくとも750,000の平均分子量を有する、請求項1〜6いずれか1項記載の眼科用組成物。
- 前記ヒアルロン酸が、少なくとも1,200,000の平均分子量を有する、請求項1〜7いずれか1項記載の眼科用組成物。
- 薬学的に活性な薬剤をさらに含む、請求項1〜8いずれか1項記載の眼科用組成物。
- 前記薬学的に活性な薬剤が、縮瞳薬、散瞳薬、および麻酔薬からなる群から選択される、請求項9記載の眼科用組成物。
- 前記製薬学的に活性な薬剤が、ピロカルピン、イソピロカルピン、塩酸ピロカルピン、硝酸ピロカルピン、塩酸イソピロカルピン、硝酸イソピロカルピン、カルバコール、フィゾスチグミン、硫酸フィゾスチグミン、亜硫酸フィゾスチグミン、臭化デメカリウム、ヨウ化エコチオフェート、および塩化アセチルコリンからなる群から選択される縮瞳薬である、請求項10記載の眼科用組成物。
- 前記縮瞳薬が、ピロカルピンおよびイソピロカルピン系の化合物からなる群から選択される、請求項11記載の眼科用組成物。
- 前記薬学的に活性な薬剤が、アトロピン、硫酸アトロピン、塩酸アトロピン、臭化メチルアトロピン、硝酸メチルアトロピン、持続性アトロピン、アトロピンN−オキシド、フェニレフリン、塩酸フェニレフリン、ヒドロキシアンフェタミン、臭化水素酸ヒドロキシアンフェタミン、塩酸ヒドロキシアンフェタミン、ヨウ化ヒドロキシアンフェタミン、シクロペントラート、塩酸シクロペントラート、ホマトロピン、臭化水素酸ホマトロピン、塩酸ホマトロピン、臭化メチルホマトロピン、スコポラミン、臭化水素酸スコポラミン、塩酸スコポラミン、臭化メチルスコポラミン、硝酸メチルスコポラミン、スコポラミンN−オキシド、トロピカミド、臭化水素酸トロピカミド、および塩酸トロピカミドからなる群から選択される散瞳薬である、請求項12記載の眼科用組成物。
- 前記散瞳薬が、アトロピン系およびフェニレフリン系の化合物からなる群から選択される、請求項13記載の眼科用組成物。
- 前記薬学的に活性な薬剤が、リドカイン、プロパラカイン、テトラカイン、フェナカイン、ナエパイン、リドカイン、コカイン、ベトキシカイン、ブピバカイン、ブタカイン、ブタニリカイン、ブトキシカイン、カルチカイン、シクロメチカイン、ジブカイン、ジメトカイン、エチドカイン、ホルムカイン、ヘキシルカイン、ヒドロキシテトラカイン、ロイシノカイン、メピバカイン、メプリルカイン、メタブトキシカイン、ミルテカイン、オクタカイン、オルトカイン、オキセタジン、パレトキシカイン、ピペロカイン、ピリドカイン、フィロカイン、プロカイン、プロパノカイン、プロピポカイン、プロポキシカイン、プソイドカイン、ピロカイン、ロピバカイン、トリルカイン、トリカイン、およびトリメカインからなる群から選択される麻酔薬である、請求項14記載の眼科用組成物。
- 前記麻酔薬が、リドカイン、プロパラカインおよびテトラカインからなる群から選択される、請求項15記載の眼科用組成物。
- 眼科用組成物を安定化させる方法であって、1〜10重量%のヒアルロン酸もしくはその塩またはそれらの混合物、および0.0001〜0.1重量%の量のジエチレントリアミンペンタ(メチレンホスホン酸)を含む前記眼科用組成物を製造する工程を含み、
前記ジエチレントリアミンペンタ(メチレンホスホン酸)が、遊離触媒金属イオンと錯体形成し、金属イオン錯体を含む組成物を生じ、それによって前記組成物中のヒアルロン酸の分解速度を下げることができる、方法。
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US33204201P | 2001-11-21 | 2001-11-21 | |
PCT/EP2002/013019 WO2003043660A2 (en) | 2001-11-21 | 2002-11-20 | Composition for stabilizing hyaluronic acid |
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US (1) | US20030133986A1 (ja) |
EP (1) | EP1480677B8 (ja) |
JP (1) | JP4436131B2 (ja) |
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AU (1) | AU2002360939A1 (ja) |
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EP2010143B1 (en) | 2006-03-17 | 2015-08-12 | Johnson & Johnson Vision Care, Inc. | Stabilized ophthalmic compositions comprising oxidatively unstable components |
US8283463B2 (en) * | 2010-02-09 | 2012-10-09 | Bausch & Lomb Incorporated | Sterile hyaluronic acid solutions |
US8455436B2 (en) | 2010-12-28 | 2013-06-04 | Depuy Mitek, Llc | Compositions and methods for treating joints |
US8398611B2 (en) | 2010-12-28 | 2013-03-19 | Depuy Mitek, Inc. | Compositions and methods for treating joints |
US8623839B2 (en) * | 2011-06-30 | 2014-01-07 | Depuy Mitek, Llc | Compositions and methods for stabilized polysaccharide formulations |
US9492474B2 (en) | 2013-07-10 | 2016-11-15 | Matrix Biology Institute | Compositions of hyaluronan with high elasticity and uses thereof |
WO2015026423A1 (en) | 2013-08-20 | 2015-02-26 | Infusion Medical, Inc. | Syringe fill system and method |
USD750768S1 (en) | 2014-06-06 | 2016-03-01 | Anutra Medical, Inc. | Fluid administration syringe |
USD763433S1 (en) | 2014-06-06 | 2016-08-09 | Anutra Medical, Inc. | Delivery system cassette |
USD774182S1 (en) | 2014-06-06 | 2016-12-13 | Anutra Medical, Inc. | Anesthetic delivery device |
US20160051723A1 (en) * | 2014-08-21 | 2016-02-25 | Gregory J. Pomrink | Bioresorbable tissue repair composition |
US9682099B2 (en) | 2015-01-20 | 2017-06-20 | DePuy Synthes Products, Inc. | Compositions and methods for treating joints |
PL3352766T3 (pl) | 2015-09-24 | 2021-08-02 | Matrix Biology Institute | Kompozycie z hialuronanem o dużej elastyczności i sposoby ich użycia |
WO2019191200A1 (en) | 2018-03-27 | 2019-10-03 | American Genomics, Llc | Method and formulation for producing anesthesia of internal aspect of eye wall by topical application |
DE102018124022A1 (de) | 2018-09-28 | 2020-04-02 | Rheinisch-Westfälische Technische Hochschule (Rwth) Aachen | Hyaluronsäurestabilisator |
WO2020197816A1 (en) * | 2019-03-26 | 2020-10-01 | Martin Uram | Anesthetic composition and method of anesthetizing the eye |
AU2020321680A1 (en) * | 2019-07-30 | 2022-02-24 | Cellix Bio Private Limited | Composition and methods for the treatment of anal and rectal disorders |
CN111803441A (zh) * | 2020-06-10 | 2020-10-23 | 西安交通大学医学院第二附属医院 | 一种含0.01%阿托品的玻璃酸钠滴眼液及其制备方法 |
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US5166331A (en) * | 1983-10-10 | 1992-11-24 | Fidia, S.P.A. | Hyaluronics acid fractions, methods for the preparation thereof, and pharmaceutical compositions containing same |
US5607698A (en) * | 1988-08-04 | 1997-03-04 | Ciba-Geigy Corporation | Method of preserving ophthalmic solution and compositions therefor |
US5612027A (en) * | 1995-04-18 | 1997-03-18 | Galin; Miles A. | Controlled release of miotic and mydriatic drugs in the anterior chamber |
US5683993A (en) * | 1995-06-22 | 1997-11-04 | Ciba Vision Corporation | Compositions and methods for stabilizing polymers |
EP0938896A1 (en) * | 1998-01-15 | 1999-09-01 | Novartis AG | Autoclavable pharmaceutical compositions containing a chelating agent |
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WO2003043660A3 (en) | 2003-09-04 |
ES2383003T3 (es) | 2012-06-15 |
AU2002360939A1 (en) | 2003-06-10 |
CA2458126C (en) | 2012-06-26 |
EP1480677B8 (en) | 2012-05-23 |
ATE547122T1 (de) | 2012-03-15 |
JP2005509665A (ja) | 2005-04-14 |
EP1480677B1 (en) | 2012-02-29 |
EP1480677A2 (en) | 2004-12-01 |
AU2002360939A8 (en) | 2003-06-10 |
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US20030133986A1 (en) | 2003-07-17 |
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