CN104093404B - 用于治疗老花眼、轻度远视和不规则散光的组合物和方法 - Google Patents
用于治疗老花眼、轻度远视和不规则散光的组合物和方法 Download PDFInfo
- Publication number
- CN104093404B CN104093404B CN201280056271.8A CN201280056271A CN104093404B CN 104093404 B CN104093404 B CN 104093404B CN 201280056271 A CN201280056271 A CN 201280056271A CN 104093404 B CN104093404 B CN 104093404B
- Authority
- CN
- China
- Prior art keywords
- compositions
- eye
- pilocarpine
- agonist
- hypermetropia
- 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.)
- Active
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 138
- 206010020675 Hypermetropia Diseases 0.000 title claims abstract description 54
- 201000006318 hyperopia Diseases 0.000 title claims abstract description 52
- 230000004305 hyperopia Effects 0.000 title claims abstract description 52
- 201000009310 astigmatism Diseases 0.000 title claims abstract description 24
- 201000010041 presbyopia Diseases 0.000 title claims abstract description 24
- 201000000766 irregular astigmatism Diseases 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 title abstract description 9
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 claims abstract description 92
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 claims abstract description 92
- 229960001416 pilocarpine Drugs 0.000 claims abstract description 92
- 239000000556 agonist Substances 0.000 claims abstract description 57
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims abstract description 52
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims abstract description 51
- 201000010099 disease Diseases 0.000 claims abstract description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 23
- 210000000695 crystalline len Anatomy 0.000 claims abstract description 11
- 201000006327 accommodative esotropia Diseases 0.000 claims abstract description 9
- 230000008859 change Effects 0.000 claims abstract description 9
- 230000032683 aging Effects 0.000 claims abstract description 5
- 230000002441 reversible effect Effects 0.000 claims abstract description 3
- WYWIFABBXFUGLM-UHFFFAOYSA-N oxymetazoline Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C)=C1CC1=NCCN1 WYWIFABBXFUGLM-UHFFFAOYSA-N 0.000 claims description 73
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 claims description 35
- 229960001528 oxymetazoline Drugs 0.000 claims description 35
- 239000003814 drug Substances 0.000 claims description 29
- 238000011282 treatment Methods 0.000 claims description 27
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 claims description 23
- 229960001929 meloxicam Drugs 0.000 claims description 23
- 229960004484 carbachol Drugs 0.000 claims description 12
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 claims description 12
- 239000011521 glass Substances 0.000 claims description 11
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 claims description 9
- 229920000858 Cyclodextrin Polymers 0.000 claims description 8
- 229960004373 acetylcholine Drugs 0.000 claims description 8
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 8
- QVRFSYRSSMDRPS-CBAPKCEASA-N Pilocarpidine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1 QVRFSYRSSMDRPS-CBAPKCEASA-N 0.000 claims description 7
- XXRMYXBSBOVVBH-UHFFFAOYSA-N bethanechol chloride Chemical compound [Cl-].C[N+](C)(C)CC(C)OC(N)=O XXRMYXBSBOVVBH-UHFFFAOYSA-N 0.000 claims description 7
- 229960002123 bethanechol chloride Drugs 0.000 claims description 7
- 229960000590 celecoxib Drugs 0.000 claims description 7
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 claims description 7
- QVRFSYRSSMDRPS-UHFFFAOYSA-N demethylmedicalpin Natural products C1OC(=O)C(CC)C1CC1=CN=CN1 QVRFSYRSSMDRPS-UHFFFAOYSA-N 0.000 claims description 7
- 229960005293 etodolac Drugs 0.000 claims description 7
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 claims description 7
- 229960004945 etoricoxib Drugs 0.000 claims description 7
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 claims description 7
- 239000003889 eye drop Substances 0.000 claims description 7
- HYWYRSMBCFDLJT-UHFFFAOYSA-N nimesulide Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1=CC=CC=C1 HYWYRSMBCFDLJT-UHFFFAOYSA-N 0.000 claims description 7
- 229960000965 nimesulide Drugs 0.000 claims description 7
- 229960000371 rofecoxib Drugs 0.000 claims description 7
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 claims description 7
- 229960002004 valdecoxib Drugs 0.000 claims description 7
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 claims description 7
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 6
- 229960004662 parecoxib Drugs 0.000 claims description 5
- TZRHLKRLEZJVIJ-UHFFFAOYSA-N parecoxib Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 TZRHLKRLEZJVIJ-UHFFFAOYSA-N 0.000 claims description 5
- RSDOPYMFZBJHRL-UHFFFAOYSA-N Oxotremorine Chemical compound O=C1CCCN1CC#CCN1CCCC1 RSDOPYMFZBJHRL-UHFFFAOYSA-N 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- 241001597008 Nomeidae Species 0.000 claims description 3
- 229940075566 naphthalene Drugs 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 238000005507 spraying Methods 0.000 claims description 2
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 claims 6
- 239000003292 glue Substances 0.000 claims 1
- 230000008595 infiltration Effects 0.000 claims 1
- 238000001764 infiltration Methods 0.000 claims 1
- 229940102223 injectable solution Drugs 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 abstract description 71
- 230000001713 cholinergic effect Effects 0.000 abstract description 55
- 230000000694 effects Effects 0.000 abstract description 39
- 125000002636 imidazolinyl group Chemical group 0.000 abstract description 13
- 150000001875 compounds Chemical class 0.000 abstract description 11
- 208000010412 Glaucoma Diseases 0.000 abstract description 10
- 238000005728 strengthening Methods 0.000 abstract description 4
- 101150071146 COX2 gene Proteins 0.000 abstract 2
- 101100114534 Caenorhabditis elegans ctc-2 gene Proteins 0.000 abstract 2
- 101150000187 PTGS2 gene Proteins 0.000 abstract 2
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 210000001508 eye Anatomy 0.000 description 95
- 208000001491 myopia Diseases 0.000 description 31
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 29
- CNIIGCLFLJGOGP-UHFFFAOYSA-N 2-(1-naphthalenylmethyl)-4,5-dihydro-1H-imidazole Chemical compound C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 CNIIGCLFLJGOGP-UHFFFAOYSA-N 0.000 description 28
- BYJAVTDNIXVSPW-UHFFFAOYSA-N tetryzoline Chemical compound N1CCN=C1C1C2=CC=CC=C2CCC1 BYJAVTDNIXVSPW-UHFFFAOYSA-N 0.000 description 28
- 238000002360 preparation method Methods 0.000 description 27
- 230000004438 eyesight Effects 0.000 description 18
- HUCJFAOMUPXHDK-UHFFFAOYSA-N Xylometazoline Chemical compound CC1=CC(C(C)(C)C)=CC(C)=C1CC1=NCCN1 HUCJFAOMUPXHDK-UHFFFAOYSA-N 0.000 description 16
- 230000035945 sensitivity Effects 0.000 description 15
- 210000003205 muscle Anatomy 0.000 description 14
- 229960005016 naphazoline Drugs 0.000 description 14
- 229960000337 tetryzoline Drugs 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 230000001886 ciliary effect Effects 0.000 description 12
- 230000004379 myopia Effects 0.000 description 10
- 210000001747 pupil Anatomy 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- 230000001965 increasing effect Effects 0.000 description 9
- 210000005252 bulbus oculi Anatomy 0.000 description 8
- 239000006196 drop Substances 0.000 description 8
- 230000006872 improvement Effects 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 238000005259 measurement Methods 0.000 description 8
- 230000004304 visual acuity Effects 0.000 description 8
- 229960000833 xylometazoline Drugs 0.000 description 8
- 241000529895 Stercorarius Species 0.000 description 7
- 210000000554 iris Anatomy 0.000 description 7
- 239000003755 preservative agent Substances 0.000 description 7
- 230000002335 preservative effect Effects 0.000 description 7
- QQJLHRRUATVHED-UHFFFAOYSA-N tramazoline Chemical compound N1CCN=C1NC1=CC=CC2=C1CCCC2 QQJLHRRUATVHED-UHFFFAOYSA-N 0.000 description 7
- 229960001262 tramazoline Drugs 0.000 description 7
- 229960000686 benzalkonium chloride Drugs 0.000 description 6
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 229960002668 sodium chloride Drugs 0.000 description 6
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 5
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 5
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 239000001768 carboxy methyl cellulose Substances 0.000 description 5
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 5
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 5
- 210000004087 cornea Anatomy 0.000 description 5
- 229960004270 nabumetone Drugs 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- -1 sulfobutyl Chemical group 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 230000004075 alteration Effects 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- 230000008602 contraction Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 210000005070 sphincter Anatomy 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XYLJNLCSTIOKRM-UHFFFAOYSA-N Alphagan Chemical compound C1=CC2=NC=CN=C2C(Br)=C1NC1=NCCN1 XYLJNLCSTIOKRM-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229960003679 brimonidine Drugs 0.000 description 3
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 3
- 229960001231 choline Drugs 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 210000000795 conjunctiva Anatomy 0.000 description 3
- 230000002079 cooperative effect Effects 0.000 description 3
- RFWZESUMWJKKRN-UHFFFAOYSA-N dapiprazole Chemical compound CC1=CC=CC=C1N1CCN(CCC=2N3CCCCC3=NN=2)CC1 RFWZESUMWJKKRN-UHFFFAOYSA-N 0.000 description 3
- 229960002947 dapiprazole Drugs 0.000 description 3
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 208000030533 eye disease Diseases 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000000472 muscarinic agonist Substances 0.000 description 3
- 201000005111 ocular hyperemia Diseases 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- JSUAJTLKVREZHV-UHFFFAOYSA-N 1-[4-(1-pyrrolidinyl)but-2-ynyl]pyrrolidine Chemical compound C1CCCN1CC#CCN1CCCC1 JSUAJTLKVREZHV-UHFFFAOYSA-N 0.000 description 2
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 2
- 102000029816 Collagenase Human genes 0.000 description 2
- 108060005980 Collagenase Proteins 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 206010015958 Eye pain Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- COBBNRKBTCBWQP-UHFFFAOYSA-N Graveoline Chemical compound C1=C2OCOC2=CC(C=2N(C3=CC=CC=C3C(=O)C=2)C)=C1 COBBNRKBTCBWQP-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 2
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000003875 Wang resin Substances 0.000 description 2
- 208000005946 Xerostomia Diseases 0.000 description 2
- NERFNHBZJXXFGY-UHFFFAOYSA-N [4-[(4-methylphenyl)methoxy]phenyl]methanol Chemical compound C1=CC(C)=CC=C1COC1=CC=C(CO)C=C1 NERFNHBZJXXFGY-UHFFFAOYSA-N 0.000 description 2
- VRYMTAVOXVTQEF-UHFFFAOYSA-N acetic acid [4-[2-(dimethylamino)ethoxy]-2-methyl-5-propan-2-ylphenyl] ester Chemical compound CC(C)C1=CC(OC(C)=O)=C(C)C=C1OCCN(C)C VRYMTAVOXVTQEF-UHFFFAOYSA-N 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- IEJXVRYNEISIKR-UHFFFAOYSA-N apraclonidine Chemical compound ClC1=CC(N)=CC(Cl)=C1NC1=NCCN1 IEJXVRYNEISIKR-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 2
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- 208000024754 bloodshot eye Diseases 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 229960002645 boric acid Drugs 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229960003260 chlorhexidine Drugs 0.000 description 2
- 229960002424 collagenase Drugs 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 229930003836 cresol Natural products 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 208000002173 dizziness Diseases 0.000 description 2
- 206010013781 dry mouth Diseases 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 2
- 239000004744 fabric Substances 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 230000004402 high myopia Effects 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 206010027599 migraine Diseases 0.000 description 2
- 229960003509 moxisylyte Drugs 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 210000001002 parasympathetic nervous system Anatomy 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 239000004334 sorbic acid Substances 0.000 description 2
- 235000010199 sorbic acid Nutrition 0.000 description 2
- 229940075582 sorbic acid Drugs 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- PCWPQSDFNIFUPO-VDQKLNDWSA-N (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36R,37S,38R,39S,40R,41S,42R,43S,44R,45S,46R,47S,48R,49S)-37,39,41,43,45,47,49-heptakis(2-hydroxyethoxy)-5,10,15,20,25,30,35-heptakis(hydroxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,38,40,42,44,46,48-heptol Chemical compound OCCO[C@H]1[C@H](O)[C@@H]2O[C@H]3O[C@H](CO)[C@@H](O[C@H]4O[C@H](CO)[C@@H](O[C@H]5O[C@H](CO)[C@@H](O[C@H]6O[C@H](CO)[C@@H](O[C@H]7O[C@H](CO)[C@@H](O[C@H]8O[C@H](CO)[C@@H](O[C@H]1O[C@@H]2CO)[C@@H](O)[C@@H]8OCCO)[C@@H](O)[C@@H]7OCCO)[C@@H](O)[C@@H]6OCCO)[C@@H](O)[C@@H]5OCCO)[C@@H](O)[C@@H]4OCCO)[C@@H](O)[C@@H]3OCCO PCWPQSDFNIFUPO-VDQKLNDWSA-N 0.000 description 1
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- VAZJLPXFVQHDFB-UHFFFAOYSA-N 1-(diaminomethylidene)-2-hexylguanidine Polymers CCCCCCN=C(N)N=C(N)N VAZJLPXFVQHDFB-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 1
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 1
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102000009660 Cholinergic Receptors Human genes 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- 229920001287 Chondroitin sulfate Polymers 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010010071 Coma Diseases 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000001692 Esotropia Diseases 0.000 description 1
- 244000182067 Fraxinus ornus Species 0.000 description 1
- 235000002917 Fraxinus ornus Nutrition 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 206010025421 Macule Diseases 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 1
- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- UQOFGTXDASPNLL-XHNCKOQMSA-N Muscarine Chemical compound C[C@@H]1O[C@H](C[N+](C)(C)C)C[C@H]1O UQOFGTXDASPNLL-XHNCKOQMSA-N 0.000 description 1
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 1
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 1
- VCOYRKXQRUGBKS-UHFFFAOYSA-N N.[Cl] Chemical compound N.[Cl] VCOYRKXQRUGBKS-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000075088 Pilocarpus jaborandi Species 0.000 description 1
- 108010003541 Platelet Activating Factor Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002413 Polyhexanide Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- 208000004350 Strabismus Diseases 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- BAECOWNUKCLBPZ-HIUWNOOHSA-N Triolein Natural products O([C@H](OCC(=O)CCCCCCC/C=C\CCCCCCCC)COC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CCCCCCC/C=C\CCCCCCCC BAECOWNUKCLBPZ-HIUWNOOHSA-N 0.000 description 1
- PHYFQTYBJUILEZ-UHFFFAOYSA-N Trioleoylglycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCCCCCCCC)COC(=O)CCCCCCCC=CCCCCCCCC PHYFQTYBJUILEZ-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 210000002159 anterior chamber Anatomy 0.000 description 1
- 230000001384 anti-glaucoma Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940059329 chondroitin sulfate Drugs 0.000 description 1
- 210000003161 choroid Anatomy 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229960002086 dextran Drugs 0.000 description 1
- 229960000633 dextran sulfate Drugs 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 210000003717 douglas' pouch Anatomy 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 210000000720 eyelash Anatomy 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 210000004209 hair Anatomy 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 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 description 1
- 150000004693 imidazolium salts Chemical class 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 208000013433 lightheadedness Diseases 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- DKXULEFCEORBJK-UHFFFAOYSA-N magnesium;octadecanoic acid Chemical compound [Mg].CCCCCCCCCCCCCCCCCC(O)=O DKXULEFCEORBJK-UHFFFAOYSA-N 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000004297 night vision Effects 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000000820 nonprescription drug Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 210000001328 optic nerve Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 230000001053 orthosympathetic effect Effects 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 230000001734 parasympathetic effect Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 238000003359 percent control normalization Methods 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- 229960005323 phenoxyethanol Drugs 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
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000012667 polymer degradation Methods 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 201000009308 regular astigmatism Diseases 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000003786 sclera Anatomy 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 210000002820 sympathetic nervous system Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- 229940117972 triolein Drugs 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
-
- 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
- A61K31/325—Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61P27/06—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
- A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
Abstract
本发明涉及用于治疗眼部疾患,包括老花眼、轻度远视、不规则散光、远视调节性内斜视和青光眼的组合物和方法。所述组合物还可用于增强或加强延迟、逆转或更改晶状体及其周围的组织的衰老过程的介入。所述组合物包括胆碱能剂,诸如毒蕈碱乙酰胆碱受体M3激动剂和具有咪唑啉基的α激动剂或具有COX‑2选择性的非甾体抗炎剂(NSAID)。已发现与胆碱能剂,诸如毛果芸香碱,联合使用的具有咪唑啉基的α激动剂或具有COX‑2选择性的非甾体抗炎剂(NSAID)协同地起作用以改善所述眼的调节能力和聚焦能力同时使来自每种化合物的副作用最小化。
Description
本申请在2012年9月19日以PCT国际专利申请提交并且要求2012年9月20日提交的美国临时申请序列号61/536,921的优先权,其主题通过引用整体并入。
背景
正常(正视)眼具有彼此平衡的屈光力和中轴长度。通过光线以无任何主动肌(active muscular)收缩的被动方式经过眼的光学系统立即出现看到远处的物体。在正常眼中,仅聚焦近处的物体需要增加眼的屈光力中的主动肌。远视眼或者较短或具有较弱的屈光力并且因此需要主动肌机制来聚焦远处的物体(约6米外),所述主动肌机制必须更进一步增加以聚焦近处的物体。近视眼或者较长或具有太强的屈光力,所以远处的物体看起来模糊但是近处的物体在完美的焦点中而无任何主动肌介入。
人类和灵长类眼睛的聚焦的主动肌机制涉及由眼的睫状肌的收缩产生的晶状体的形状和位置的改变,这进一步增加了眼的基线屈光力。从儿童期开始,晶状体开始逐渐丧失其展性及其响应于睫状肌的收缩而改变形状和位置的能力。从光学观点来看,远视眼一般首先受该展性丧失的影响由于需要增加远视眼的屈光力以看的更清楚。在40岁左右时,当在称作老花眼的过程中正常眼不能以舒适的方式聚焦于近处(离眼40厘米或以下)的物体时展性的丧失开始影响正常眼。
在眼中,睫状肌经由乙酰胆碱及其毒蕈碱受体处于副交感神经系统的控制之下。交感神经系统经由其α和β受体起到次要(调控)的作用。毒蕈碱激动剂或刺激剂增加睫状肌的收缩并因此增加眼的屈光力。从交感神经的观点来看,α-2和β-2刺激剂部分通过使副交感神经系统以非对抗性方式发挥作用而对睫状肌产生相同的收缩作用。如果该刺激足够强,那么当刺激适当时,可克服通常随着年龄的增长发生的晶状体改变形状和位置的某些能力的丧失。
考虑治疗老花眼的另一机制为改变瞳孔直径的虹膜的舒张和括约肌的作用。所述虹膜括约肌主要处于经由毒蕈碱受体的副交感神经的控制下,虽然括约肌确实具有某些α和β受体。虹膜舒张肌处于交感神经的控制下,主要为α-1和α-2受体以及产生舒张的α-1刺激剂和限制舒张的α-2刺激剂。眼的视野的深度可通过减少瞳孔的直径而增加。这类似于照相机,其中当光圈闭合时景深增加。因此使用毒蕈碱激动剂(激活虹膜括约肌)或α-2激动剂(放松虹膜的舒张肌)可以收缩瞳孔从而增加眼的焦深。
矫正老花眼的最常用方法为使用阅读眼镜(reading glasses)或双焦点眼镜。还存在为本目的设计的专用的隐形眼镜。还设计了用于治疗老花眼的若干手术疗法,包括专用的人工晶状体、角膜的激光矫形和巩膜扩张术(scleral expansor)。已经提议将锻炼作为延迟老花眼发作的方法。然而,锻炼在治疗或预防老花眼中的有效性未在医学研究中得到证明。已经提议对老花眼进行药理学治疗。然而,这些治疗中的多数已证明为无效的和/或具有不希望的副作用。
毛果芸香碱为乙酰胆碱类似物,其充当副交感神经系统的毒蕈碱受体上的激动剂。它为熟知的已被用作眼用制剂超过100年的抗青光眼药物。也将其以口服形式使用以治疗口干/眼干。美国专利No.6,291,466和6,410,544描述了一名患者,所述患者在局部施用0.3%的毛果芸香碱之后,他/她的小于一半屈光度的远视有所下降。近视患者在施用相同剂量的毛果芸香碱之后,其近视有所下降,这是违反直觉的。
美国申请No.2010/0016395A1报道能够通过加入但比被FDA批准的浓度浓五倍的浓度的非甾体抗炎剂双氯芬酸将毛果芸香碱的剂量从1%增长至2%。Congdon等人报道双氯芬酸与严重的副作用诸如持续性上皮缺损、角膜溶解和角膜穿孔(cornealperforation)相关。(Congdon等人,2001,Corneal complications associated withtopical ophthalmic use of nonsteroidal anti-inflammatory drugs,Ophthalmology,27:622-631)
WO2009/077736公开了以治疗视敏度的缺损、老花眼、近视、远视、低夜视和散光的毛果芸香碱和达哌唑(或莫西赛利)以及毛果芸香碱和溴莫尼定(或爱必定)的组合。列出的组合为毛果芸香碱和达哌唑(或莫西赛利)以及毛果芸香碱和溴莫尼定(或爱必定)。毛果芸香碱和产生红眼且刺激眼的达哌唑(WO2009/077736)以及局部施用的溴莫尼定的组合产生(除了别的副作用之外)头昏目眩、头晕、口干、心动过速和胃不适对本领域技术人员而言是熟知的,这限制了甚至将其用于严重的眼疾患诸如青光眼的患者之间的使用。
虽然超过75种分子已被公开了用于老花眼的医学治疗,但是未发现适合于公众使用而无不当的副作用的临床上有效的制剂。
发明概述
本发明公开了用于治疗眼部疾患的组合物和方法,所述眼部疾患包括老花眼和轻度远视(高达约4.00的屈光度或在非常年轻的患者中更高)、不规则散光、远视的调节性内斜视和青光眼。本发明的组合物包括胆碱能剂,诸如毒蕈碱乙酰胆碱受体M3激动剂和具有咪唑啉基的α-刺激剂激动剂或具有COX-2选择性的非甾体抗炎剂(NSAID)。毒蕈碱乙酰胆碱受体M3激动剂的实例包括毛果芸香碱、乙酰胆碱、毛果芸香次碱、氯贝胆碱、卡巴胆碱和氧代震颤素。具有咪唑啉基的α-刺激剂激动剂的实例包括羟甲唑啉、萘甲唑啉、四氢唑啉和赛洛唑啉。具有COX-2选择性的NSAID的实例包括美洛昔康、塞来考昔、罗非昔布、伐地考昔、帕瑞考昔、依托考昔、尼美舒利、依托度酸和萘丁美酮。
令人惊讶地和预料之外发现本发明的组合物增强胆碱能剂(诸如毛果芸香碱)的作用并减少所述胆碱能剂的副作用使得胆碱能剂可有效地与具有咪唑啉基的α-刺激剂激动剂或具有COX-2选择性的非甾体抗炎剂(NSAID)联合使用以收缩睫状肌和瞳孔括约肌用于治疗眼部疾患,诸如老花眼、轻度远视和不规则散光、远视调节性内斜视和青光眼,而不用患者经历通常与毛果芸香碱治疗相关的不希望的副作用。本发明还可用于增强或加强延迟、逆转或更改晶状体及其周围的组织的衰老过程的介入。不像现有技术公开的先前的组合物,据信本发明的组合物可在慢性基础上由患者安全地用于治疗眼部疾患,包括老花眼、轻度远视、不规则散光、远视调节性内斜视和青光眼。
附图简述
图1示出随时间推移包含毛果芸香碱和羟甲唑啉的组合物对近视力的影响(Jaeger当量)。
图2示出随时间推移包含毛果芸香碱和羟甲唑啉的组合物对远视力的影响(LogMAR当量)。
图3示出随时间推移包含毛果芸香碱和羟甲唑啉的组合物以及仅包含毛果芸香碱的组合物对近视力的影响的比较(Jaeger当量)。
图4示出随时间推移包含毛果芸香碱和羟甲唑啉的组合物以及仅包含毛果芸香碱的组合物对远视力的影响的比较(LogMAR当量)。
图5示出随时间推移包含毛果芸香碱和美洛昔康的组合物对近视力的影响(Jaeger当量)。
图6示出随时间推移包含毛果芸香碱和美洛昔康的组合物对远视力的影响(LogMAR当量)。
发明详述
定义
本文使用的短语“一个(a)”或“一种(an)”是指一种或多种该实体;例如,化合物是指一种或多种化合物或至少一种化合物。因此,术语“一个”(或“一种”)、“一种或多种”和“至少一种”可在本文中互换使用。
如本文所用,“组合物“是指适于施用至受试者的眼睛的物质。如果需要组合物可以包括聚合药物递送系统。组合物可以包含液体载体。还可使用术语来指诸如溶液、悬浮液、乳液等的物质。
本文使用的术语“治疗有效量”,是指治疗眼部疾患需要的而不会对眼或眼部区域产生显著的负面的或不良副作用的药剂的水平或量。
如本文所用,“眼部疾患”为病症、疾病或疾患,其影响或涉及眼或眼的一部分或区域,包括眼球以及构成眼球的组织和液体、眼周肌肉(诸如斜肌和直肌)以及在眼球内或邻近眼球的部分视神经。眼部疾患的实例包括老花眼和轻度远视、不规则散光、远视调节性内斜视和青光眼。
以下术语为本领域技术人员常用的眼科术语。“OD”代表右眼(oculus dexter)并且意指右眼(right eye)。“OS”代表左眼(oculus sinister)并且意指左眼(left eye)。“UDVA”代表裸眼远视敏度。“UNVA”代表裸眼近视敏度。“Sph”为球体或眼睛需要看清楚的放大/缩小的量。负球体指示近视,正球体指示远视。“Cyl”为圆柱体,其为散光的量度。“Pre“指示在治疗之前眼的疾患。1h指示在治疗1小时后眼的疾患,4h指示在4小时治疗后眼的疾患,6h指示在治疗6小时后眼的疾患。“Sph Eq”为等效球镜。
本文使用和描述在Jaeger标度(近视力标度)上的测量。本文使用的Jaeger标度值的一些实例包括以下:J1+为优良的“正常”近视力(在Snellen术语中等价于20/20),其能够阅读在近视力视力表上的最下面一行(在3-点字体字母中);J1为良好的近视力(在Snellen术语中等价于20/25),其能够阅读在近视力视力表上的与最下面行相邻的一行(在4-点字体字母中);J2和J3分别为一般近视力和功能性近视力(在Snellen术语中分别等价于20/30和20/40,),其分别能够阅读近视力视力表上从最下面起的3行和4行,其中J3为6-点字体字母的“阅读视力”。
“LogMAR”为通常使用的视敏度标度,表示为最小分辨角度的(十的)对数。LogMAR标度将传统图表的几何数列转换成线性标度。
实施本发明的方式
具有咪唑啉基的α-刺激剂,诸如羟甲唑啉、萘甲唑啉和四氢唑啉,已经在大范围内以自开处方药物使用,自从20世纪70年代在美国以非处方药获得,对于眼部发红/刺激的副作用报道非常少。赛洛唑啉,咪唑啉的另一衍生物,已被用作鼻血管收缩药。尽管这些药剂由公众广泛使用,但是这些药剂先前并未用于治疗眼部疾患,诸如老花眼,因为当单独使用时它们缺乏显著的临床效果。
毛果芸香碱,一种胆碱能剂,已被用作单独的药物用于治疗老花眼和轻度远视,但是并未非常有效的因为低于0.5%的局部浓度对于调解眼产生极小的作用而高于0.5%的浓度由于诸如红眼、眼部疼痛、偏头痛和头痛的副作用而无法容忍。此外,在毛果芸香碱的浓度足以有效改善远视患者的阅读能力下,眼睛呈现这样的近视使得眼的远视力存在显著的下降(Gilmartin等人,1995,Ophthalmic and Physiological Optics,Pergamon Press,Oxford,GB,15(5):475-479)。
非甾体抗炎剂(NSAID)抑制产生前列腺素的环加氧酶。该酶具有两种形式:环加氧酶-1(COX-1),其被认为具有“固有的”和“看家”功能以及环加氧酶-2(COX-2),其在炎症和癌症的情况下发生上调。与抑制COX-1和COX-2相对,选择性地抑制COX-2的药剂被认为阻断炎症而不会影响正常的稳态体机制。(Fitzgerald GA and Patrono C.The coxibs,selective inhibitors of cyclooxygenase-2.NEJM2001;345:433-442)。尽管这对于胃肠道粘膜的保护为正确的,但是已经报道诸如血栓形成事件或肾损伤的副作用,诸如在口服罗非昔布的情况下。在角膜水平COX-2产物的抑制减少胶原酶,所述胶原酶增加NSAID的已知的眼部副作用诸如角膜溶解(Ottino P和Bazan HE.Corneal stimulation of MMP-1,-9and uPA by platelet-activating factor is mediated by cyclooxygenase-2metabolites.Curr Eye Res.2001年8月;23(2):77-85)。
已经令人惊讶地和预料之外发现本发明的组合物增强胆碱能剂(诸如毛果芸香碱)的作用并减少所述胆碱能剂的副作用使得胆碱能剂可有效地与具有咪唑啉基的α-刺激剂激动剂或具有COX-2选择性的NSAID联合使用以收缩眼睫毛肌和瞳孔肌用于治疗眼部疾患,诸如老花眼、轻度远视和不规则散光、远视调节性内斜视或青光眼,而不用患者经历通常与毛果芸香碱治疗相关的不希望的副作用。此外,具有咪唑啉基的α-刺激剂,在与胆碱能剂(诸如毛果芸香碱)联合使用时具有协同效应,先前发现的所述α-刺激剂对于治疗眼部疾患缺乏显著的临床效果。尽管不希望受任何特定理论的束缚,据信协同效应由于毒蕈碱和肾上腺素能受体之间可能经由G蛋白的受体后交叉感知,产生咪唑化合物与毒蕈碱激动剂的观察到的新型相互作用。不像现有技术公开的先前的组合物,本发明的组合物可在慢性基础上由患者安全地用于治疗眼部疾患,诸如老花眼、轻度远视和不规则散光、远视调节性内斜视或青光眼。本发明还可用于增强或加强延迟、逆转或更改晶状体及其周围的组织的衰老过程的介入。
本发明的组合物包括与具有咪唑啉基的α-刺激剂激动剂或具有COX-2选择性的NSAID联合使用的胆碱能剂。胆碱能剂可为作用于眼的睫状肌并引起其收缩的毒蕈碱乙酰胆碱受体M3激动剂。毛果芸香碱和卡巴胆碱为合适的毒蕈碱乙酰胆碱受体M3激动剂的实例。其它的实例包括乙酰胆碱、氯贝胆碱、氧代震颤素、毛果芸香次碱等。在一个实施方案中,胆碱能剂为毛果芸香碱。
适用于本发明的组合物的具有咪唑啉基的α-刺激剂激动剂的实例包括羟甲唑啉、萘甲唑啉、四氢唑啉、曲马唑啉、赛洛唑啉等。在一个实施方案中,α-刺激剂激动剂包含羟甲唑啉、萘甲唑啉、四氢唑啉、曲马唑啉和赛洛唑啉中的一种或多种。在一个实施方案中,α-刺激剂激动剂包含羟甲唑啉。在另一实施方案中,α-刺激剂激动剂包含萘甲唑啉。在再另一实施方案中,α-刺激剂激动剂包含四氢唑啉。
具有COX-2选择性的NSAID的实例包括美洛昔康、塞来考昔、罗非昔布、伐地考昔、帕瑞考昔、依托考昔、尼美舒利、依托度酸和萘丁美酮等。在一个实施方案中,NSAID包含美洛昔康、塞来考昔、罗非昔布、伐地考昔、帕瑞考昔、依托考昔、尼美舒利、依托度酸和萘丁美酮中的一种或多种。在另一实施方案中,NSAID包含美洛昔康。
胆碱能剂与具有咪唑啉基的α-刺激剂激动剂或具有COX-2选择性的NSAID联合使用增强胆碱能剂和α-刺激剂激动剂或NSAID的作用,从而收缩睫状肌并并减少瞳孔直径以有效地治疗眼部疾患,诸如老花眼、轻度远视和不规则散光、远视调节性内斜视或青光眼。本文描述的组合还减少胆碱能剂的副作用而未添加来自α-刺激剂激动剂或NSAID的显著的副作用,使患者更容易耐受长期使用本发明的组合物。
通过与α-刺激剂激动剂或NSAID联合施用胆碱能剂,该药剂同时地且精确地以调节彼此效果的方式作用于眼部受体。当在顺次的基础上分别地施用药剂时,存在在施用另一种药剂之前受体被药剂中的一种饱和,导致不稳定的临床反应。这可在第一药剂之后通过施用一滴在结膜穹窿的第二药剂的冲洗作用进一步复杂化,产生递送至眼的未知浓度的活性化合物。
本发明的组合物适于眼科使用。组合物一般包括约0.01%至约4%w/w的胆碱能剂以及约0.01%至约0.5%w/w的具有咪唑啉基的α-刺激剂激动剂或约0.01%至约2%w/w的具有COX-2选择性的NSAID,或两者。组合物可包括与如本文描述的任何浓度的胆碱能剂联合使用的如本文描述的任何浓度的具有咪唑啉基的α-刺激剂激动剂和/或具有COX-2选择性的NSAID。
根据一个实施方案,组合物的眼用制剂包含约0.01%至约4%w/w的胆碱能剂,诸如毛果芸香碱或卡巴胆碱。在另一实施方案中,组合物的眼用制剂包含约0.01%至约3.5%w/w的胆碱能剂。在再另一实施方案中,组合物的眼用制剂包含约0.01%至约3%w/w的胆碱能剂。在再另一实施方案中,组合物的眼用制剂包含约0.01%至约2.5%w/w的胆碱能剂。在再另一实施方案中,组合物的眼用制剂包含约0.01%至约2%w/w的胆碱能剂。在再另一实施方案中,组合物的眼用制剂包含约0.1%至约2.0%w/w的胆碱能剂。
根据一个实施方案,组合物的眼用制剂包含约0.01%至约0.5%w/w的具有咪唑啉基的α-刺激剂激动剂,诸如羟甲唑啉。在另一实施方案中,组合物的眼用制剂包含约0.01%至约0.25%w/w的具有咪唑啉基的α-刺激剂激动剂。根据优选的实施方案中,组合物的眼用制剂包含约0.01%至约0.1%w/w的具有咪唑啉基的α-刺激剂激动剂。根据另一优选的实施方案,组合物的眼用制剂包含约0.01%至约0.05%w/w的具有咪唑啉基的α-刺激剂激动剂。根据另一优选的实施方案,组合物的眼用制剂包含约0.025%w/w的具有咪唑啉基的α-刺激剂激动剂。
根据一个实施方案,组合物的眼用制剂包含约0.01%至约2%w/w的具有COX-2选择性的NSAID,诸如美洛昔康。在另一实施方案中,组合物的眼用制剂包含约0.01%至约1%w/w的具有COX-2选择性的NSAID。在另一实施方案中,组合物的眼用制剂包含约0.01%至约0.5%w/w的具有COX-2选择性的NSAID。根据优选的实施方案中,组合物的眼用制剂包含约0.01%至约0.2%w/w的具有COX-2选择性的NSAID。根据另一优选的实施方案,组合物的眼用制剂包含约0.01%至约0.1%w/w的具有COX-2选择性的NSAID。
一方面,本发明组合物的眼用制剂可包括约0.01%至约4%、约0.01%至约3.5%、约0.01%至约3.0%或约0.01%至约2.5%w/w的胆碱能剂和约0.01%至约0.2%w/w的具有咪唑啉基的α-刺激剂激动剂。在一个实施方案中,组合物包含约0.01%至约2%w/w的胆碱能剂和约0.01%至约0.2%w/w的具有咪唑啉基的α-刺激剂激动剂。在一个实施方案中,组合物包含约0.5%至约1.5%w/w的胆碱能剂和约0.02%至约0.1%的α-刺激剂激动剂。在另一实施方案中,组合物包含约0.9%至约1.1%w/w的胆碱能剂和约0.0125%至约0.5%w/w的α-刺激剂激动剂。胆碱能剂可为作用于眼的睫状肌并引起其收缩的毒蕈碱乙酰胆碱受体M3激动剂。毛果芸香碱和卡巴胆碱为合适的毒蕈碱乙酰胆碱受体M3激动剂的实例。其它的实例包括乙酰胆碱、氯贝胆碱、氧代震颤素、毛果芸香次碱等。具有咪唑啉基的α-刺激剂激动剂的实例包括羟甲唑啉、萘甲唑啉、四氢唑啉、曲马唑啉、赛洛唑啉等。
在实施方案中,组合物包含毛果芸香碱和羟甲唑啉。这些组合物中毛果芸香碱的剂量范围可为约0.01%至约2%w/w以及羟甲唑啉的剂量范围可为约0.01%至约0.1%w/w。在一个实施方案中,组合物包含约0.5%至约0.9%w/w的浓度的毛果芸香碱以及约0.01%至约0.024%w/w的浓度的羟甲唑啉。在另一实施方案中,组合物包含约1.1%至约2%w/w的浓度的毛果芸香碱以及约0.026%至约0.1%w/w的浓度的羟甲唑啉。在再另一实施方案中,组合物包含约1%w/w的浓度的毛果芸香碱以及约0.0125%w/w的浓度的羟甲唑啉。
在实施方案中,组合物包含毛果芸香碱和萘甲唑啉。这些组合物中毛果芸香碱的剂量范围可为约0.01%至约2%w/w以及萘甲唑啉的剂量范围可为约0.01%至约0.2%w/w。在一个实施方案中,组合物包含约0.01%至约0.9%w/w的浓度的毛果芸香碱以及约0.01%至约0.09%w/w的浓度的萘甲唑啉。在另一实施方案中,组合物包含约1.1%至约2%w/w的浓度的毛果芸香碱以及约0.11%至约0.2%w/w的浓度的萘甲唑啉。在再另一实施方案中,组合物包含约1%w/w的浓度的毛果芸香碱以及约0.1%w/w的浓度的萘甲唑啉。
在实施方案中,组合物包含毛果芸香碱和四氢唑啉。这些组合物中毛果芸香碱的剂量范围为约0.01%至约2%w/w以及四氢唑啉的剂量范围为约0.01至约0.1%w/w。在一个实施方案中,组合物包含约0.01%至约0.9%w/w的浓度的毛果芸香碱以及约0.01%至约0.04%w/w的浓度的四氢唑啉。在另一实施方案中,组合物包含约1.1%至约2%w/w的浓度的毛果芸香碱以及约0.06%至约0.1%w/w的浓度的四氢唑啉。在再另一实施方案中,组合物包含约1%w/w的浓度的毛果芸香碱以及约0.05%w/w的浓度的四氢唑啉。
具有咪唑啉基的其它合适的α-刺激剂激动剂,诸如曲马唑啉和赛洛唑啉可在本文公开的羟甲唑啉、萘甲唑啉或四氢唑啉的剂量和浓度范围下与毛果芸香碱联合配制。在一个实施方案中,曲马唑啉以约0.03%w/w至约0.12%w/w存在。在另一实施方案中,将在本文公开的浓度下的毛果芸香碱与在约0.06%w/w的浓度下的曲马唑啉组合。在一个实施方案中,赛洛唑啉以约0.01%w/w至约0.10%w/w存在。在另一实施方案中,将在本文公开的浓度下的毛果芸香碱与在约0.025%w/w的浓度下的赛洛唑啉组合。其它合适的胆碱能剂,诸如乙酰胆碱、氯贝胆碱、卡巴胆碱、氧代震颤素和毛果芸香次碱,可在本文公开的毛果芸香碱的剂量和浓度范围下与羟甲唑啉、萘甲唑啉、四氢唑啉、曲马唑啉或赛洛唑啉联合配制。
在另一方面,本发明组合物的眼用制剂可包括约0.01%至约4%、约0.01%至约3.5%、约0.01%至约3.0%或约0.01%至约2.5%w/w的胆碱能剂以及约0.001%至约2%w/w的具有COX-2选择性的NSAID。在一个实施方案中,组合物包含约0.01%至约2%w/w的胆碱能剂和约0.001%至约2%w/w的具有COX-2选择性的NSAID。在一个实施方案中,组合物包含约0.5%至约1.5%w/w的胆碱能剂和约0.1%至约1%的NSAID。在另一实施方案中,组合物包含约0.9%至约1.1%w/w的胆碱能剂和约0.01%至约0.1%w/w的NSAID。胆碱能剂可为作用于眼的睫状肌并引起其收缩的毒蕈碱乙酰胆碱受体M3激动剂。毛果芸香碱和卡巴胆碱为合适的毒蕈碱乙酰胆碱受体M3激动剂的实例。其它的实例包括乙酰胆碱、氯贝胆碱、氧代震颤素、毛果芸香次碱等。具有COX-2选择性的NSAID的实例包括美洛昔康、塞来考昔、罗非昔布、伐地考昔、帕瑞考昔、依托考昔、尼美舒利、依托度酸、萘丁美酮等。
在实施方案中,组合物包含毛果芸香碱和美洛昔康。这些组合物中毛果芸香碱的剂量范围为约0.01%至约2%w/w以及美洛昔康的剂量范围为约0.001%至约2%w/w。在一个实施方案中,组合物包含约0.01%至约0.9%w/w的浓度的毛果芸香碱以及约0.01%至约1%w/w的浓度的美洛昔康。在另一实施方案中,组合物包含约1.1%至约2%w/w的浓度的毛果芸香碱以及约0.1%至约0.5%w/w的浓度的美洛昔康。在再另一实施方案中,组合物包含约1%w/w的浓度的毛果芸香碱和约0.03%w/w的浓度的美洛昔康。
具有COX-2选择性的其它合适的NSAID,诸如塞来考昔、罗非昔布、伐地考昔、帕瑞考昔、依托考昔、尼美舒利、依托度酸或萘丁美酮可在本文公开的美洛昔康的剂量和浓度范围下与毛果芸香碱联合配制。其它合适的胆碱能剂,诸如乙酰胆碱、氯贝胆碱、卡巴胆碱、氧代震颤素和毛果芸香次碱,可在本文公开的毛果芸香碱的剂量和浓度范围下与美洛昔康、塞来考昔、罗非昔布、伐地考昔、帕瑞考昔、依托考昔、尼美舒利、依托度酸或萘丁美酮联合配制。在一个实施方案中,M3激动剂卡巴胆碱以与具有咪唑啉基的α-刺激剂激动剂或具有COX-2选择性的非甾体抗炎剂(NSAID)联合的约0.1%w/w至约4%w/w或约0.1%w/w至约3%w/w的浓度存在,其中所述α-刺激剂或NSAID在以上实施方案中的一者中描述的浓度下使用。在另一实施方案中,M3激动剂卡巴胆碱以与具有咪唑啉基的α-刺激剂激动剂或具有COX-2选择性的非甾体抗炎剂(NSAID)联合的约2.5%w/w的浓度存在,其中所述α-刺激剂或NSAID在以上实施方案中的一者中描述的浓度下使用。
本发明的组合物可基于患者对视力矫正的需求和患者对组合物的反应性而针对患者定制。例如,对具有轻度形式的远视或老花眼需要微小矫正的患者可以提供有具有较低浓度的胆碱能剂的组合物。在另一方面,对具有较严重的远视或老花眼的患者可以提供有具有较高浓度的胆碱能剂的组合物。通常,年轻的患者(如小于四十岁的患者)可以经历远视或老花眼的初期症状并可以仅需要微小矫正,然而年长的患者(如五十岁及以上的患者)可以经历更显著的老花眼或远视和老花眼的组合的症状并且可能需要更多矫正。一些患者可能需要较低浓度的胆碱能剂因为他们对药物的反应更强烈。例如,非常年轻的患者(如,儿童)可能比年长的患者反应更强烈因此可以从较低浓度的胆碱能剂中获益。
根据示例性实施方案,对于治疗具有非常轻度疾患的患者或反应强烈的患者的组合物包含约0.1%至约0.5%w/w的胆碱能剂,诸如毛果芸香碱,或约0.2%至约0.4%w/w的胆碱能剂或约0.3%w/w的胆碱能剂。用于治疗具有轻度疾患的患者或其视力可用具有约+0.5D至约+1.0D或约+0.75D镜片的眼镜替代地矫正的患者的组合物可以包含约0.3%至约1.0%w/w的胆碱能剂,诸如毛果芸香碱,或约0.4%至约0.8%w/w的胆碱能剂或约0.5%至约0.7%w/w的胆碱能剂或约0.6%w/w的胆碱能剂。用于治疗其视力可用具有约+1.0D至约+1.5D镜片或约+1.2D至+1.3D镜片的眼镜替代地矫正的患者的组合物可以包含约0.8%至约1.6%w/w的胆碱能剂诸如毛果芸香碱,或约1.0%至约1.4%w/w的胆碱能剂或约1.1%至约1.3%w/w的胆碱能剂或约1.2%w/w的胆碱能剂。用于治疗其视力可用具有约+1.5D至约+2.0D或约+1.75D镜片的眼镜替代地矫正的患者的组合物可以包含约1.4%至约2.2%w/w的胆碱能剂诸如毛果芸香碱,或约1.6%至约2.0%w/w的胆碱能剂或约1.7%至约1.9%w/w的胆碱能剂或约1.8%w/w的胆碱能剂。
非常年轻的患者(如儿童)可以特别地从使用本文公开的组合物中获益。非常年轻的患者可能对组合物反应更强烈,并且可能因此需要较低浓度的胆碱能剂。本发明的组合物还可以用于治疗比在年长的患者中更严重的非常年轻的患者的疾患;例如,所述组合物可以用于治疗儿童中的中度远视(高达+4.0D)。
本发明的组合物还可以基于患者对刺激或副作用的敏感性而针对患者定制。例如,对具有较大敏感性的患者可以提供有具有减少发红和刺激的较高浓度的药剂的组合物,诸如具有咪唑啉基的α-刺激剂激动剂或具有COX-2选择性的NSAID。根据一个实施方案,用于治疗具有较大敏感性的患者的组合物可以包含约0.05%至约0.2%w/w的具有咪唑啉基的α-刺激剂激动剂或具有COX-2选择性的NSAID或两者的组合。
本发明的组合物可进一步包括环糊精或其衍生物。环糊精为环状寡糖,其具有较不的亲水性内腔和亲水性外表面并且能够与多种分子形成非共价的复合物。可获得自然形成的(α-、β-和γ-)和合成的(如,化学修饰的羟乙基-β-或磺丁基醚-β-)环糊精。在将本发明的组合物滴注至眼后,环糊精及其衍生物可用于加强胆碱能剂、α-刺激剂激动剂和/或具有COX-2选择性的NSAID的眼部渗透并减少患者的不适感以及改善刺激。合适的环糊精的实例包括亲水性环糊精,诸如羟乙基-β-环糊精和磺丁基醚-β-环糊精。环糊精也可以包括在本发明的组合物中以改善组合物的活性成分的溶解度、生物利用率和保质期。根据示例性实施方案,组合物包含约0.1%至约4.0%的毛果芸香碱、约0.01%至约0.1%的羟甲唑啉或约0.01%至约0.2%的美洛昔康和约0.1%至约2.0%的β-环糊精。根据另一示例性实施方案,组合物包含约0.75%至约4%的卡巴胆碱、约0.01%至约0.1%的羟甲唑啉或约0.01%至约0.2%的美洛昔康和约0.1%至约2.0%的β-环糊精。
本文描述的组合物包括但不限于含液体的组合物,诸如制剂,和聚合药物递送系统。可以将组合物理解为包括溶液、悬浮液、乳液等,诸如用于眼科治疗的其它含液体的组合物。可以将本发明的组合物掺入包括聚合物组分的聚合药物递送系统,并且可以理解为包括可生物降解的聚合物、可生物降解的移植物、不可生物降解的移植物、可生物降解的微粒诸如可生物降解的微球、纳米颗粒等。所述可生物降解的聚合物在体内降解,其中随时间推移同时或随后发生一种聚合物或多种聚合物的降解或侵蚀以释放掺入及加载至聚合物上的本发明的组合物。具有不同半衰期的组合物的物质可以以不同类型(尺寸、形式、组分或数目)的纳米颗粒掺入,在处理的组织中产生每个组分的适当的释放速率和浓度。可生物降解的聚合物可以为均聚物、共聚物或包含多于两种不同的聚合单元的聚合物。本文公开的药物递送系统可以涵盖呈片剂、圆片、竿状、片材、线状、丝状等形式的元件。聚合的药物递送系统可以为固体、半固体或粘弹性的。
在某些实施方案中,本发明中使用的载体可以为固相支撑物,包括聚合物珠或树脂,诸如王氏树脂(Wang resin)。支撑物可为具有一定程度的硬度的固体诸如硅、塑料等。支撑物还可为柔性材料诸如塑料或另外合成材料(诸如尼龙)、由天然聚合物(诸如纤维素或丝)或其衍生物(诸如硝化纤维)制成的材料等。在某些实施方案中,支撑物为多孔材料,所述多孔材料可为刚性的或柔性的相互结合的纤维,其包括织物等。在某些实施方案中,所述固相支撑物为小珠或小球,所述小珠或小球可为多孔的。在某些实施方案中,可以将所述一种载体或多种载体最优化用于缓慢释放或定时释放活性剂。可以将包括聚合物珠载体或其它此类载体或如以上描述的载体的制剂结膜下(subconjuctivally)注射,直接注射进眼或眼周围的组织,可以局部施用至眼或周围组织或可以以位于鼻泪点处的管栓的形式施用。
在实施方案中,配制本发明的组合物用于递送至眼或眼周围的组织或液体。所述组合物可呈悬浮液、滴眼剂、软膏、凝胶、喷雾、粉末、缓释制剂的形式用于结膜下或在任何其它眼位置施用,或其它合适的形式用于将本发明的组合物施用至眼或眼周围的液体和/或组织。在药物组合物的制备中使用缓冲剂、稳定剂、还原剂、抗氧化剂和螯合剂在本领域为熟知的。参见,Wang等人,"Review of Excipients and pHs for Parenteral ProductsUsed in the United States."J.Parent.Drug Assn.,34(6):452-462(1980);Wang等人,"Parenteral Formulations of Proteins and Peptides:Stability and Stabilizers,"J.Parent.Sci.and Tech.,42:S4-S26(增刊1988);Lachman等人,"Antioxidants andChelating Agents as Stabilizers in Liquid Dosage Forms-Part1,"Drug andCosmetic Industry,102(1):36-38,40和146-148(1968);Akers,M.J.,"Antioxidants inPharmaceutical Products,"J.Parent.Sci.and Tech.,36(5):222-228(1988);以及Methods in Enzymology,第XXV卷,Colowick和Kaplan编辑,Konigsberg的"Reduction ofDisulfide Bonds in Proteins with Dithiothreitol,"第185-188页。
合适的载体包括药学上可接受的载体、赋形剂或稳定剂,其在使用的剂量和浓度下对暴露至其的细胞或哺乳动物为无毒的。通常生理上可接受的载体为无菌水或含水pH缓冲液。pH调控剂包括硼酸、磷酸、乙酸、碳酸、柠檬酸、山梨酸等。pH调节剂包括酸诸如盐酸或碱诸如氢氧化钠或氢氧化钾、碳酸氢钠等。合适的生理上或眼科上可接受的载体包括缓冲剂诸如磷酸盐、柠檬酸盐和其它有机酸;抗氧化剂,包括抗坏血酸;低分子量(小于约10个残基)的多肽;蛋白诸如血清白蛋白、明胶或免疫球蛋白;亲水性聚合物诸如聚乙烯吡咯烷酮;氨基酸诸如甘氨酸、谷氨酰胺、天冬酰胺、精氨酸或赖氨酸;单糖、二糖和其它碳水化合物包括葡萄糖、甘露糖或糊精;螯合剂诸如EDTA;糖醇诸如甘露醇或山梨醇;成盐抗衡离子诸如钠;和/或非离子表面活性剂诸如TWEENTM聚乙二醇(PEG)和PLURONICSTM。
本发明的组合物可包括一种或多种防腐剂诸如苯酚、甲酚、对氨基苯甲酸、BDSA、硝酸异山梨酯、氯己定、苯扎氯铵、山梨酸和硼酸、(氯氧化物化合物)、(季胺)、聚六亚甲基双胍、过硼酸钠等。可配制并包装预期长期用于慢性疾患的组合物以使可以刺激眼的防腐剂的使用最小化。例如,可以将组合物包装于单剂量容器中或在利用替代的装置的容器(诸如膜、阀门机制或银)中用于使微生物污染最小化。
组合物可包括稳定剂和粘度增强剂(viscosant agents)诸如微晶纤维素、硬脂酸镁、甘露醇、蔗糖、EDTA、亚硫酸氢钠、甲基纤维素、羧甲基纤维素、羟丙基甲基纤维素、透明质酸、藻酸盐、硫酸软骨素(chonodroitin sulfate)、右旋糖酐、麦芽糖糊精、硫酸右旋糖酐、聚乙烯吡咯烷酮、聚乙烯醇等中的一种或多种。组合物可包括乳化剂诸如聚山梨酯20、聚山梨酯80、普流尼克、三油精、大豆油、卵磷脂、角鲨烯和角鲨烷、失水山梨糖醇三油酸酯(sorbitan treioleate)等。组合物可包括抗微生物剂诸如苯乙基醇、苯酚、甲酚、苯扎氨氯、苯氧乙醇、氯己定、硫柳汞(thimerosol)等。合适的增稠剂包括天然的多糖诸如甘露聚糖、阿拉伯聚糖、藻酸盐、透明质酸、右旋糖等;以及合成的多糖像低分子量的PEG水凝胶以及前述的悬浮剂。组合物还可包括渗透剂,诸如氯化钠、氯化钾、硫酸镁、氯化钙、磷酸氢二钠等,和增湿剂,诸如丙二醇、甘油、山梨糖醇、甘露醇等。
本发明的组合物可用于治疗眼部疾患。优选的眼部疾患包括老花眼、轻度远视、不规则散光(在眼的前端中增加的高度有序的光学像差)、远视调节性内斜视和青光眼(开角;急性、亚急性和慢性窄角;高原型虹膜等)。本发明还可用于增强或加强延迟、逆转或更改晶状体及其周围的组织的衰老过程的介入。本发明的组合物一般施用于经历治疗的受试者的“眼部区域”或“眼部位点”。所述受试者一般为人类,但是可包括其它的哺乳动物诸如犬、猫、马等。术语“眼部区域”和“眼部位点”一般是指眼球的任何区域,包括眼的前段和后段,并且其一般包括但不限于在眼球或部分地或完全地与眼球的内部或外部排成一行的组织或细胞层中发现的任何功能性(如,视力)或结构组织。眼部位点的具体的实例包括晶状体、小带、睫状肌、虹膜和瞳孔。在眼部区域中眼球区域的具体的实例包括前房、后房、玻璃体腔、脉络膜、脉络膜周隙、视网膜下间隙、结膜、结膜下间隙、巩膜外隙、角膜内间隙、角膜外间隙(epicorneal space)、巩膜、睫状环、手术诱导的无血管区域、黄斑部和视网膜。将本发明的组合物用于老花眼患者的双眼可以产生最佳加强的近视力,但是可以略微减少远视力。也可以将本发明的组合物仅用于一只眼睛,通常为非主眼,从而改善该眼的近视力并保留未治疗眼的远视力。在一个实施方案中,将本发明的组合物仅施用于患者的主眼以改善阅读能力。
本发明的组合物可将眼的屈光力增加高达约4屈光度,或在非常年轻的患者(如儿童)中甚至更高。在一个实施方案中,本发明的组合物将眼的屈光力增加高达约0.5屈光度、约0.75屈光度、约1.0屈光度、约1.25屈光度、约1.50屈光度、约1.75屈光度、约2.0屈光度、约2.5屈光度、约3.0屈光度、约3.5屈光度或约4.0屈光度。在一个实施方案中,本发明的组合物将眼的屈光力从约0.5增加至约0.75屈光度、约0.5增加至约1.0屈光度、约0.5增加至约1.25屈光度、约0.5增加至约1.5屈光度、约0.5增加至约1.75屈光度,约0.5屈光度增加至约2.0屈光度、约0.5屈光度增加至约2.5屈光度、约0.5屈光度增加至约3.0屈光度、约0.5屈光度增加至约3.5屈光度或约0.5屈光度增加至约4.0屈光度。在一个实施方案中,进行眼的屈光力的增加而不会实质上影响眼的圆柱体(散光)组分。在一个实施方案中,眼的圆柱体组分的作用小于0.5屈光度。在一个实施方案中,散光的效果小于约2.0屈光度。
在本发明的另一方面,提供了用于治疗眼部疾患的药盒。所述药盒一般包括:a)容器,诸如注射器、管、小瓶、滴管(诸如将用于滴眼剂)或其它敷药器,所述容器包含如本文描述的组合物;和b)使用说明,除正文之外其可以包括图表、附图或照片。所述说明可以包括以下步骤:怎样处理材料(其可以包括储存条件,诸如用于储存的温度范围),怎样将材料插入可见区域(任选地包括图表、附图或照片),施用组合物的频率以及使用所述组合物有什么期待。容器可以含有单剂量的组合物或多剂量的组合物。所述容器可以通过滴加递送组合物。所述容器可以包括显窃启特征诸如箔或塑料密封。
实施例
对于以下实施例,术语“一个/一种/所述”包括复数替代物(至少一个)。所公开的信息为示例性的,并且存在其它实施方案且在本发明的范围内。
实施例1
将一组被认为正视或略微远视(等效球镜从+0.88D至-0.50D,具有小于1.00D的散光)的10名患者(20只眼)用本发明的组合物治疗。在治疗之前将每名患者进行大量的眼部检查,其包括:1)每只眼的屈光力;2)使用斯内伦视力表(Snellen chart)测量的裸眼远视敏度(UDVA);3)在40厘米处使用手持式Rosembaum视力表和Jaeger记法测量的裸眼近视力(UNVA);以及4)在中等照明(中间视力的)条件下用专门的红外线摄影机测量瞳孔直径。
将溶解于0.5%的氯化钠溶液用羧甲基纤维素作为粘度增强剂以及苯扎氯铵作为防腐剂的含有1%的毛果芸香碱和0.125%的羟甲唑啉w/w的三滴药剂以每个间隔5分钟分三次滴入每只眼并在一小时、四小时和六小时后进行相同测量(表1)。如表1和图1-2所示,在滴入之后一小时存在平均3.7单元增加的裸眼近视敏度同时失去0.7行未矫正的远视敏度。如图1所示,在4小时下存在一些效果的衰减而在六小时下效果减少至几乎一半。近视力的改善在较年轻患者中更显著并且不存在远视力的损害(图2)在远视患者中更显著。屈光的改变主要与球体相关而圆柱体几乎保持未变。
表1.(毛果芸香碱+羟甲唑啉)
续表1.(毛果芸香碱+羟甲唑啉)
续表1.(毛果芸香碱+羟甲唑啉)
据信已经发生在近视力中观察到的改善存在至少两个原因。第一,在治疗之后观察到眼的屈光力增加大约+0.70屈光度,所述治疗可校正老花眼和轻度远视。第二,在治疗之后眼的视野的深度从0.50增加至0.75屈光度(可能与瞳孔直径减少至约2.0mm相关)。据信观察到的视野深度的增加具有:
1)增强眼的屈光力中观察到的增加以改善正视者、近视者和远视者的近视力;
2)增强眼的屈光力中观察到的增加以改善轻度远视者中的远视敏度;以及
3)校正正视或近视患者中由在眼的屈光力中观察到的改变引起的任何远视力的丧失。
实施例2
将30至55岁具有“轻度远视”(即,具有+0.50至+2.00D等效球镜的眼)的五名患者(十只眼)用1%毛果芸香碱和0.125%羟甲唑啉的三滴药剂以间隔5分钟治疗。在治疗之后,在一小时和四小时下所有的患者能够改善他们的裸眼远视敏度。在六小时下35%具有一行远视力的改善。
实施例3
将一组被认为正视或略微远视(等效球镜从+0.88D至-0.13D,具有小于1.00D的散光)的10名患者(20只眼)用本发明的组合物治疗。在治疗之前将每名患者进行大量的眼部检查,其包括:1)每只眼的屈光力;2)使用斯内伦视力表测量的裸眼远视敏度(UDVA);3)在40厘米处使用手持式Rosembaum视力表和Jaeger记法测量的裸眼近视力(UNVA);以及4)在中等照明(中间视力的)条件下用专门的红外线摄影机测量瞳孔直径。
将溶解于0.5%的氯化钠溶液用羧甲基纤维素作为粘度增强剂以及苯扎氯铵作为防腐剂的含有1%的毛果芸香碱和0.025%的羟甲唑啉w/w的一滴药剂一次滴入右眼,将含有1%的毛果芸香碱而无羟甲唑啉的相同溶液一次滴入左眼并在一小时、四小时和六小时候进行相同测量。(每名患者充当自己的对照)(表2)。如表2和图3和4所示,可看出当仅使用毛果芸香碱时,在1和4小时时间点下,近视力的改善较小并且倾向于较早耗尽,远视力也下降更多。从屈光观点来看,仅毛果芸香碱似乎诱导更多的散光。该结果可能由于晶状体的改变,然而当毛果芸香碱与羟甲唑啉一起施用时,诱导较少的散光。加入羟甲唑啉改善毛果芸香碱对瞳孔收缩的作用从而增强光学性能。在两组中在获得的屈光以及裸眼远和近敏度之间显示一些偏差,这可以表明其它因素参与视力的改善,例如增加的高度有序的光学测量(像差)诸如球面像差、慧形像差、三叶形像差等。
表2.[毛果芸香碱+羟甲唑啉(OD)对比仅毛果芸香碱(OS)
续表2.[毛果芸香碱+羟甲唑啉(OD)对比仅毛果芸香碱(OS)]
续表2.[毛果芸香碱+羟甲唑啉(OD)对比仅毛果芸香碱(OS)]
实施例4
对具有小于-1.00D散光的+0.50D至-0.25D屈光(等效球镜)的40至56岁的大量患者(n=65)给予滴眼剂,一天使用三次。所述滴眼剂含有1%的毛果芸香碱和0.0125%的羟甲唑啉。在开始治疗之后一周观察患者,然后每月观察患者以补充持续六个月的滴剂药方。仅有四名患者中断滴眼剂的使用由于缺乏效果(一名患者)或诸如偏头痛或眼痛的副作用(三名患者)。剩余的患者继续使用该药物以代替近阅读眼镜改善其近视力。未报道来自这群真实生活的患者的显著的副作用。在若干情况下报道了对患者包括对光照的感觉降低(可能与瞳孔收缩相关)和眼睛漂浮物(针孔效应不仅改善对眼外部的物体的视力而且改善漂浮在眼内部的微小的不规则的视力)的微小的副作用。
在另一组具有高度近视、远视或散光的患者中,将滴眼剂用于其隐形眼镜或远视眼镜上以避免使用双焦点眼镜。
该屈光改善非常类似于实施例1,其中眼的屈光力平均增加约0.50屈光度而不会影响圆柱体(散光)组分。在具有高度近视、远视或散光的患者中,根据基线屈光,近视敏度中通常有2至4行的增益,而远视敏度或改善一行,保持不变或下降一或两行。效果随时间推移持续并且患者注意到当他们定期地使用所述滴剂时,存在累积效应,其中所述滴剂的效应似乎持续更长。另外,这些患者显示由滴剂可能最初引起的任何轻度刺激/发红的减少。三分之二的患者仅仅使用本文提及的滴剂并且其它三分之一(the other third)患者大部分时间使用所述滴剂,但是也偶尔使用近视眼镜(在晚上在家中等)代替所述滴剂。
实施例5
在两周清除期之后,将来自实施例1的五名患者用溶解于0.5%的氯化钠水溶液外加羧甲基纤维素作为粘度增强剂以及苯扎氯铵作为防腐剂的1%的毛果芸香碱和0.015%的美洛昔康的组合治疗,并在一小时、四小时和八小时之后进行在实施例1中的相同测量。
表3.(毛果芸香碱+美洛昔康)
续表3.(毛果芸香碱+美洛昔康)
续表3.(毛果芸香碱+美洛昔康)
如表3和图5所示,当使用毛果芸香碱和美洛昔康的组合时,存在约0.57屈光度的近视化和在一小时下2.6行的裸眼近敏度的改善,这小于在实施例1中呈现的通过药理学组合获得的改善但是仍为良好的临床使用。在1小时下远视敏度的下降为0.6行(图6)。总之,毛果芸香碱/美洛昔康的结果可被解释为后者对毛果芸香碱的副作用具有减轻的作用因为影响参与近视力的任何受体为未知的。这与实施例1中的制剂相反,因为在两个描述的化合物之间似乎存在协同效应。
实施例6
在两周清除期之后,将来自实施例5的患者用溶解于0.5%的氯化钠水溶液外加羧甲基纤维素作为粘度增强剂以及苯扎氯铵作为防腐剂的1%的毛果芸香碱和0.1%的萘甲唑啉组合治疗。治疗患者的两只眼睛并且在一小时、四小时和八小时后进行与实施例5相同的测量。在另一两周清除期之后,将患者用溶解于0.5%的氯化钠水溶液外加羧甲基纤维素作为粘度增强剂以及苯扎氯铵作为防腐剂的1%的毛果芸香碱和0.05%的四氢唑啉组合治疗。治疗患者的两只眼睛并且在一小时、四小时和八小时后进行与实施例5相同的测量。在两个治疗组中,观察到裸眼远视力具有很小的降低的近视力的改善。这些结果类似于实施例5中观察到的结果并且显示通过对毛果芸香碱具有很小加强的治疗效果的萘甲唑啉和四氢唑啉减轻毛果芸香碱的副作用。
尽管已经描述了本发明的某些实施方案,但是可以存在其它实施方案。虽然说明书包括详述,但是本发明的范围通过以下权利要求来表明。此外,尽管本说明书已经以对结构特征和/或方法行为特定的语言进行了描述,但是权利要求书不限于以上描述的特征或行为。而是,以上描述的具体特征和行为公开为本发明的示例性方面和实施方案。在阅读本文描述之后的各种其它方面、实施方案、修改及其等同物可以在不脱离本发明或权利要求的主题的范围的精神的前提下对于本领域普通技术人员表明其本身。
Claims (15)
1.一种用于治疗眼部疾患的组合物,其包含
毒蕈碱乙酰胆碱受体M3激动剂,
和羟甲唑啉;和任选地
具有COX-2选择性的非甾体抗炎剂(NSAID);
其中所述眼部疾患是老花眼、轻度远视、不规则散光或远视调节性内斜视。
2.根据权利要求1所述的组合物,其中所述组合物包含:
0.01%至4%w/w的毒蕈碱乙酰胆碱受体M3激动剂;和
0.01%至0.5%w/w的羟甲唑啉和任选地0.01%至2%的具有COX-2选择性的NSAID。
3.根据权利要求1所述的组合物,其中所述组合物包含:
0.01%至2%w/w的毒蕈碱乙酰胆碱受体M3激动剂;和
0.01%至0.2%w/w的羟甲唑啉和任选地0.01%至1%的具有COX-2选择性的NSAID。
4.根据权利要求1所述的组合物,其中所述组合物包含:
0.5%至1.5%w/w的毒蕈碱乙酰胆碱受体M3激动剂;和
0.02%至0.1%w/w的羟甲唑啉和任选地具有COX-2选择性的NSAID。
5.根据权利要求1至4中任一项所述的组合物,其中所述毒蕈碱乙酰胆碱受体M3激动剂包含乙酰胆碱、氯贝胆碱、卡巴胆碱、氧代震颤素、毛果芸香次碱或毛果芸香碱。
6.根据权利要求1至4中任一项所述的组合物,其中所述毒蕈碱乙酰胆碱受体M3激动剂为毛果芸香碱。
7.根据权利要求1或权利要求2所述的组合物,其中所述毒蕈碱乙酰胆碱受体M3激动剂为卡巴胆碱。
8.根据权利要求1至4中任一项所述的组合物,其中所述具有COX-2选择性的NSAID包含美洛昔康、塞来考昔、罗非昔布、伐地考昔、帕瑞考昔、依托考昔、尼美舒利、依托度酸或萘丁美酮。
9.根据权利要求1至4中任一项所述的组合物,其中所述具有COX-2选择性的NSAID为美洛昔康。
10.根据权利要求1至4中任一项所述的组合物,其中所述组合物进一步包含眼科上可接受的载体。
11.根据权利要求1至4中任一项所述的组合物,其中所述组合物进一步包含环糊精或其衍生物以加强所述组合物的眼部渗透。
12.根据权利要求1至4中任一项所述的组合物,其中所述组合物呈滴眼剂、悬浮液、凝胶、软膏、可注射的溶液或喷雾的形式。
13.根据权利要求1至12中任一项所述的组合物用于制备治疗受试者中老花眼、轻度远视、不规则散光、远视调节性内斜视,或在受试者中增强或加强延迟、逆转或更改晶状体及其周围组织的衰老过程的药剂的用途。
14.根据权利要求13所述的用途,其中所述药剂将所述受试者的眼的屈光力增加了高达4.0屈光度,其中所述受试者任选地为人类。
15.根据权利要求1至12中任一项所述的组合物用于制备治疗受试者眼部疾患的药剂的用途,包括将治疗有效量的所述药剂给予所述受试者,
其中所述眼部疾患是老花眼、轻度远视、不规则散光、远视调节性内斜视,
且其中所述任选地眼部疾患可替代地用具有+0.5D至+1.0D的镜片的眼镜矫正并且其中所述治疗有效量包含0.3%至1.0%的毛果芸香碱,
或任选地其中所述眼部疾患可替代地用具有+1.0D至+1.5D的镜片的眼镜矫正并且其中所述治疗有效量包含0.8%至1.6%的毛果芸香碱,或任选地
其中所述眼部疾患可替代地用具有+1.5D至+2.0D的镜片的眼镜矫正并且其中所述治疗有效量包含1.4%至2.2%的毛果芸香碱。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161536921P | 2011-09-20 | 2011-09-20 | |
US61/536,921 | 2011-09-20 | ||
PCT/IB2012/002335 WO2013041967A2 (en) | 2011-09-20 | 2012-09-19 | Compositions and methods for treating presbyopia, mild hyperopia, and irregular astigmatism |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104093404A CN104093404A (zh) | 2014-10-08 |
CN104093404B true CN104093404B (zh) | 2016-12-07 |
Family
ID=47522725
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201280056271.8A Active CN104093404B (zh) | 2011-09-20 | 2012-09-19 | 用于治疗老花眼、轻度远视和不规则散光的组合物和方法 |
Country Status (23)
Country | Link |
---|---|
US (6) | US9579308B2 (zh) |
EP (3) | EP4272743A2 (zh) |
JP (1) | JP6141850B2 (zh) |
KR (1) | KR102017916B1 (zh) |
CN (1) | CN104093404B (zh) |
AU (2) | AU2012311239B2 (zh) |
BR (1) | BR112014006607A2 (zh) |
CA (2) | CA3049795A1 (zh) |
CL (1) | CL2014000689A1 (zh) |
CO (1) | CO7000769A2 (zh) |
DK (1) | DK2758047T3 (zh) |
ES (1) | ES2715296T3 (zh) |
HK (1) | HK1198426A1 (zh) |
IL (1) | IL231631B (zh) |
IN (1) | IN2014CN02961A (zh) |
MX (1) | MX357635B (zh) |
MY (1) | MY168643A (zh) |
RU (1) | RU2630968C2 (zh) |
SG (1) | SG11201400828RA (zh) |
TR (1) | TR201903465T4 (zh) |
UA (1) | UA113525C2 (zh) |
WO (1) | WO2013041967A2 (zh) |
ZA (1) | ZA201402049B (zh) |
Families Citing this family (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10206813B2 (en) | 2009-05-18 | 2019-02-19 | Dose Medical Corporation | Implants with controlled drug delivery features and methods of using same |
DK2758047T3 (en) | 2011-09-20 | 2019-04-01 | Allergan Inc | COMPOSITIONS AND PROCEDURES FOR TREATING PRESBYOPY, MILD HYPEROPY AND IRREGULAR ASTIGMATISM |
TWI588560B (zh) | 2012-04-05 | 2017-06-21 | 布萊恩荷登視覺協會 | 用於屈光不正之鏡片、裝置、方法及系統 |
US10507245B2 (en) * | 2012-07-19 | 2019-12-17 | Luis Felipe Vejarano Restrepo | Ophthalmic formulation and method for ameliorating presbyopia |
US9201250B2 (en) | 2012-10-17 | 2015-12-01 | Brien Holden Vision Institute | Lenses, devices, methods and systems for refractive error |
CA2887655C (en) | 2012-10-17 | 2021-11-02 | Brien Holden Vision Institute | Lenses, devices, methods and systems for refractive error |
US9320709B2 (en) | 2013-08-28 | 2016-04-26 | Presbyopia Therapies Llc | Storage stable compositions and methods for the treatment of refractive errors of the eye |
US9844537B2 (en) | 2013-08-28 | 2017-12-19 | Presbyopia Therapies Llc | Compositions and methods for the treatment of presbyopia |
US9833441B2 (en) | 2013-08-28 | 2017-12-05 | Presbyopia Therapies Llc | Compositions and methods for the treatment of presbyopia |
US10617763B2 (en) | 2013-08-28 | 2020-04-14 | Presbyopia Therapies, LLC | Compositions and methods for the treatment of presbyopia |
US10307408B2 (en) | 2013-08-28 | 2019-06-04 | Presbyopia Therapies, LLC | Contact lens compositions and methods for the treatment of presbyopia |
US9968594B2 (en) | 2013-08-28 | 2018-05-15 | Presbyopia Therapies Llc | Compositions and methods for the treatment of presbyopia |
US9089562B2 (en) | 2013-08-28 | 2015-07-28 | Presbyopia Therapies Llc | Compositions and methods for the treatment of presbyopia |
US9314427B2 (en) | 2013-08-28 | 2016-04-19 | Presbyopia Therapies Llc | Compositions and methods for the improvement of distance vision and the treatment of refractive errors of the eye |
US11179327B2 (en) | 2013-08-28 | 2021-11-23 | Lenz Therapeutics, Inc. | Compositions and methods for the treatment of presbyopia |
US10064818B2 (en) | 2013-08-28 | 2018-09-04 | Presbyopia Therapies, LLC | Compositions and methods for the treatment of presbyopia |
ES2538551B1 (es) * | 2013-12-20 | 2016-01-13 | Eurocanarias Oftalmológica, Sl | Composición Oftálmica para la corrección de la presbicia |
JP2018510668A (ja) | 2015-01-12 | 2018-04-19 | ケダリオン セラピューティックス,インコーポレイテッド | 微小液滴の繰り出し装置及び方法 |
CN104622800A (zh) * | 2015-02-03 | 2015-05-20 | 吉林修正药业新药开发有限公司 | 苄达赖氨酸滴眼液及制备方法 |
CA2981070A1 (en) | 2015-04-10 | 2016-10-13 | Kedalion Therapeutics, Inc. | Piezoelectric dispenser with replaceable ampoule |
CN116808032A (zh) | 2015-06-18 | 2023-09-29 | 伦茨治疗股份有限公司 | 储存稳定的组合物以及治疗眼睛屈光不正的方法 |
US20190000808A1 (en) * | 2015-07-13 | 2019-01-03 | Allergan, Inc. | Composition and methods for the treatment of blephopharoptosis |
CH711969A2 (it) * | 2015-12-29 | 2017-06-30 | Pinelli Roberto | Composizione per il trattamento della presbiopia. |
WO2018033792A2 (en) | 2016-08-19 | 2018-02-22 | Orasis Pharmaceuticals Ltd. | Ophthalmic pharmaceutical compositions and uses relating thereto |
WO2018136618A2 (en) | 2017-01-20 | 2018-07-26 | Kedalion Therapeutics, Inc. | Piezoelectric fluid dispenser |
EP3720397A4 (en) | 2017-12-08 | 2021-08-11 | Kedalion Therapeutics, Inc. | SYSTEM FOR ALIGNMENT OF FLUID DISPENSING |
US20190314198A1 (en) * | 2018-04-12 | 2019-10-17 | Kedalion Therapeutics, Inc. | Topical Ocular Delivery Methods and Devices for Use in the Same |
LT3681500T (lt) | 2018-04-24 | 2022-06-27 | Allergan, Inc. | Pilokarpino hidrochlorido naudojimas presbiopijos gydymui |
US11679028B2 (en) | 2019-03-06 | 2023-06-20 | Novartis Ag | Multi-dose ocular fluid delivery system |
US20220257593A1 (en) * | 2019-06-10 | 2022-08-18 | Visus Therapeutics, Inc. | Carabachol-bromonidine formulation to enhance anti-presbyopia effects |
EP3980017A4 (en) * | 2019-06-10 | 2023-06-28 | Visus Therapeutics, Inc. | Using parasympathomimetic drugs alone or, in combination with one or more alpha agonists in pseudophakic patients, to create multi-focality |
US11938057B2 (en) | 2020-04-17 | 2024-03-26 | Bausch + Lomb Ireland Limited | Hydrodynamically actuated preservative free dispensing system |
CA3180199A1 (en) | 2020-04-17 | 2021-10-21 | Yehuda Ivri | Hydrodynamically actuated preservative free dispensing system |
WO2022055796A1 (en) * | 2020-09-11 | 2022-03-17 | Intratus-Nevada, Inc. | Compositions and methods for treating presbyopia, hyperopia, astigmatism, decreased stereopsis, and decreased contrast sensitivity |
MX2020012116A (es) * | 2020-11-12 | 2022-08-09 | Cesar Alejandro Sanchez Galeana | Composicion oftalmologica sinergica en dosis de baja concentracion eficaz en la prevencion, control y erradicacion de la presbicia. |
US11648247B1 (en) | 2021-12-16 | 2023-05-16 | Lenz Therapeutics, Inc. | Compositions and methods for the treatment of presbyopia |
CN116350790A (zh) * | 2021-12-28 | 2023-06-30 | 沈阳兴齐眼药股份有限公司 | 组合物及其在制备用于治疗老花眼的药物中的用途 |
US20230277521A1 (en) * | 2022-03-07 | 2023-09-07 | Harrow Ip, Llc | Extended-release pharmaceutical compositions for treating eye conditions |
Family Cites Families (44)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3670087A (en) | 1970-10-16 | 1972-06-13 | Miles Lab | Method of lowering intraocular pressure |
US5122522A (en) | 1989-06-21 | 1992-06-16 | The Trustees Of The University Of Pennsylvania | Treatment and control of ocular development |
US5055467A (en) | 1989-11-13 | 1991-10-08 | Allergan, Inc. | Pharmaceutical epinephrine-pilocarpine compounds |
US5776916A (en) | 1990-07-10 | 1998-07-07 | Gramer; Eugen | Medicament for reducing the intraocular pressure |
US5459133A (en) | 1992-06-05 | 1995-10-17 | Telor Ophthalmic Pharmaceuticals, Inc. | Methods and products for treating presbyopia |
WO1994001096A1 (en) | 1992-07-02 | 1994-01-20 | Telor Ophthalmic Pharmaceuticals, Inc. | Methods and products for treating presbyopia |
SE512871C2 (sv) | 1992-08-20 | 2000-05-29 | Santen Oy | Oftalmologisk beredning innehållande pilokarpin och ytterligare medel för behandling av okular hypertension |
US5422116A (en) | 1994-02-18 | 1995-06-06 | Ciba-Geigy Corporation | Liquid ophthalmic sustained release delivery system |
US6066675A (en) | 1996-09-13 | 2000-05-23 | The Regents Of The University Of California | Method for treatment of retinal diseases |
CN1175904C (zh) | 1998-05-15 | 2004-11-17 | 若素制药株式会社 | 抗炎滴眼剂 |
US6291466B1 (en) | 1998-07-30 | 2001-09-18 | Allergan Sales, Inc. | Cholinergic agents in the treatment of presbyopia |
US6164282A (en) | 1999-01-27 | 2000-12-26 | Allergan Sales, Inc. | Methods for restoring and/or enhancing accommodation in pseudo phakia |
AU7581000A (en) | 1999-09-16 | 2001-04-17 | Gerald D. Horn | A method for optimizing pupil size using alpha antagonist |
US6420407B1 (en) | 1999-09-16 | 2002-07-16 | Gerald Horn | Ophthalmic formulation which modulates dilation |
US6730065B1 (en) | 2000-09-15 | 2004-05-04 | Ocularis Pharma, Inc. | Night vision composition |
AU1548001A (en) | 1999-11-24 | 2001-06-04 | Wakamoto Pharmaceutical Co., Ltd. | Ophthalmic aqueous preparation |
US6730691B1 (en) | 2000-02-10 | 2004-05-04 | Miles A. Galin | Uses of alpha adrenergic blocking agents |
PE20020146A1 (es) | 2000-07-13 | 2002-03-31 | Upjohn Co | Formulacion oftalmica que comprende un inhibidor de ciclooxigenasa-2 (cox-2) |
US6273092B1 (en) | 2000-09-22 | 2001-08-14 | Gerard M. Nolan | Methods for treating various eye disorders |
US6515006B2 (en) | 2000-11-08 | 2003-02-04 | Hmt Pharma, Inc. | Ophthalmic formulation which modulates dilation |
US20050205101A1 (en) | 2002-10-17 | 2005-09-22 | Lin J T | Combined pharmocological and surgical method and system for the treatment of eye disorders |
US20040078009A1 (en) | 2002-10-17 | 2004-04-22 | Lin J. T. | Method and apparatus for the treatment of presbyopia and other eye disorders combining pharmocological and surgical means |
US20060177430A1 (en) | 2002-12-20 | 2006-08-10 | Chakshu Research Inc | Treatment of ocular disorders with ophthalmic formulations containing methylsulfonylmethane as a transport enhancer |
US20050119262A1 (en) * | 2003-08-21 | 2005-06-02 | Pharmacia Corporation | Method for preventing or treating an optic neuropathy with a cox-2 inhibitor and an intraocular pressure reducing agent |
MXPA03011987A (es) | 2003-12-19 | 2005-06-23 | Osio Sancho Alberto | Metodo para el tratamiento de la presbicia induciendo cambios en el poder y fisiologia corneal. |
DK1938839T3 (da) | 2006-12-18 | 2009-11-30 | Jorge Luis Benozzi | Oftalmiske sammensætninger af parasympatiske stimulanter og anti-inflammatoriske midler til anvendelse i behandlingen af presbyopi |
GB0724558D0 (en) * | 2007-12-15 | 2008-01-30 | Sharma Anant | Optical correction |
TNSN08110A1 (en) | 2008-03-11 | 2009-07-14 | Rekik Raouf Dr | Drug delivery to the anterior and posterior segment of the eye from drops |
CN102119120B (zh) * | 2008-08-08 | 2013-08-07 | 株式会社东芝 | 纳米碳生成装置 |
WO2010046865A2 (en) * | 2008-10-21 | 2010-04-29 | Pharmalight Inc. | Ophthalmic administration of a composition including brimonidine as a mist |
US20110091459A1 (en) | 2008-12-11 | 2011-04-21 | Auspex Pharmaceuticals, Inc. | Imidazole modulators of muscarinic acetylcholine receptor m3 |
WO2010125416A1 (en) | 2009-04-27 | 2010-11-04 | Raouf Rekik | Drug delivery to the anterior and posterior segments of the eye |
US20100298335A1 (en) | 2009-05-22 | 2010-11-25 | Kaufman Herbert E | Preparations and Methods for Ameliorating or Reducing Presbyopia |
US8299079B2 (en) | 2009-05-22 | 2012-10-30 | Kaufman Herbert E | Preparations and methods for ameliorating or reducing presbyopia |
JP2012015266A (ja) | 2010-06-30 | 2012-01-19 | Sony Corp | 半導体光増幅器 |
AR081049A1 (es) | 2010-08-17 | 2012-06-06 | Gonzalez Santos Alejandro Raul | Medicamento oftalmico para el tratamiento de la hipermetropia |
TN2010000566A1 (en) | 2010-12-03 | 2012-05-24 | Rekik Raouf | Folic acid - ramipril combination : cell protective neuroprotective and retinoprotective ophtalmologic drugs |
US20120208858A1 (en) | 2011-02-15 | 2012-08-16 | Allergan, Inc. | Pharmaceutical Cream Compositions of Oxymetazoline and Methods of Use |
US20120225918A1 (en) | 2011-03-03 | 2012-09-06 | Voom, Llc | Compositions and Methods for Non-Surgical Treatment of Ptosis |
DK2758047T3 (en) | 2011-09-20 | 2019-04-01 | Allergan Inc | COMPOSITIONS AND PROCEDURES FOR TREATING PRESBYOPY, MILD HYPEROPY AND IRREGULAR ASTIGMATISM |
WO2013061161A2 (en) | 2011-10-28 | 2013-05-02 | Green Bcn Consulting Services Sl | New combination therapies for treating neurological disorders |
US10507245B2 (en) | 2012-07-19 | 2019-12-17 | Luis Felipe Vejarano Restrepo | Ophthalmic formulation and method for ameliorating presbyopia |
US9089562B2 (en) | 2013-08-28 | 2015-07-28 | Presbyopia Therapies Llc | Compositions and methods for the treatment of presbyopia |
ES2538551B1 (es) | 2013-12-20 | 2016-01-13 | Eurocanarias Oftalmológica, Sl | Composición Oftálmica para la corrección de la presbicia |
-
2012
- 2012-09-19 DK DK12813089.5T patent/DK2758047T3/en active
- 2012-09-19 SG SG11201400828RA patent/SG11201400828RA/en unknown
- 2012-09-19 CA CA3049795A patent/CA3049795A1/en not_active Abandoned
- 2012-09-19 JP JP2014531333A patent/JP6141850B2/ja active Active
- 2012-09-19 MY MYPI2014000825A patent/MY168643A/en unknown
- 2012-09-19 RU RU2014115439A patent/RU2630968C2/ru active
- 2012-09-19 BR BR112014006607A patent/BR112014006607A2/pt not_active Application Discontinuation
- 2012-09-19 EP EP23177574.3A patent/EP4272743A2/en active Pending
- 2012-09-19 EP EP12813089.5A patent/EP2758047B1/en active Active
- 2012-09-19 ES ES12813089T patent/ES2715296T3/es active Active
- 2012-09-19 KR KR1020147010384A patent/KR102017916B1/ko active IP Right Grant
- 2012-09-19 WO PCT/IB2012/002335 patent/WO2013041967A2/en active Application Filing
- 2012-09-19 US US14/129,012 patent/US9579308B2/en active Active
- 2012-09-19 EP EP18211269.8A patent/EP3517111A3/en not_active Withdrawn
- 2012-09-19 CN CN201280056271.8A patent/CN104093404B/zh active Active
- 2012-09-19 AU AU2012311239A patent/AU2012311239B2/en active Active
- 2012-09-19 MX MX2014003421A patent/MX357635B/es active IP Right Grant
- 2012-09-19 CA CA2849366A patent/CA2849366C/en active Active
- 2012-09-19 TR TR2019/03465T patent/TR201903465T4/tr unknown
- 2012-09-19 UA UAA201404109A patent/UA113525C2/uk unknown
-
2013
- 2013-12-24 US US14/140,103 patent/US9301933B2/en active Active
-
2014
- 2014-03-20 ZA ZA2014/02049A patent/ZA201402049B/en unknown
- 2014-03-20 IL IL231631A patent/IL231631B/en active IP Right Grant
- 2014-03-20 CL CL2014000689A patent/CL2014000689A1/es unknown
- 2014-04-16 CO CO14083073A patent/CO7000769A2/es not_active Application Discontinuation
- 2014-04-18 IN IN2961CHN2014 patent/IN2014CN02961A/en unknown
- 2014-11-26 HK HK14111938.6A patent/HK1198426A1/zh unknown
-
2016
- 2016-02-23 US US15/050,921 patent/US20160310466A1/en not_active Abandoned
-
2017
- 2017-10-05 AU AU2017239563A patent/AU2017239563B2/en active Active
- 2017-12-14 US US15/842,697 patent/US20180333392A1/en not_active Abandoned
-
2019
- 2019-04-04 US US16/375,499 patent/US20200069651A1/en not_active Abandoned
-
2021
- 2021-03-17 US US17/204,743 patent/US20220040152A1/en active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN104093404B (zh) | 用于治疗老花眼、轻度远视和不规则散光的组合物和方法 | |
CN1753683B (zh) | 预防和治疗不良眼部病症的眼用制剂 | |
US20220273605A1 (en) | Compositions and methods for treatment of presbyopia | |
AU2011334617A2 (en) | Folic acid - Ramipril combination: cellprotective, neuroprotective and retinoprotective ophtalmologic compositions | |
Nair et al. | Current trends in ocular drug delivery systems and its applications | |
TWI805705B (zh) | 選擇性syk抑制劑之使用方法及醫藥組合物 | |
NZ623037B2 (en) | Compositions and methods for treating presbyopia, mild hyperopia, and irregular astigmatism | |
Reshma Hegden et al. | Reshma et al. World Journal of Pharmaceutical Research | |
Dada et al. | Ocular Hypotensives and Neuroprotectants in Glaucoma | |
US20060058345A1 (en) | Use of papaverine-like vasodilator and pharmaceutical composition | |
CN101460152A (zh) | 治疗以及预防眼皮肿胀的组合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant |