CN1512882A - 包含cox-2抑制剂的可稀释配制的胃肠外组合物 - Google Patents
包含cox-2抑制剂的可稀释配制的胃肠外组合物 Download PDFInfo
- Publication number
- CN1512882A CN1512882A CNA028107659A CN02810765A CN1512882A CN 1512882 A CN1512882 A CN 1512882A CN A028107659 A CNA028107659 A CN A028107659A CN 02810765 A CN02810765 A CN 02810765A CN 1512882 A CN1512882 A CN 1512882A
- Authority
- CN
- China
- Prior art keywords
- compositions
- parecoxib
- medicine
- parenteral
- salt
- 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.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 163
- 229940111134 coxibs Drugs 0.000 title description 2
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 title description 2
- 239000003814 drug Substances 0.000 claims abstract description 115
- 238000002360 preparation method Methods 0.000 claims abstract description 81
- 150000003839 salts Chemical class 0.000 claims abstract description 39
- ICJGKYTXBRDUMV-UHFFFAOYSA-N trichloro(6-trichlorosilylhexyl)silane Chemical compound Cl[Si](Cl)(Cl)CCCCCC[Si](Cl)(Cl)Cl ICJGKYTXBRDUMV-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229960003925 parecoxib sodium Drugs 0.000 claims abstract description 30
- 239000000651 prodrug Substances 0.000 claims abstract description 27
- 229940002612 prodrug Drugs 0.000 claims abstract description 27
- 239000002904 solvent Substances 0.000 claims abstract description 19
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 claims abstract description 18
- 239000007788 liquid Substances 0.000 claims abstract description 18
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 18
- 239000000843 powder Substances 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 4
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 claims abstract 3
- 229960004662 parecoxib Drugs 0.000 claims description 96
- 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 96
- 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 59
- 229960002004 valdecoxib Drugs 0.000 claims description 58
- 239000000243 solution Substances 0.000 claims description 51
- 238000000034 method Methods 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 42
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 31
- 201000010099 disease Diseases 0.000 claims description 28
- 238000004108 freeze drying Methods 0.000 claims description 27
- 239000003795 chemical substances by application Substances 0.000 claims description 26
- 238000010790 dilution Methods 0.000 claims description 22
- 239000012895 dilution Substances 0.000 claims description 22
- 238000002347 injection Methods 0.000 claims description 22
- 239000007924 injection Substances 0.000 claims description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 16
- 238000001990 intravenous administration Methods 0.000 claims description 12
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical group [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 11
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 10
- 235000019800 disodium phosphate Nutrition 0.000 claims description 10
- 238000007710 freezing Methods 0.000 claims description 9
- 230000008014 freezing Effects 0.000 claims description 9
- 239000011780 sodium chloride Substances 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 238000007865 diluting Methods 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 6
- 229960000281 trometamol Drugs 0.000 claims description 6
- 239000008215 water for injection Substances 0.000 claims description 6
- 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 claims description 5
- 239000008103 glucose Substances 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 230000003139 buffering effect Effects 0.000 claims description 4
- 229960000590 celecoxib Drugs 0.000 claims description 4
- 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 4
- 239000002131 composite material Substances 0.000 claims description 4
- 229960004945 etoricoxib Drugs 0.000 claims description 4
- 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 4
- 238000010253 intravenous injection Methods 0.000 claims description 4
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 3
- 239000003125 aqueous solvent Substances 0.000 claims description 3
- 230000001965 increasing effect Effects 0.000 claims description 3
- 238000001802 infusion Methods 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- 229960000371 rofecoxib Drugs 0.000 claims description 3
- 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 3
- 239000001488 sodium phosphate Substances 0.000 claims description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 3
- 235000011008 sodium phosphates Nutrition 0.000 claims description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical group [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 2
- 229960003314 deracoxib Drugs 0.000 claims description 2
- WAZQAZKAZLXFMK-UHFFFAOYSA-N deracoxib Chemical compound C1=C(F)C(OC)=CC=C1C1=CC(C(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 WAZQAZKAZLXFMK-UHFFFAOYSA-N 0.000 claims description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 238000007918 intramuscular administration Methods 0.000 claims description 2
- 239000001508 potassium citrate Substances 0.000 claims description 2
- 229960002635 potassium citrate Drugs 0.000 claims description 2
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 claims description 2
- 235000011082 potassium citrates Nutrition 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 2
- 235000011083 sodium citrates Nutrition 0.000 claims description 2
- 238000007920 subcutaneous administration Methods 0.000 claims description 2
- 210000001258 synovial membrane Anatomy 0.000 claims description 2
- 239000007925 intracardiac injection Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 15
- 239000006172 buffering agent Substances 0.000 abstract 1
- 239000004615 ingredient Substances 0.000 abstract 1
- 229940102223 injectable solution Drugs 0.000 abstract 1
- 238000012792 lyophilization process Methods 0.000 abstract 1
- 229940124597 therapeutic agent Drugs 0.000 abstract 1
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 15
- 208000002193 Pain Diseases 0.000 description 15
- 239000000126 substance Substances 0.000 description 14
- 206010061218 Inflammation Diseases 0.000 description 13
- 239000000428 dust Substances 0.000 description 13
- 230000004054 inflammatory process Effects 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 229910052736 halogen Inorganic materials 0.000 description 12
- 230000001225 therapeutic effect Effects 0.000 description 11
- -1 undersaturated heterocyclic radical Chemical class 0.000 description 11
- 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 9
- 229930195725 Mannitol Natural products 0.000 description 9
- 230000000202 analgesic effect Effects 0.000 description 9
- 230000006378 damage Effects 0.000 description 9
- 150000002367 halogens Chemical class 0.000 description 9
- 239000000594 mannitol Substances 0.000 description 9
- 235000010355 mannitol Nutrition 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 8
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 206010029113 Neovascularisation Diseases 0.000 description 7
- 238000013459 approach Methods 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 229940068196 placebo Drugs 0.000 description 6
- 239000000902 placebo Substances 0.000 description 6
- 230000036470 plasma concentration Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000004606 Fillers/Extenders Substances 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 230000004087 circulation Effects 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 208000008035 Back Pain Diseases 0.000 description 4
- 206010012289 Dementia Diseases 0.000 description 4
- 208000010412 Glaucoma Diseases 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 4
- 125000002521 alkyl halide group Chemical group 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 4
- 206010003246 arthritis Diseases 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 4
- 201000008482 osteoarthritis Diseases 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 150000003180 prostaglandins Chemical class 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 206010008190 Cerebrovascular accident Diseases 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 3
- 201000006107 Familial adenomatous polyposis Diseases 0.000 description 3
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 3
- 208000032843 Hemorrhage Diseases 0.000 description 3
- 208000008930 Low Back Pain Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 3
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 3
- 208000006011 Stroke Diseases 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000008859 change 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
- 208000029664 classic familial adenomatous polyposis Diseases 0.000 description 3
- 230000008602 contraction Effects 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 230000007850 degeneration Effects 0.000 description 3
- 230000009477 glass transition Effects 0.000 description 3
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000009826 neoplastic cell growth Effects 0.000 description 3
- 238000012856 packing Methods 0.000 description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- WVTKBKWTSCPRNU-KYJUHHDHSA-N (+)-Tetrandrine Chemical compound C([C@H]1C=2C=C(C(=CC=2CCN1C)OC)O1)C(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2C[C@@H]2N(C)CCC3=CC(OC)=C(OC)C1=C23 WVTKBKWTSCPRNU-KYJUHHDHSA-N 0.000 description 2
- LVYLCBNXHHHPSB-UHFFFAOYSA-N 2-hydroxyethyl salicylate Chemical compound OCCOC(=O)C1=CC=CC=C1O LVYLCBNXHHHPSB-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 206010004146 Basal cell carcinoma Diseases 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 208000006386 Bone Resorption Diseases 0.000 description 2
- 206010065687 Bone loss Diseases 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 206010006811 Bursitis Diseases 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 208000002177 Cataract Diseases 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 208000002691 Choroiditis Diseases 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 206010010741 Conjunctivitis Diseases 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 206010012689 Diabetic retinopathy Diseases 0.000 description 2
- 208000005171 Dysmenorrhea Diseases 0.000 description 2
- 206010013935 Dysmenorrhoea Diseases 0.000 description 2
- 208000007882 Gastritis Diseases 0.000 description 2
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 2
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 2
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- FWKQNCXZGNBPFD-UHFFFAOYSA-N Guaiazulene Chemical compound CC(C)C1=CC=C(C)C2=CC=C(C)C2=C1 FWKQNCXZGNBPFD-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 206010025421 Macule Diseases 0.000 description 2
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 2
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 2
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 2
- DEXMFYZAHXMZNM-UHFFFAOYSA-N Narceine Chemical compound OC(=O)C1=C(OC)C(OC)=CC=C1C(=O)CC1=C(CCN(C)C)C=C(OCO2)C2=C1OC DEXMFYZAHXMZNM-UHFFFAOYSA-N 0.000 description 2
- 206010028836 Neck pain Diseases 0.000 description 2
- MITFXPHMIHQXPI-UHFFFAOYSA-N Oraflex Chemical compound N=1C2=CC(C(C(O)=O)C)=CC=C2OC=1C1=CC=C(Cl)C=C1 MITFXPHMIHQXPI-UHFFFAOYSA-N 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- 208000003971 Posterior uveitis Diseases 0.000 description 2
- 208000004550 Postoperative Pain Diseases 0.000 description 2
- 208000006399 Premature Obstetric Labor Diseases 0.000 description 2
- 206010036600 Premature labour Diseases 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- 206010038933 Retinopathy of prematurity Diseases 0.000 description 2
- 235000016639 Syzygium aromaticum Nutrition 0.000 description 2
- 244000223014 Syzygium aromaticum Species 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 201000004810 Vascular dementia Diseases 0.000 description 2
- 208000036142 Viral infection Diseases 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 230000009692 acute damage Effects 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 2
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 description 2
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- NWGGKKGAFZIVBJ-UHFFFAOYSA-N antrafenine Chemical compound FC(F)(F)C1=CC=CC(N2CCN(CCOC(=O)C=3C(=CC=CC=3)NC=3C4=CC=C(C=C4N=CC=3)C(F)(F)F)CC2)=C1 NWGGKKGAFZIVBJ-UHFFFAOYSA-N 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 description 2
- 125000001769 aryl amino group Chemical group 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- CNBGNNVCVSKAQZ-UHFFFAOYSA-N benzydamine Chemical compound C12=CC=CC=C2C(OCCCN(C)C)=NN1CC1=CC=CC=C1 CNBGNNVCVSKAQZ-UHFFFAOYSA-N 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
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 230000024279 bone resorption Effects 0.000 description 2
- 201000008275 breast carcinoma Diseases 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- NCEXYHBECQHGNR-UHFFFAOYSA-N chembl421 Chemical compound C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 2
- 229960004126 codeine Drugs 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- RRAFCDWBNXTKKO-UHFFFAOYSA-N eugenol Chemical compound COC1=CC(CC=C)=CC=C1O RRAFCDWBNXTKKO-UHFFFAOYSA-N 0.000 description 2
- 208000030533 eye disease Diseases 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 201000011066 hemangioma Diseases 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 206010023332 keratitis Diseases 0.000 description 2
- 229960004752 ketorolac Drugs 0.000 description 2
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 229960005181 morphine Drugs 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 2
- 229960002009 naproxen Drugs 0.000 description 2
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 2
- 230000003533 narcotic effect Effects 0.000 description 2
- 201000003142 neovascular glaucoma Diseases 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229960000482 pethidine Drugs 0.000 description 2
- CPJSUEIXXCENMM-UHFFFAOYSA-N phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 2
- 230000002980 postoperative effect Effects 0.000 description 2
- 208000026440 premature labor Diseases 0.000 description 2
- 201000001514 prostate carcinoma Diseases 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 210000001525 retina Anatomy 0.000 description 2
- 201000003068 rheumatic fever Diseases 0.000 description 2
- WVYADZUPLLSGPU-UHFFFAOYSA-N salsalate Chemical compound OC(=O)C1=CC=CC=C1OC(=O)C1=CC=CC=C1O WVYADZUPLLSGPU-UHFFFAOYSA-N 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 201000008261 skin carcinoma Diseases 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 208000004371 toothache Diseases 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- RJMIEHBSYVWVIN-LLVKDONJSA-N (2r)-2-[4-(3-oxo-1h-isoindol-2-yl)phenyl]propanoic acid Chemical compound C1=CC([C@H](C(O)=O)C)=CC=C1N1C(=O)C2=CC=CC=C2C1 RJMIEHBSYVWVIN-LLVKDONJSA-N 0.000 description 1
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 description 1
- GUHPRPJDBZHYCJ-SECBINFHSA-N (2s)-2-(5-benzoylthiophen-2-yl)propanoic acid Chemical compound S1C([C@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CC=C1 GUHPRPJDBZHYCJ-SECBINFHSA-N 0.000 description 1
- MDKGKXOCJGEUJW-VIFPVBQESA-N (2s)-2-[4-(thiophene-2-carbonyl)phenyl]propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-VIFPVBQESA-N 0.000 description 1
- DKSZLDSPXIWGFO-BLOJGBSASA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O.OP(O)(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC DKSZLDSPXIWGFO-BLOJGBSASA-N 0.000 description 1
- BCXHDORHMMZBBZ-DORFAMGDSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;sulfuric acid Chemical compound OS(O)(=O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC BCXHDORHMMZBBZ-DORFAMGDSA-N 0.000 description 1
- ZZMSHBOVYPIYOB-UHFFFAOYSA-N 1,4-diphenylpyrazolidine-3,5-dione Chemical compound O=C1NN(C=2C=CC=CC=2)C(=O)C1C1=CC=CC=C1 ZZMSHBOVYPIYOB-UHFFFAOYSA-N 0.000 description 1
- XOZLRRYPUKAKMU-UHFFFAOYSA-N 1,5-dimethyl-2-phenyl-4-(propan-2-ylamino)-3-pyrazolone Chemical compound O=C1C(NC(C)C)=C(C)N(C)N1C1=CC=CC=C1 XOZLRRYPUKAKMU-UHFFFAOYSA-N 0.000 description 1
- XLVXAUNDHWERBM-IVGWJTKZSA-N 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]-n-[(2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-1-oxohexan-2-yl]acetamide Chemical compound CC1=C(CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 XLVXAUNDHWERBM-IVGWJTKZSA-N 0.000 description 1
- APBSKHYXXKHJFK-UHFFFAOYSA-N 2-[2-(4-chlorophenyl)-1,3-thiazol-4-yl]acetic acid Chemical compound OC(=O)CC1=CSC(C=2C=CC(Cl)=CC=2)=N1 APBSKHYXXKHJFK-UHFFFAOYSA-N 0.000 description 1
- BOFYHBVFGWJLIZ-UHFFFAOYSA-N 2-[2-(diethylamino)ethoxy]-n-phenylbenzamide Chemical compound CCN(CC)CCOC1=CC=CC=C1C(=O)NC1=CC=CC=C1 BOFYHBVFGWJLIZ-UHFFFAOYSA-N 0.000 description 1
- ANMLJLFWUCQGKZ-UHFFFAOYSA-N 2-[3-(trifluoromethyl)anilino]-3-pyridinecarboxylic acid (3-oxo-1H-isobenzofuran-1-yl) ester Chemical compound FC(F)(F)C1=CC=CC(NC=2C(=CC=CN=2)C(=O)OC2C3=CC=CC=C3C(=O)O2)=C1 ANMLJLFWUCQGKZ-UHFFFAOYSA-N 0.000 description 1
- XILVEPYQJIOVNB-UHFFFAOYSA-N 2-[3-(trifluoromethyl)anilino]benzoic acid 2-(2-hydroxyethoxy)ethyl ester Chemical compound OCCOCCOC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 XILVEPYQJIOVNB-UHFFFAOYSA-N 0.000 description 1
- YAMFWQIVVMITPG-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)pyrazol-3-yl]acetic acid Chemical compound OC(=O)CC1=NN(C=2C=CC(F)=CC=2)C=C1C1=CC=C(Cl)C=C1 YAMFWQIVVMITPG-UHFFFAOYSA-N 0.000 description 1
- JIEKMACRVQTPRC-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)-2-phenyl-5-thiazolyl]acetic acid Chemical compound OC(=O)CC=1SC(C=2C=CC=CC=2)=NC=1C1=CC=C(Cl)C=C1 JIEKMACRVQTPRC-UHFFFAOYSA-N 0.000 description 1
- IQPPOXSMSDPZKU-JQIJEIRASA-N 2-[4-[(3e)-3-hydroxyiminocyclohexyl]phenyl]propanoic acid Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C1CC(=N/O)/CCC1 IQPPOXSMSDPZKU-JQIJEIRASA-N 0.000 description 1
- JJBCTCGUOQYZHK-UHFFFAOYSA-N 2-acetyloxybenzoate;(5-amino-1-carboxypentyl)azanium Chemical compound OC(=O)C(N)CCCC[NH3+].CC(=O)OC1=CC=CC=C1C([O-])=O JJBCTCGUOQYZHK-UHFFFAOYSA-N 0.000 description 1
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 description 1
- BURBNIPKSRJAIQ-UHFFFAOYSA-N 2-azaniumyl-3-[3-(trifluoromethyl)phenyl]propanoate Chemical compound OC(=O)C(N)CC1=CC=CC(C(F)(F)F)=C1 BURBNIPKSRJAIQ-UHFFFAOYSA-N 0.000 description 1
- XCHHJFVNQPPLJK-UHFFFAOYSA-N 2-carboxyphenolate;1h-imidazol-1-ium Chemical compound C1=CNC=N1.OC(=O)C1=CC=CC=C1O XCHHJFVNQPPLJK-UHFFFAOYSA-N 0.000 description 1
- UJABSZITRMATFL-UHFFFAOYSA-N 2-methyl-5-phenylfuran-3-carbonyl chloride Chemical compound ClC(=O)C1=C(C)OC(C=2C=CC=CC=2)=C1 UJABSZITRMATFL-UHFFFAOYSA-N 0.000 description 1
- YTRMTPPVNRALON-UHFFFAOYSA-N 2-phenyl-4-quinolinecarboxylic acid Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=CC=C1 YTRMTPPVNRALON-UHFFFAOYSA-N 0.000 description 1
- FFKUDWZICMJVPA-UHFFFAOYSA-N 2-phosphonooxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1OP(O)(O)=O FFKUDWZICMJVPA-UHFFFAOYSA-N 0.000 description 1
- IYNWSQDZXMGGGI-NUEKZKHPSA-N 3-hydroxymorphinan Chemical compound C1CCC[C@H]2[C@H]3CC4=CC=C(O)C=C4[C@]21CCN3 IYNWSQDZXMGGGI-NUEKZKHPSA-N 0.000 description 1
- HNPVERUJGFNNRV-UHFFFAOYSA-N 3-iodophthalic acid Chemical compound OC(=O)C1=CC=CC(I)=C1C(O)=O HNPVERUJGFNNRV-UHFFFAOYSA-N 0.000 description 1
- WOVTUUKKGNHVFZ-UHFFFAOYSA-N 4-(fluoren-9-ylidenemethyl)benzenecarboximidamide Chemical compound C1=CC(C(=N)N)=CC=C1C=C1C2=CC=CC=C2C2=CC=CC=C21 WOVTUUKKGNHVFZ-UHFFFAOYSA-N 0.000 description 1
- KNKRHSVKIORZQB-UHFFFAOYSA-N 4-bromo-2-(hydroxymethyl)phenol Chemical compound OCC1=CC(Br)=CC=C1O KNKRHSVKIORZQB-UHFFFAOYSA-N 0.000 description 1
- IMKNHLPRDSWAHW-UHFFFAOYSA-N 4-butyl-1,2-diphenylpyrazolidine-3,5-dione;4,5-dihydro-1,3-thiazol-2-amine Chemical compound NC1=NCCS1.O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 IMKNHLPRDSWAHW-UHFFFAOYSA-N 0.000 description 1
- LBFGQUCAQWAFNN-UHFFFAOYSA-N 4-ethyl-2-(1-methylpiperidin-4-yl)-5-phenyl-1h-pyrazol-3-one Chemical compound O=C1C(CC)=C(C=2C=CC=CC=2)NN1C1CCN(C)CC1 LBFGQUCAQWAFNN-UHFFFAOYSA-N 0.000 description 1
- ORLGLBZRQYOWNA-UHFFFAOYSA-N 4-methylpyridin-2-amine Chemical compound CC1=CC=NC(N)=C1 ORLGLBZRQYOWNA-UHFFFAOYSA-N 0.000 description 1
- DVEQCIBLXRSYPH-UHFFFAOYSA-N 5-butyl-1-cyclohexylbarbituric acid Chemical compound O=C1C(CCCC)C(=O)NC(=O)N1C1CCCCC1 DVEQCIBLXRSYPH-UHFFFAOYSA-N 0.000 description 1
- XKVUYEYANWFIJX-UHFFFAOYSA-N 5-methyl-1h-pyrazole Chemical compound CC1=CC=NN1 XKVUYEYANWFIJX-UHFFFAOYSA-N 0.000 description 1
- PCYLDXMXEPSXFW-UHFFFAOYSA-N 6-amino-2-(2-chloroethyl)-2,3-dihydro-1,3-benzoxazin-4-one Chemical compound O1C(CCCl)NC(=O)C2=CC(N)=CC=C21 PCYLDXMXEPSXFW-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 208000004804 Adenomatous Polyps Diseases 0.000 description 1
- RLFWWDJHLFCNIJ-UHFFFAOYSA-N Aminoantipyrine Natural products CN1C(C)=C(N)C(=O)N1C1=CC=CC=C1 RLFWWDJHLFCNIJ-UHFFFAOYSA-N 0.000 description 1
- RMMXTBMQSGEXHJ-UHFFFAOYSA-N Aminophenazone Chemical compound O=C1C(N(C)C)=C(C)N(C)N1C1=CC=CC=C1 RMMXTBMQSGEXHJ-UHFFFAOYSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- 206010059245 Angiopathy Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000032467 Aplastic anaemia Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 208000036487 Arthropathies Diseases 0.000 description 1
- 208000030016 Avascular necrosis Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000027496 Behcet disease Diseases 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- MNIPYSSQXLZQLJ-UHFFFAOYSA-N Biofenac Chemical compound OC(=O)COC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl MNIPYSSQXLZQLJ-UHFFFAOYSA-N 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- LIAWQASKBFCRNR-UHFFFAOYSA-N Bucetin Chemical compound CCOC1=CC=C(NC(=O)CC(C)O)C=C1 LIAWQASKBFCRNR-UHFFFAOYSA-N 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- NPBVQXIMTZKSBA-UHFFFAOYSA-N Chavibetol Natural products COC1=CC=C(CC=C)C=C1O NPBVQXIMTZKSBA-UHFFFAOYSA-N 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- UDKCHVLMFQVBAA-UHFFFAOYSA-M Choline salicylate Chemical compound C[N+](C)(C)CCO.OC1=CC=CC=C1C([O-])=O UDKCHVLMFQVBAA-UHFFFAOYSA-M 0.000 description 1
- OIRAEJWYWSAQNG-UHFFFAOYSA-N Clidanac Chemical compound ClC=1C=C2C(C(=O)O)CCC2=CC=1C1CCCCC1 OIRAEJWYWSAQNG-UHFFFAOYSA-N 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010010071 Coma Diseases 0.000 description 1
- 208000033131 Congenital factor II deficiency Diseases 0.000 description 1
- 206010011017 Corneal graft rejection Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 206010011715 Cyclitis Diseases 0.000 description 1
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical compound O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 206010011831 Cytomegalovirus infection Diseases 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical group CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 1
- IJVCSMSMFSCRME-KBQPJGBKSA-N Dihydromorphine Chemical compound O([C@H]1[C@H](CC[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O IJVCSMSMFSCRME-KBQPJGBKSA-N 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- URJQOOISAKEBKW-UHFFFAOYSA-N Emorfazone Chemical compound C1=NN(C)C(=O)C(OCC)=C1N1CCOCC1 URJQOOISAKEBKW-UHFFFAOYSA-N 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- RHAXSHUQNIEUEY-UHFFFAOYSA-N Epirizole Chemical compound COC1=CC(C)=NN1C1=NC(C)=CC(OC)=N1 RHAXSHUQNIEUEY-UHFFFAOYSA-N 0.000 description 1
- 206010015084 Episcleritis Diseases 0.000 description 1
- OGDVEMNWJVYAJL-LEPYJNQMSA-N Ethyl morphine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OCC OGDVEMNWJVYAJL-LEPYJNQMSA-N 0.000 description 1
- 239000005770 Eugenol Substances 0.000 description 1
- 206010015943 Eye inflammation Diseases 0.000 description 1
- 206010015958 Eye pain Diseases 0.000 description 1
- RBBWCVQDXDFISW-UHFFFAOYSA-N Feprazone Chemical compound O=C1C(CC=C(C)C)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 RBBWCVQDXDFISW-UHFFFAOYSA-N 0.000 description 1
- APQPGQGAWABJLN-UHFFFAOYSA-N Floctafenine Chemical compound OCC(O)COC(=O)C1=CC=CC=C1NC1=CC=NC2=C(C(F)(F)F)C=CC=C12 APQPGQGAWABJLN-UHFFFAOYSA-N 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 206010061459 Gastrointestinal ulcer Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000031220 Hemophilia Diseases 0.000 description 1
- 208000009292 Hemophilia A Diseases 0.000 description 1
- LHFKHAVGGJJQFF-UEOYEZOQSA-N Hydroxy-alpha-sanshool Chemical compound C\C=C\C=C\C=C/CC\C=C\C(=O)NCC(C)(C)O LHFKHAVGGJJQFF-UEOYEZOQSA-N 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000007646 Hypoprothrombinemias Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 206010022941 Iridocyclitis Diseases 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- ALFGKMXHOUSVAD-UHFFFAOYSA-N Ketobemidone Chemical compound C=1C=CC(O)=CC=1C1(C(=O)CC)CCN(C)CC1 ALFGKMXHOUSVAD-UHFFFAOYSA-N 0.000 description 1
- 208000034800 Leukoencephalopathies Diseases 0.000 description 1
- JAQUASYNZVUNQP-USXIJHARSA-N Levorphanol Chemical compound C1C2=CC=C(O)C=C2[C@]23CCN(C)[C@H]1[C@@H]2CCCC3 JAQUASYNZVUNQP-USXIJHARSA-N 0.000 description 1
- 206010024453 Ligament sprain Diseases 0.000 description 1
- 206010062038 Lip neoplasm Diseases 0.000 description 1
- 208000001344 Macular Edema Diseases 0.000 description 1
- 206010025415 Macular oedema Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- DJEIHHYCDCTAAH-UHFFFAOYSA-N Mofezolac (TN) Chemical compound C1=CC(OC)=CC=C1C1=NOC(CC(O)=O)=C1C1=CC=C(OC)C=C1 DJEIHHYCDCTAAH-UHFFFAOYSA-N 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 208000005314 Multi-Infarct Dementia Diseases 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- IDBPHNDTYPBSNI-UHFFFAOYSA-N N-(1-(2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl)-4-(methoxymethyl)-4-piperidyl)propionanilide Chemical compound C1CN(CCN2C(N(CC)N=N2)=O)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 IDBPHNDTYPBSNI-UHFFFAOYSA-N 0.000 description 1
- JUUFBMODXQKSTD-UHFFFAOYSA-N N-[2-amino-6-[(4-fluorophenyl)methylamino]-3-pyridinyl]carbamic acid ethyl ester Chemical compound N1=C(N)C(NC(=O)OCC)=CC=C1NCC1=CC=C(F)C=C1 JUUFBMODXQKSTD-UHFFFAOYSA-N 0.000 description 1
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 1
- RGPDEAGGEXEMMM-UHFFFAOYSA-N Nefopam Chemical compound C12=CC=CC=C2CN(C)CCOC1C1=CC=CC=C1 RGPDEAGGEXEMMM-UHFFFAOYSA-N 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- BRZANEXCSZCZCI-UHFFFAOYSA-N Nifenazone Chemical compound O=C1N(C=2C=CC=CC=2)N(C)C(C)=C1NC(=O)C1=CC=CN=C1 BRZANEXCSZCZCI-UHFFFAOYSA-N 0.000 description 1
- JZFPYUNJRRFVQU-UHFFFAOYSA-N Niflumic acid Chemical compound OC(=O)C1=CC=CN=C1NC1=CC=CC(C(F)(F)F)=C1 JZFPYUNJRRFVQU-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- ONBWJWYUHXVEJS-ZTYRTETDSA-N Normorphine Chemical compound C([C@@H](NCC1)[C@@H]2C=C[C@@H]3O)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 ONBWJWYUHXVEJS-ZTYRTETDSA-N 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 239000008896 Opium Substances 0.000 description 1
- 206010031264 Osteonecrosis Diseases 0.000 description 1
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 description 1
- UQCNKQCJZOAFTQ-ISWURRPUSA-N Oxymorphone Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O UQCNKQCJZOAFTQ-ISWURRPUSA-N 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 206010034960 Photophobia Diseases 0.000 description 1
- 208000037062 Polyps Diseases 0.000 description 1
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 description 1
- 206010036631 Presenile dementia Diseases 0.000 description 1
- VSQMKHNDXWGCDB-UHFFFAOYSA-N Protizinic acid Chemical compound OC(=O)C(C)C1=CC=C2SC3=CC(OC)=CC=C3N(C)C2=C1 VSQMKHNDXWGCDB-UHFFFAOYSA-N 0.000 description 1
- UVMRYBDEERADNV-UHFFFAOYSA-N Pseudoeugenol Natural products COC1=CC(C(C)=C)=CC=C1O UVMRYBDEERADNV-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- ZTVQQQVZCWLTDF-UHFFFAOYSA-N Remifentanil Chemical compound C1CN(CCC(=O)OC)CCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC=C1 ZTVQQQVZCWLTDF-UHFFFAOYSA-N 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038910 Retinitis Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 102100033717 Retroviral-like aspartic protease 1 Human genes 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- MEFKEPWMEQBLKI-AIRLBKTGSA-N S-adenosyl-L-methioninate Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-N 0.000 description 1
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 1
- NGFMICBWJRZIBI-JZRPKSSGSA-N Salicin Natural products O([C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@H](CO)O1)c1c(CO)cccc1 NGFMICBWJRZIBI-JZRPKSSGSA-N 0.000 description 1
- 241000124033 Salix Species 0.000 description 1
- 206010039705 Scleritis Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 206010054184 Small intestine carcinoma Diseases 0.000 description 1
- 101710188689 Small, acid-soluble spore protein 1 Proteins 0.000 description 1
- 101710188693 Small, acid-soluble spore protein 2 Proteins 0.000 description 1
- 101710166422 Small, acid-soluble spore protein A Proteins 0.000 description 1
- 101710166404 Small, acid-soluble spore protein C Proteins 0.000 description 1
- 101710174019 Small, acid-soluble spore protein C1 Proteins 0.000 description 1
- 101710174017 Small, acid-soluble spore protein C2 Proteins 0.000 description 1
- 101710174574 Small, acid-soluble spore protein gamma-type Proteins 0.000 description 1
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 208000006045 Spondylarthropathies Diseases 0.000 description 1
- 208000010040 Sprains and Strains Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 208000010513 Stupor Diseases 0.000 description 1
- 206010042496 Sunburn Diseases 0.000 description 1
- 102000019197 Superoxide Dismutase Human genes 0.000 description 1
- 108010012715 Superoxide dismutase Proteins 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- MUXFZBHBYYYLTH-UHFFFAOYSA-N Zaltoprofen Chemical compound O=C1CC2=CC(C(C(O)=O)C)=CC=C2SC2=CC=CC=C21 MUXFZBHBYYYLTH-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960004420 aceclofenac Drugs 0.000 description 1
- 229960004892 acemetacin Drugs 0.000 description 1
- FSQKKOOTNAMONP-UHFFFAOYSA-N acemetacin Chemical compound CC1=C(CC(=O)OCC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 FSQKKOOTNAMONP-UHFFFAOYSA-N 0.000 description 1
- TWIIVLKQFJBFPW-UHFFFAOYSA-N acetaminosalol Chemical compound C1=CC(NC(=O)C)=CC=C1OC(=O)C1=CC=CC=C1O TWIIVLKQFJBFPW-UHFFFAOYSA-N 0.000 description 1
- 229950007008 acetaminosalol Drugs 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229960001570 ademetionine Drugs 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 229960005142 alclofenac Drugs 0.000 description 1
- ARHWPKZXBHOEEE-UHFFFAOYSA-N alclofenac Chemical compound OC(=O)CC1=CC=C(OCC=C)C(Cl)=C1 ARHWPKZXBHOEEE-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229960001391 alfentanil Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000006350 alkyl thio alkyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- KGYFOSCXVAXULR-UHFFFAOYSA-N allylprodine Chemical compound C=1C=CC=CC=1C1(OC(=O)CC)CCN(C)CC1CC=C KGYFOSCXVAXULR-UHFFFAOYSA-N 0.000 description 1
- 229950004361 allylprodine Drugs 0.000 description 1
- 229960004663 alminoprofen Drugs 0.000 description 1
- FPHLBGOJWPEVME-UHFFFAOYSA-N alminoprofen Chemical compound OC(=O)C(C)C1=CC=C(NCC(C)=C)C=C1 FPHLBGOJWPEVME-UHFFFAOYSA-N 0.000 description 1
- 229960004685 aloxiprin Drugs 0.000 description 1
- MANKSFVECICGLK-UHFFFAOYSA-K aloxiprin Chemical compound [OH-].[Al+3].CC(=O)OC1=CC=CC=C1C([O-])=O.CC(=O)OC1=CC=CC=C1C([O-])=O MANKSFVECICGLK-UHFFFAOYSA-K 0.000 description 1
- RGZSQWQPBWRIAQ-LSDHHAIUSA-N alpha-Bisabolol Natural products CC(C)=CCC[C@@](C)(O)[C@@H]1CCC(C)=CC1 RGZSQWQPBWRIAQ-LSDHHAIUSA-N 0.000 description 1
- NGFMICBWJRZIBI-UHFFFAOYSA-N alpha-salicin Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=CC=C1CO NGFMICBWJRZIBI-UHFFFAOYSA-N 0.000 description 1
- UVAZQQHAVMNMHE-XJKSGUPXSA-N alphaprodine Chemical compound C=1C=CC=CC=1[C@@]1(OC(=O)CC)CCN(C)C[C@@H]1C UVAZQQHAVMNMHE-XJKSGUPXSA-N 0.000 description 1
- 229960001349 alphaprodine Drugs 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- WEUCPZFPBXPCQU-UHFFFAOYSA-K aluminum;2-acetyloxybenzoate;dihydroxide Chemical compound O[Al+]O.CC(=O)OC1=CC=CC=C1C([O-])=O WEUCPZFPBXPCQU-UHFFFAOYSA-K 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 229960000212 aminophenazone Drugs 0.000 description 1
- UQNCVOXEVRELFR-UHFFFAOYSA-N aminopropylone Chemical compound O=C1C(NC(=O)C(N(C)C)C)=C(C)N(C)N1C1=CC=CC=C1 UQNCVOXEVRELFR-UHFFFAOYSA-N 0.000 description 1
- 229950002372 aminopropylone Drugs 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- ISRODTBNJUAWEJ-UHFFFAOYSA-N amixetrine Chemical compound C=1C=CC=CC=1C(OCCC(C)C)CN1CCCC1 ISRODTBNJUAWEJ-UHFFFAOYSA-N 0.000 description 1
- 229950001993 amixetrine Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940063284 ammonium salicylate Drugs 0.000 description 1
- LSNWBKACGXCGAJ-UHFFFAOYSA-N ampiroxicam Chemical compound CN1S(=O)(=O)C2=CC=CC=C2C(OC(C)OC(=O)OCC)=C1C(=O)NC1=CC=CC=N1 LSNWBKACGXCGAJ-UHFFFAOYSA-N 0.000 description 1
- 229950011249 ampiroxicam Drugs 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- CWJNMKKMGIAGDK-UHFFFAOYSA-N amtolmetin guacil Chemical compound COC1=CC=CC=C1OC(=O)CNC(=O)CC(N1C)=CC=C1C(=O)C1=CC=C(C)C=C1 CWJNMKKMGIAGDK-UHFFFAOYSA-N 0.000 description 1
- 229950003227 amtolmetin guacil Drugs 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 229960002512 anileridine Drugs 0.000 description 1
- LKYQLAWMNBFNJT-UHFFFAOYSA-N anileridine Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC1=CC=C(N)C=C1 LKYQLAWMNBFNJT-UHFFFAOYSA-N 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 201000004612 anterior uveitis Diseases 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- VEQOALNAAJBPNY-UHFFFAOYSA-N antipyrine Chemical compound CN1C(C)=CC(=O)N1C1=CC=CC=C1 VEQOALNAAJBPNY-UHFFFAOYSA-N 0.000 description 1
- 229950004064 antrafenine Drugs 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 125000001691 aryl alkyl amino group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000004659 aryl alkyl thio group Chemical group 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 229960001671 azapropazone Drugs 0.000 description 1
- WOIIIUDZSOLAIW-NSHDSACASA-N azapropazone Chemical compound C1=C(C)C=C2N3C(=O)[C@H](CC=C)C(=O)N3C(N(C)C)=NC2=C1 WOIIIUDZSOLAIW-NSHDSACASA-N 0.000 description 1
- 208000019804 backache Diseases 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 235000013405 beer Nutrition 0.000 description 1
- 229960005149 bendazac Drugs 0.000 description 1
- BYFMCKSPFYVMOU-UHFFFAOYSA-N bendazac Chemical compound C12=CC=CC=C2C(OCC(=O)O)=NN1CC1=CC=CC=C1 BYFMCKSPFYVMOU-UHFFFAOYSA-N 0.000 description 1
- 229960004277 benorilate Drugs 0.000 description 1
- FEJKLNWAOXSSNR-UHFFFAOYSA-N benorilate Chemical compound C1=CC(NC(=O)C)=CC=C1OC(=O)C1=CC=CC=C1OC(C)=O FEJKLNWAOXSSNR-UHFFFAOYSA-N 0.000 description 1
- 229960005430 benoxaprofen Drugs 0.000 description 1
- KMGARVOVYXNAOF-UHFFFAOYSA-N benzpiperylone Chemical compound C1CN(C)CCC1N1C(=O)C(CC=2C=CC=CC=2)=C(C=2C=CC=CC=2)N1 KMGARVOVYXNAOF-UHFFFAOYSA-N 0.000 description 1
- 229960000333 benzydamine Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- RDJGWRFTDZZXSM-RNWLQCGYSA-N benzylmorphine Chemical compound O([C@@H]1[C@]23CCN([C@H](C4)[C@@H]3C=C[C@@H]1O)C)C1=C2C4=CC=C1OCC1=CC=CC=C1 RDJGWRFTDZZXSM-RNWLQCGYSA-N 0.000 description 1
- REHLODZXMGOGQP-UHFFFAOYSA-N bermoprofen Chemical compound C1C(=O)C2=CC(C(C(O)=O)C)=CC=C2OC2=CC=C(C)C=C21 REHLODZXMGOGQP-UHFFFAOYSA-N 0.000 description 1
- 229950007517 bermoprofen Drugs 0.000 description 1
- 229960004611 bezitramide Drugs 0.000 description 1
- FLKWNFFCSSJANB-UHFFFAOYSA-N bezitramide Chemical compound O=C1N(C(=O)CC)C2=CC=CC=C2N1C(CC1)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 FLKWNFFCSSJANB-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- QRZAKQDHEVVFRX-UHFFFAOYSA-N biphenyl-4-ylacetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1C1=CC=CC=C1 QRZAKQDHEVVFRX-UHFFFAOYSA-N 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 208000010217 blepharitis Diseases 0.000 description 1
- 201000005668 blepharoconjunctivitis Diseases 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 229960005470 bucetin Drugs 0.000 description 1
- IJTPQQVCKPZIMV-UHFFFAOYSA-N bucloxic acid Chemical compound ClC1=CC(C(=O)CCC(=O)O)=CC=C1C1CCCCC1 IJTPQQVCKPZIMV-UHFFFAOYSA-N 0.000 description 1
- 229950005608 bucloxic acid Drugs 0.000 description 1
- 229950003872 bucolome Drugs 0.000 description 1
- 229960000962 bufexamac Drugs 0.000 description 1
- MXJWRABVEGLYDG-UHFFFAOYSA-N bufexamac Chemical compound CCCCOC1=CC=C(CC(=O)NO)C=C1 MXJWRABVEGLYDG-UHFFFAOYSA-N 0.000 description 1
- 229960003354 bumadizone Drugs 0.000 description 1
- FLWFHHFTIRLFPV-UHFFFAOYSA-N bumadizone Chemical compound C=1C=CC=CC=1N(C(=O)C(C(O)=O)CCCC)NC1=CC=CC=C1 FLWFHHFTIRLFPV-UHFFFAOYSA-N 0.000 description 1
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 1
- 229960001736 buprenorphine Drugs 0.000 description 1
- RHDGNLCLDBVESU-UHFFFAOYSA-N but-3-en-4-olide Chemical compound O=C1CC=CO1 RHDGNLCLDBVESU-UHFFFAOYSA-N 0.000 description 1
- QTNZYVAMNRDUAD-UHFFFAOYSA-N butacetin Chemical compound CC(=O)NC1=CC=C(OC(C)(C)C)C=C1 QTNZYVAMNRDUAD-UHFFFAOYSA-N 0.000 description 1
- 229950011189 butacetin Drugs 0.000 description 1
- UULSXYSSHHRCQK-UHFFFAOYSA-N butibufen Chemical compound CCC(C(O)=O)C1=CC=C(CC(C)C)C=C1 UULSXYSSHHRCQK-UHFFFAOYSA-N 0.000 description 1
- 229960002973 butibufen Drugs 0.000 description 1
- 229960001113 butorphanol Drugs 0.000 description 1
- IFKLAQQSCNILHL-QHAWAJNXSA-N butorphanol Chemical compound N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 IFKLAQQSCNILHL-QHAWAJNXSA-N 0.000 description 1
- GAWOVNGQYQVFLI-ISLYRVAYSA-N c1cc(OCC)ccc1\N=N\c1ccc(N)cc1N Chemical compound c1cc(OCC)ccc1\N=N\c1ccc(N)cc1N GAWOVNGQYQVFLI-ISLYRVAYSA-N 0.000 description 1
- KRALOLGXHLZTCW-UHFFFAOYSA-L calcium;2-acetyloxybenzoate Chemical compound [Ca+2].CC(=O)OC1=CC=CC=C1C([O-])=O.CC(=O)OC1=CC=CC=C1C([O-])=O KRALOLGXHLZTCW-UHFFFAOYSA-L 0.000 description 1
- 229930003827 cannabinoid Natural products 0.000 description 1
- 239000003557 cannabinoid Substances 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- NQIZDFMZAXUZCZ-UHFFFAOYSA-N carbifene Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCC)C(=O)N(C)CCN(C)CCC1=CC=CC=C1 NQIZDFMZAXUZCZ-UHFFFAOYSA-N 0.000 description 1
- 229950003365 carbifene Drugs 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- IVUMCTKHWDRRMH-UHFFFAOYSA-N carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 description 1
- 229960003184 carprofen Drugs 0.000 description 1
- OAYRYNVEFFWSHK-UHFFFAOYSA-N carsalam Chemical compound C1=CC=C2OC(=O)NC(=O)C2=C1 OAYRYNVEFFWSHK-UHFFFAOYSA-N 0.000 description 1
- 229950004289 carsalam Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- YEKMWXFHPZBZLR-UHFFFAOYSA-N chlorthenoxazine Chemical compound C1=CC=C2OC(CCCl)NC(=O)C2=C1 YEKMWXFHPZBZLR-UHFFFAOYSA-N 0.000 description 1
- 229950007438 chlorthenoxazine Drugs 0.000 description 1
- 229960002688 choline salicylate Drugs 0.000 description 1
- 201000004709 chorioretinitis Diseases 0.000 description 1
- 229960002468 cinchophen Drugs 0.000 description 1
- NKPPORKKCMYYTO-DHZHZOJOSA-N cinmetacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)\C=C\C1=CC=CC=C1 NKPPORKKCMYYTO-DHZHZOJOSA-N 0.000 description 1
- 229950011171 cinmetacin Drugs 0.000 description 1
- UVTLONZTPXCUPU-ZNMIVQPWSA-N ciramadol Chemical compound C([C@@H]1[C@@H](N(C)C)C=2C=C(O)C=CC=2)CCC[C@H]1O UVTLONZTPXCUPU-ZNMIVQPWSA-N 0.000 description 1
- 229950007653 ciramadol Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229950010886 clidanac Drugs 0.000 description 1
- DGMZLCLHHVYDIS-UHFFFAOYSA-N clometacin Chemical compound CC=1N(CC(O)=O)C2=CC(OC)=CC=C2C=1C(=O)C1=CC=C(Cl)C=C1 DGMZLCLHHVYDIS-UHFFFAOYSA-N 0.000 description 1
- 229950001647 clometacin Drugs 0.000 description 1
- GPZLDQAEBHTMPG-UHFFFAOYSA-N clonitazene Chemical compound N=1C2=CC([N+]([O-])=O)=CC=C2N(CCN(CC)CC)C=1CC1=CC=C(Cl)C=C1 GPZLDQAEBHTMPG-UHFFFAOYSA-N 0.000 description 1
- 229950001604 clonitazene Drugs 0.000 description 1
- CLOMYZFHNHFSIQ-UHFFFAOYSA-N clonixin Chemical compound CC1=C(Cl)C=CC=C1NC1=NC=CC=C1C(O)=O CLOMYZFHNHFSIQ-UHFFFAOYSA-N 0.000 description 1
- 229960001209 clonixin Drugs 0.000 description 1
- SJCRQMUYEQHNTC-UHFFFAOYSA-N clopirac Chemical compound CC1=CC(CC(O)=O)=C(C)N1C1=CC=C(Cl)C=C1 SJCRQMUYEQHNTC-UHFFFAOYSA-N 0.000 description 1
- 229950009185 clopirac Drugs 0.000 description 1
- KIKLDWULAZATJG-YZZSNFJZSA-M codeine methylbromide Chemical compound [Br-].C([C@H]1[C@H]([N+](CC[C@@]112)(C)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC KIKLDWULAZATJG-YZZSNFJZSA-M 0.000 description 1
- 229960004415 codeine phosphate Drugs 0.000 description 1
- 229960003871 codeine sulfate Drugs 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 208000020992 contracted pupil Diseases 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 238000011262 co‐therapy Methods 0.000 description 1
- CYZWCBZIBJLKCV-RMKNXTFCSA-N cropropamide Chemical compound CN(C)C(=O)C(CC)N(CCC)C(=O)\C=C\C CYZWCBZIBJLKCV-RMKNXTFCSA-N 0.000 description 1
- 229950008982 cropropamide Drugs 0.000 description 1
- LSAMUAYPDHUBQD-RMKNXTFCSA-N crotetamide Chemical compound CN(C)C(=O)C(CC)N(CC)C(=O)\C=C\C LSAMUAYPDHUBQD-RMKNXTFCSA-N 0.000 description 1
- 229950008678 crotetamide Drugs 0.000 description 1
- 125000004966 cyanoalkyl group Chemical group 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- LNNWVNGFPYWNQE-GMIGKAJZSA-N desomorphine Chemical compound C1C2=CC=C(O)C3=C2[C@]24CCN(C)[C@H]1[C@@H]2CCC[C@@H]4O3 LNNWVNGFPYWNQE-GMIGKAJZSA-N 0.000 description 1
- 229950003851 desomorphine Drugs 0.000 description 1
- HGKAMARNFGKMLC-RBUKOAKNSA-N dexoxadrol Chemical compound C([C@H]1[C@@H]2OC(OC2)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCCN1 HGKAMARNFGKMLC-RBUKOAKNSA-N 0.000 description 1
- 229950004665 dexoxadrol Drugs 0.000 description 1
- WDEFBBTXULIOBB-WBVHZDCISA-N dextilidine Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)OCC)CCC=C[C@H]1N(C)C WDEFBBTXULIOBB-WBVHZDCISA-N 0.000 description 1
- INUNXTSAACVKJS-OAQYLSRUSA-N dextromoramide Chemical compound C([C@@H](C)C(C(=O)N1CCCC1)(C=1C=CC=CC=1)C=1C=CC=CC=1)N1CCOCC1 INUNXTSAACVKJS-OAQYLSRUSA-N 0.000 description 1
- 229960003701 dextromoramide Drugs 0.000 description 1
- 229960004193 dextropropoxyphene Drugs 0.000 description 1
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 description 1
- 229960003461 dezocine Drugs 0.000 description 1
- VTMVHDZWSFQSQP-VBNZEHGJSA-N dezocine Chemical compound C1CCCC[C@H]2CC3=CC=C(O)C=C3[C@]1(C)[C@H]2N VTMVHDZWSFQSQP-VBNZEHGJSA-N 0.000 description 1
- 125000004472 dialkylaminosulfonyl group Chemical group 0.000 description 1
- RXTHKWVSXOIHJS-UHFFFAOYSA-N diampromide Chemical compound C=1C=CC=CC=1N(C(=O)CC)CC(C)N(C)CCC1=CC=CC=C1 RXTHKWVSXOIHJS-UHFFFAOYSA-N 0.000 description 1
- 229950001059 diampromide Drugs 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 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
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- PCXMKBOWWVXEDT-UHFFFAOYSA-N difenamizole Chemical compound CN(C)C(C)C(=O)NC1=CC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 PCXMKBOWWVXEDT-UHFFFAOYSA-N 0.000 description 1
- 229950000061 difenamizole Drugs 0.000 description 1
- 229960001536 difenpiramide Drugs 0.000 description 1
- PWHROYKAGRUWDQ-UHFFFAOYSA-N difenpiramide Chemical compound C=1C=CC=NC=1NC(=O)CC(C=C1)=CC=C1C1=CC=CC=C1 PWHROYKAGRUWDQ-UHFFFAOYSA-N 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 229960000920 dihydrocodeine Drugs 0.000 description 1
- RBOXVHNMENFORY-DNJOTXNNSA-N dihydrocodeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC RBOXVHNMENFORY-DNJOTXNNSA-N 0.000 description 1
- QIRAYNIFEOXSPW-UHFFFAOYSA-N dimepheptanol Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(O)CC)C1=CC=CC=C1 QIRAYNIFEOXSPW-UHFFFAOYSA-N 0.000 description 1
- 229950004655 dimepheptanol Drugs 0.000 description 1
- CANBGVXYBPOLRR-UHFFFAOYSA-N dimethylthiambutene Chemical compound C=1C=CSC=1C(=CC(C)N(C)C)C1=CC=CS1 CANBGVXYBPOLRR-UHFFFAOYSA-N 0.000 description 1
- 229950005563 dimethylthiambutene Drugs 0.000 description 1
- LQGIXNQCOXNCRP-UHFFFAOYSA-N dioxaphetyl butyrate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)OCC)CCN1CCOCC1 LQGIXNQCOXNCRP-UHFFFAOYSA-N 0.000 description 1
- 229950008972 dioxaphetyl butyrate Drugs 0.000 description 1
- SVDHSZFEQYXRDC-UHFFFAOYSA-N dipipanone Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)CC)CC(C)N1CCCCC1 SVDHSZFEQYXRDC-UHFFFAOYSA-N 0.000 description 1
- 229960002500 dipipanone Drugs 0.000 description 1
- DGLRDKLJZLEJCY-UHFFFAOYSA-L disodium hydrogenphosphate dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O DGLRDKLJZLEJCY-UHFFFAOYSA-L 0.000 description 1
- 229960005067 ditazole Drugs 0.000 description 1
- UUCMDZWCRNZCOY-UHFFFAOYSA-N ditazole Chemical compound O1C(N(CCO)CCO)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 UUCMDZWCRNZCOY-UHFFFAOYSA-N 0.000 description 1
- 208000007784 diverticulitis Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229950010243 emorfazone Drugs 0.000 description 1
- 238000013171 endarterectomy Methods 0.000 description 1
- 206010014801 endophthalmitis Diseases 0.000 description 1
- 229950010996 enfenamic acid Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000000222 eosinocyte Anatomy 0.000 description 1
- 229950003801 epirizole Drugs 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- ZOWQTJXNFTWSCS-IAQYHMDHSA-N eptazocine Chemical compound C1N(C)CC[C@@]2(C)C3=CC(O)=CC=C3C[C@@H]1C2 ZOWQTJXNFTWSCS-IAQYHMDHSA-N 0.000 description 1
- 229950010920 eptazocine Drugs 0.000 description 1
- 201000005619 esophageal carcinoma Diseases 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- PXBFSRVXEKCBFP-UHFFFAOYSA-N etersalate Chemical compound C1=CC(NC(=O)C)=CC=C1OCCOC(=O)C1=CC=CC=C1OC(C)=O PXBFSRVXEKCBFP-UHFFFAOYSA-N 0.000 description 1
- 229950006159 etersalate Drugs 0.000 description 1
- 229960000514 ethenzamide Drugs 0.000 description 1
- SBNKFTQSBPKMBZ-UHFFFAOYSA-N ethenzamide Chemical compound CCOC1=CC=CC=C1C(N)=O SBNKFTQSBPKMBZ-UHFFFAOYSA-N 0.000 description 1
- WGJHHMKQBWSQIY-UHFFFAOYSA-N ethoheptazine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCCN(C)CC1 WGJHHMKQBWSQIY-UHFFFAOYSA-N 0.000 description 1
- 229960000569 ethoheptazine Drugs 0.000 description 1
- FRQSLQPWXFAJFO-UHFFFAOYSA-N ethoxymethyl 2-(2,6-dichloro-3-methylanilino)benzoate Chemical compound CCOCOC(=O)C1=CC=CC=C1NC1=C(Cl)C=CC(C)=C1Cl FRQSLQPWXFAJFO-UHFFFAOYSA-N 0.000 description 1
- SEISMQVOJUJKGE-UHFFFAOYSA-M ethyl 1,6-dimethyl-4-oxo-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-1-ium-3-carboxylate;methyl sulfate Chemical compound COS([O-])(=O)=O.C1CCC(C)N2C(=O)C(C(=O)OCC)=C[N+](C)=C21 SEISMQVOJUJKGE-UHFFFAOYSA-M 0.000 description 1
- MORSAEFGQPDBKM-UHFFFAOYSA-N ethylmethylthiambutene Chemical compound C=1C=CSC=1C(=CC(C)N(C)CC)C1=CC=CS1 MORSAEFGQPDBKM-UHFFFAOYSA-N 0.000 description 1
- 229950006111 ethylmethylthiambutene Drugs 0.000 description 1
- 229960005293 etodolac Drugs 0.000 description 1
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 description 1
- 229960001493 etofenamate Drugs 0.000 description 1
- PXDBZSCGSQSKST-UHFFFAOYSA-N etonitazene Chemical compound C1=CC(OCC)=CC=C1CC1=NC2=CC([N+]([O-])=O)=CC=C2N1CCN(CC)CC PXDBZSCGSQSKST-UHFFFAOYSA-N 0.000 description 1
- 229950004538 etonitazene Drugs 0.000 description 1
- 229950008765 etoxazene Drugs 0.000 description 1
- 229960002217 eugenol Drugs 0.000 description 1
- 229960000192 felbinac Drugs 0.000 description 1
- 208000011404 female reproductive system disease Diseases 0.000 description 1
- 229960001395 fenbufen Drugs 0.000 description 1
- ZPAKPRAICRBAOD-UHFFFAOYSA-N fenbufen Chemical compound C1=CC(C(=O)CCC(=O)O)=CC=C1C1=CC=CC=C1 ZPAKPRAICRBAOD-UHFFFAOYSA-N 0.000 description 1
- 229950011481 fenclozic acid Drugs 0.000 description 1
- HAWWPSYXSLJRBO-UHFFFAOYSA-N fendosal Chemical compound C1=C(O)C(C(=O)O)=CC(N2C(=CC=3C4=CC=CC=C4CCC=32)C=2C=CC=CC=2)=C1 HAWWPSYXSLJRBO-UHFFFAOYSA-N 0.000 description 1
- 229950005416 fendosal Drugs 0.000 description 1
- 229960001419 fenoprofen Drugs 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 description 1
- 229960002679 fentiazac Drugs 0.000 description 1
- ZEAJXCPGHPJVNP-UHFFFAOYSA-N fenyramidol Chemical compound C=1C=CC=CC=1C(O)CNC1=CC=CC=N1 ZEAJXCPGHPJVNP-UHFFFAOYSA-N 0.000 description 1
- 229960000555 fenyramidol Drugs 0.000 description 1
- PVOOBRUZWPQOER-UHFFFAOYSA-N fepradinol Chemical compound OCC(C)(C)NCC(O)C1=CC=CC=C1 PVOOBRUZWPQOER-UHFFFAOYSA-N 0.000 description 1
- 229950008205 fepradinol Drugs 0.000 description 1
- 229960000489 feprazone Drugs 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229960003240 floctafenine Drugs 0.000 description 1
- 229960004369 flufenamic acid Drugs 0.000 description 1
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 1
- 229960001321 flunoxaprofen Drugs 0.000 description 1
- ARPYQKTVRGFPIS-VIFPVBQESA-N flunoxaprofen Chemical compound N=1C2=CC([C@@H](C(O)=O)C)=CC=C2OC=1C1=CC=C(F)C=C1 ARPYQKTVRGFPIS-VIFPVBQESA-N 0.000 description 1
- PRNNIHPVNFPWAH-UHFFFAOYSA-N fluoresone Chemical compound CCS(=O)(=O)C1=CC=C(F)C=C1 PRNNIHPVNFPWAH-UHFFFAOYSA-N 0.000 description 1
- 229950011300 fluoresone Drugs 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 229960003667 flupirtine Drugs 0.000 description 1
- ZWOUXWWGKJBAHQ-UHFFFAOYSA-N fluproquazone Chemical compound N=1C(=O)N(C(C)C)C2=CC(C)=CC=C2C=1C1=CC=C(F)C=C1 ZWOUXWWGKJBAHQ-UHFFFAOYSA-N 0.000 description 1
- 229950004250 fluproquazone Drugs 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229950010892 fosfosal Drugs 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000003844 furanonyl group Chemical group 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 208000018685 gastrointestinal system disease Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 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
- XOXYHGOIRWABTC-UHFFFAOYSA-N gentisin Chemical compound C1=C(O)C=C2C(=O)C3=C(O)C=C(OC)C=C3OC2=C1 XOXYHGOIRWABTC-UHFFFAOYSA-N 0.000 description 1
- 208000007565 gingivitis Diseases 0.000 description 1
- 229960001650 glafenine Drugs 0.000 description 1
- GWOFUCIGLDBNKM-UHFFFAOYSA-N glafenine Chemical compound OCC(O)COC(=O)C1=CC=CC=C1NC1=CC=NC2=CC(Cl)=CC=C12 GWOFUCIGLDBNKM-UHFFFAOYSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229960004410 glucametacin Drugs 0.000 description 1
- 229960002389 glycol salicylate Drugs 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229960002350 guaiazulen Drugs 0.000 description 1
- 125000004970 halomethyl group Chemical group 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 125000001145 hydrido group Chemical group *[H] 0.000 description 1
- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 description 1
- 229960000240 hydrocodone Drugs 0.000 description 1
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 description 1
- 229960001410 hydromorphone Drugs 0.000 description 1
- WTJBNMUWRKPFRS-UHFFFAOYSA-N hydroxypethidine Chemical compound C=1C=CC(O)=CC=1C1(C(=O)OCC)CCN(C)CC1 WTJBNMUWRKPFRS-UHFFFAOYSA-N 0.000 description 1
- 229950008496 hydroxypethidine Drugs 0.000 description 1
- CYWFCPPBTWOZSF-UHFFFAOYSA-N ibufenac Chemical compound CC(C)CC1=CC=C(CC(O)=O)C=C1 CYWFCPPBTWOZSF-UHFFFAOYSA-N 0.000 description 1
- 229950009183 ibufenac Drugs 0.000 description 1
- 229960002595 ibuproxam Drugs 0.000 description 1
- BYPIURIATSUHDW-UHFFFAOYSA-N ibuproxam Chemical compound CC(C)CC1=CC=C(C(C)C(=O)NO)C=C1 BYPIURIATSUHDW-UHFFFAOYSA-N 0.000 description 1
- 229960004769 imidazole salicylate Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 229960004187 indoprofen Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 201000004614 iritis Diseases 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- LZRDDINFIHUVCX-UHFFFAOYSA-N isofezolac Chemical compound OC(=O)CC1=C(C=2C=CC=CC=2)C(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 LZRDDINFIHUVCX-UHFFFAOYSA-N 0.000 description 1
- 229950004425 isofezolac Drugs 0.000 description 1
- IFKPLJWIEQBPGG-UHFFFAOYSA-N isomethadone Chemical compound C=1C=CC=CC=1C(C(C)CN(C)C)(C(=O)CC)C1=CC=CC=C1 IFKPLJWIEQBPGG-UHFFFAOYSA-N 0.000 description 1
- 229950009272 isomethadone Drugs 0.000 description 1
- WJDDCFNFNAHLAF-UHFFFAOYSA-N isonixin Chemical compound CC1=CC=CC(C)=C1NC(=O)C1=CC=CNC1=O WJDDCFNFNAHLAF-UHFFFAOYSA-N 0.000 description 1
- 229950000248 isonixin Drugs 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- QFGMXJOBTNZHEL-UHFFFAOYSA-N isoxepac Chemical compound O1CC2=CC=CC=C2C(=O)C2=CC(CC(=O)O)=CC=C21 QFGMXJOBTNZHEL-UHFFFAOYSA-N 0.000 description 1
- 229950011455 isoxepac Drugs 0.000 description 1
- YYUAYBYLJSNDCX-UHFFFAOYSA-N isoxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC=1C=C(C)ON=1 YYUAYBYLJSNDCX-UHFFFAOYSA-N 0.000 description 1
- 229950002252 isoxicam Drugs 0.000 description 1
- 239000002618 kappa opiate receptor antagonist Substances 0.000 description 1
- 201000010666 keratoconjunctivitis Diseases 0.000 description 1
- 229960003029 ketobemidone Drugs 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- BWHLPLXXIDYSNW-UHFFFAOYSA-N ketorolac tromethamine Chemical compound OCC(N)(CO)CO.OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 BWHLPLXXIDYSNW-UHFFFAOYSA-N 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- YEJZJVJJPVZXGX-MRXNPFEDSA-N lefetamine Chemical compound C([C@@H](N(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 YEJZJVJJPVZXGX-MRXNPFEDSA-N 0.000 description 1
- 229950008279 lefetamine Drugs 0.000 description 1
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 description 1
- 229960003406 levorphanol Drugs 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 201000006721 lip cancer Diseases 0.000 description 1
- IMYHGORQCPYVBZ-NLFFAJNJSA-N lofentanil Chemical compound CCC(=O)N([C@@]1([C@@H](CN(CCC=2C=CC=CC=2)CC1)C)C(=O)OC)C1=CC=CC=C1 IMYHGORQCPYVBZ-NLFFAJNJSA-N 0.000 description 1
- 229950010274 lofentanil Drugs 0.000 description 1
- 229960003768 lonazolac Drugs 0.000 description 1
- XVUQHFRQHBLHQD-UHFFFAOYSA-N lonazolac Chemical compound OC(=O)CC1=CN(C=2C=CC=CC=2)N=C1C1=CC=C(Cl)C=C1 XVUQHFRQHBLHQD-UHFFFAOYSA-N 0.000 description 1
- OXROWJKCGCOJDO-JLHYYAGUSA-N lornoxicam Chemical compound O=C1C=2SC(Cl)=CC=2S(=O)(=O)N(C)\C1=C(\O)NC1=CC=CC=N1 OXROWJKCGCOJDO-JLHYYAGUSA-N 0.000 description 1
- 229960002202 lornoxicam Drugs 0.000 description 1
- 229960002373 loxoprofen Drugs 0.000 description 1
- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical compound O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 description 1
- 201000010230 macular retinal edema Diseases 0.000 description 1
- RBLKLJDYAHZCFW-UHFFFAOYSA-L magnesium;2-acetyloxybenzoate Chemical compound [Mg+2].CC(=O)OC1=CC=CC=C1C([O-])=O.CC(=O)OC1=CC=CC=C1C([O-])=O RBLKLJDYAHZCFW-UHFFFAOYSA-L 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960003803 meclofenamic acid Drugs 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- JLICHNCFTLFZJN-HNNXBMFYSA-N meptazinol Chemical compound C=1C=CC(O)=CC=1[C@@]1(CC)CCCCN(C)C1 JLICHNCFTLFZJN-HNNXBMFYSA-N 0.000 description 1
- 229960000365 meptazinol Drugs 0.000 description 1
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 description 1
- 229960004963 mesalazine Drugs 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- DJGAAPFSPWAYTJ-UHFFFAOYSA-M metamizole sodium Chemical compound [Na+].O=C1C(N(CS([O-])(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 DJGAAPFSPWAYTJ-UHFFFAOYSA-M 0.000 description 1
- 208000011645 metastatic carcinoma Diseases 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- YGSVZRIZCHZUHB-COLVAYQJSA-N metazocine Chemical compound C1C2=CC=C(O)C=C2[C@]2(C)CCN(C)[C@@]1([H])[C@@H]2C YGSVZRIZCHZUHB-COLVAYQJSA-N 0.000 description 1
- 229950009131 metazocine Drugs 0.000 description 1
- 229960005189 methadone hydrochloride Drugs 0.000 description 1
- FJQXCDYVZAHXNS-UHFFFAOYSA-N methadone hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 FJQXCDYVZAHXNS-UHFFFAOYSA-N 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- VRQVVMDWGGWHTJ-CQSZACIVSA-N methotrimeprazine Chemical compound C1=CC=C2N(C[C@H](C)CN(C)C)C3=CC(OC)=CC=C3SC2=C1 VRQVVMDWGGWHTJ-CQSZACIVSA-N 0.000 description 1
- 229940042053 methotrimeprazine Drugs 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- LMINNBXUMGNKMM-UHFFFAOYSA-N metiazinic acid Chemical compound C1=C(CC(O)=O)C=C2N(C)C3=CC=CC=C3SC2=C1 LMINNBXUMGNKMM-UHFFFAOYSA-N 0.000 description 1
- 229950005798 metiazinic acid Drugs 0.000 description 1
- YBCPYHQFUMNOJG-UHFFFAOYSA-N metofoline Chemical compound C1=2C=C(OC)C(OC)=CC=2CCN(C)C1CCC1=CC=C(Cl)C=C1 YBCPYHQFUMNOJG-UHFFFAOYSA-N 0.000 description 1
- 229950009818 metofoline Drugs 0.000 description 1
- NPZXCTIHHUUEEJ-CMKMFDCUSA-N metopon Chemical compound O([C@@]1(C)C(=O)CC[C@@H]23)C4=C5[C@@]13CCN(C)[C@@H]2CC5=CC=C4O NPZXCTIHHUUEEJ-CMKMFDCUSA-N 0.000 description 1
- 229950006080 metopon Drugs 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960005285 mofebutazone Drugs 0.000 description 1
- REOJLIXKJWXUGB-UHFFFAOYSA-N mofebutazone Chemical compound O=C1C(CCCC)C(=O)NN1C1=CC=CC=C1 REOJLIXKJWXUGB-UHFFFAOYSA-N 0.000 description 1
- 229960000429 mofezolac Drugs 0.000 description 1
- OOGNFQMTGRZRAB-UHFFFAOYSA-N morazone Chemical compound CC1C(C=2C=CC=CC=2)OCCN1CC(C1=O)=C(C)N(C)N1C1=CC=CC=C1 OOGNFQMTGRZRAB-UHFFFAOYSA-N 0.000 description 1
- 229960004610 morazone Drugs 0.000 description 1
- 229960005195 morphine hydrochloride Drugs 0.000 description 1
- XELXKCKNPPSFNN-BJWPBXOKSA-N morphine hydrochloride trihydrate Chemical compound O.O.O.Cl.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O XELXKCKNPPSFNN-BJWPBXOKSA-N 0.000 description 1
- 229960004715 morphine sulfate Drugs 0.000 description 1
- GRVOTVYEFDAHCL-RTSZDRIGSA-N morphine sulfate pentahydrate Chemical compound O.O.O.O.O.OS(O)(=O)=O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O GRVOTVYEFDAHCL-RTSZDRIGSA-N 0.000 description 1
- 239000002623 mu opiate receptor antagonist Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- GODGZZGKTZQSAL-VXFFQEMOSA-N myrophine Chemical compound C([C@@H]1[C@@H]2C=C[C@@H]([C@@H]3OC4=C5[C@]23CCN1C)OC(=O)CCCCCCCCCCCCC)C5=CC=C4OCC1=CC=CC=C1 GODGZZGKTZQSAL-VXFFQEMOSA-N 0.000 description 1
- 229950007471 myrophine Drugs 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 229960004270 nabumetone Drugs 0.000 description 1
- 229960000805 nalbuphine Drugs 0.000 description 1
- NETZHAKZCGBWSS-CEDHKZHLSA-N nalbuphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@@H]3O)CN2CC1CCC1 NETZHAKZCGBWSS-CEDHKZHLSA-N 0.000 description 1
- CVRCFLFEGNKMEC-UHFFFAOYSA-N naphthalen-1-yl 2-hydroxybenzoate Chemical compound OC1=CC=CC=C1C(=O)OC1=CC=CC2=CC=CC=C12 CVRCFLFEGNKMEC-UHFFFAOYSA-N 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 210000001989 nasopharynx Anatomy 0.000 description 1
- 229960000751 nefopam Drugs 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000013315 neuromuscular junction disease Diseases 0.000 description 1
- 229960004300 nicomorphine Drugs 0.000 description 1
- HNDXBGYRMHRUFN-CIVUWBIHSA-N nicomorphine Chemical compound O([C@H]1C=C[C@H]2[C@H]3CC=4C5=C(C(=CC=4)OC(=O)C=4C=NC=CC=4)O[C@@H]1[C@]52CCN3C)C(=O)C1=CC=CN=C1 HNDXBGYRMHRUFN-CIVUWBIHSA-N 0.000 description 1
- 229960002187 nifenazone Drugs 0.000 description 1
- 229960000916 niflumic acid Drugs 0.000 description 1
- 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 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229950011519 norlevorphanol Drugs 0.000 description 1
- 229960004013 normethadone Drugs 0.000 description 1
- WCJFBSYALHQBSK-UHFFFAOYSA-N normethadone Chemical compound C=1C=CC=CC=1C(CCN(C)C)(C(=O)CC)C1=CC=CC=C1 WCJFBSYALHQBSK-UHFFFAOYSA-N 0.000 description 1
- 229950006134 normorphine Drugs 0.000 description 1
- WCDSHELZWCOTMI-UHFFFAOYSA-N norpipanone Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)CC)CCN1CCCCC1 WCDSHELZWCOTMI-UHFFFAOYSA-N 0.000 description 1
- 229950007418 norpipanone Drugs 0.000 description 1
- QQBDLJCYGRGAKP-FOCLMDBBSA-N olsalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=C(C(O)=CC=2)C(O)=O)=C1 QQBDLJCYGRGAKP-FOCLMDBBSA-N 0.000 description 1
- 229960004110 olsalazine Drugs 0.000 description 1
- 229960001027 opium Drugs 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 238000012829 orthopaedic surgery Methods 0.000 description 1
- 229960005113 oxaceprol Drugs 0.000 description 1
- 229960000273 oxametacin Drugs 0.000 description 1
- AJRNYCDWNITGHF-UHFFFAOYSA-N oxametacin Chemical compound CC1=C(CC(=O)NO)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 AJRNYCDWNITGHF-UHFFFAOYSA-N 0.000 description 1
- 229960002739 oxaprozin Drugs 0.000 description 1
- OFPXSFXSNFPTHF-UHFFFAOYSA-N oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 229960002085 oxycodone Drugs 0.000 description 1
- 229960005118 oxymorphone Drugs 0.000 description 1
- 229960000649 oxyphenbutazone Drugs 0.000 description 1
- HFHZKZSRXITVMK-UHFFFAOYSA-N oxyphenbutazone Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=C(O)C=C1 HFHZKZSRXITVMK-UHFFFAOYSA-N 0.000 description 1
- 238000010422 painting Methods 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- DXHYQIJBUNRPJT-UHFFFAOYSA-N parsalmide Chemical compound CCCCNC(=O)C1=CC(N)=CC=C1OCC#C DXHYQIJBUNRPJT-UHFFFAOYSA-N 0.000 description 1
- 229950001060 parsalmide Drugs 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 1
- 229960005301 pentazocine Drugs 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- XKFIQZCHJUUSBA-UHFFFAOYSA-N perisoxal Chemical compound C1=C(C=2C=CC=CC=2)ON=C1C(O)CN1CCCCC1 XKFIQZCHJUUSBA-UHFFFAOYSA-N 0.000 description 1
- 229950005491 perisoxal Drugs 0.000 description 1
- 229960003893 phenacetin Drugs 0.000 description 1
- LOXCOAXRHYDLOW-UHFFFAOYSA-N phenadoxone Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)CC)CC(C)N1CCOCC1 LOXCOAXRHYDLOW-UHFFFAOYSA-N 0.000 description 1
- 229950004540 phenadoxone Drugs 0.000 description 1
- LQJARUQXWJSDFL-UHFFFAOYSA-N phenamine Chemical compound CCOC1=CC=C(NC(=O)CN)C=C1 LQJARUQXWJSDFL-UHFFFAOYSA-N 0.000 description 1
- 229950010879 phenamine Drugs 0.000 description 1
- ZQHYKVKNPWDQSL-KNXBSLHKSA-N phenazocine Chemical compound C([C@@]1(C)C2=CC(O)=CC=C2C[C@@H]2[C@@H]1C)CN2CCC1=CC=CC=C1 ZQHYKVKNPWDQSL-KNXBSLHKSA-N 0.000 description 1
- 229960000897 phenazocine Drugs 0.000 description 1
- 229960005222 phenazone Drugs 0.000 description 1
- 229960003799 phenazopyridine hydrochloride Drugs 0.000 description 1
- 229960004315 phenoperidine Drugs 0.000 description 1
- IPOPQVVNCFQFRK-UHFFFAOYSA-N phenoperidine Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC(O)C1=CC=CC=C1 IPOPQVVNCFQFRK-UHFFFAOYSA-N 0.000 description 1
- PSBAIJVSCTZDDB-UHFFFAOYSA-N phenyl acetylsalicylate Chemical compound CC(=O)OC1=CC=CC=C1C(=O)OC1=CC=CC=C1 PSBAIJVSCTZDDB-UHFFFAOYSA-N 0.000 description 1
- 229950009058 phenyl acetylsalicylate Drugs 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- ASFKKFRSMGBFRO-UHFFFAOYSA-N piketoprofen Chemical compound C=1C=CC(C(=O)C=2C=CC=CC=2)=CC=1C(C)C(=O)NC1=CC(C)=CC=N1 ASFKKFRSMGBFRO-UHFFFAOYSA-N 0.000 description 1
- 229960001503 piketoprofen Drugs 0.000 description 1
- PXXKIYPSXYFATG-UHFFFAOYSA-N piminodine Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCCNC1=CC=CC=C1 PXXKIYPSXYFATG-UHFFFAOYSA-N 0.000 description 1
- 229950006445 piminodine Drugs 0.000 description 1
- XGNKHIPCARGLGS-UHFFFAOYSA-N pipebuzone Chemical compound O=C1N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C(=O)C1(CCCC)CN1CCN(C)CC1 XGNKHIPCARGLGS-UHFFFAOYSA-N 0.000 description 1
- 229950004769 pipebuzone Drugs 0.000 description 1
- 229950001532 piperylone Drugs 0.000 description 1
- 229950007914 pirazolac Drugs 0.000 description 1
- 229940068170 pirinitramide Drugs 0.000 description 1
- IHEHEFLXQFOQJO-UHFFFAOYSA-N piritramide Chemical compound C1CC(C(=O)N)(N2CCCCC2)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 IHEHEFLXQFOQJO-UHFFFAOYSA-N 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229960000825 proglumetacin Drugs 0.000 description 1
- PTXGHCGBYMQQIG-UHFFFAOYSA-N proglumetacin Chemical compound C=1C=CC=CC=1C(=O)NC(C(=O)N(CCC)CCC)CCC(=O)OCCCN(CC1)CCN1CCOC(=O)CC(C1=CC(OC)=CC=C11)=C(C)N1C(=O)C1=CC=C(Cl)C=C1 PTXGHCGBYMQQIG-UHFFFAOYSA-N 0.000 description 1
- ZXWAUWBYASJEOE-UHFFFAOYSA-N proheptazine Chemical compound C=1C=CC=CC=1C1(OC(=O)CC)CCCN(C)CC1C ZXWAUWBYASJEOE-UHFFFAOYSA-N 0.000 description 1
- 229950010387 proheptazine Drugs 0.000 description 1
- 229960003192 propacetamol Drugs 0.000 description 1
- QTGAJCQTLIRCFL-UHFFFAOYSA-N propacetamol Chemical compound CCN(CC)CC(=O)OC1=CC=C(NC(C)=O)C=C1 QTGAJCQTLIRCFL-UHFFFAOYSA-N 0.000 description 1
- ZBAFFZBKCMWUHM-UHFFFAOYSA-N propiram Chemical compound C=1C=CC=NC=1N(C(=O)CC)C(C)CN1CCCCC1 ZBAFFZBKCMWUHM-UHFFFAOYSA-N 0.000 description 1
- 229950003779 propiram Drugs 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 229960002189 propyphenazone Drugs 0.000 description 1
- PXWLVJLKJGVOKE-UHFFFAOYSA-N propyphenazone Chemical compound O=C1C(C(C)C)=C(C)N(C)N1C1=CC=CC=C1 PXWLVJLKJGVOKE-UHFFFAOYSA-N 0.000 description 1
- 229960002466 proquazone Drugs 0.000 description 1
- JTIGKVIOEQASGT-UHFFFAOYSA-N proquazone Chemical compound N=1C(=O)N(C(C)C)C2=CC(C)=CC=C2C=1C1=CC=CC=C1 JTIGKVIOEQASGT-UHFFFAOYSA-N 0.000 description 1
- 201000007183 prothrombin deficiency Diseases 0.000 description 1
- 229950001856 protizinic acid Drugs 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- WVTKBKWTSCPRNU-UHFFFAOYSA-N rac-Tetrandrin Natural products O1C(C(=CC=2CCN3C)OC)=CC=2C3CC(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2CC2N(C)CCC3=CC(OC)=C(OC)C1=C23 WVTKBKWTSCPRNU-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229950000385 ramifenazone Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 229960003394 remifentanil Drugs 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- 229950001521 rimazolium metilsulfate Drugs 0.000 description 1
- JZWFDVDETGFGFC-UHFFFAOYSA-N salacetamide Chemical compound CC(=O)NC(=O)C1=CC=CC=C1O JZWFDVDETGFGFC-UHFFFAOYSA-N 0.000 description 1
- 229950009280 salacetamide Drugs 0.000 description 1
- RLISWLLILOTWGG-UHFFFAOYSA-N salamidacetic acid Chemical compound NC(=O)C1=CC=CC=C1OCC(O)=O RLISWLLILOTWGG-UHFFFAOYSA-N 0.000 description 1
- 229950000417 salamidacetic acid Drugs 0.000 description 1
- NGFMICBWJRZIBI-UJPOAAIJSA-N salicin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=CC=C1CO NGFMICBWJRZIBI-UJPOAAIJSA-N 0.000 description 1
- 229940120668 salicin Drugs 0.000 description 1
- 229960000581 salicylamide Drugs 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- MOODSJOROWROTO-UHFFFAOYSA-N salicylsulfuric acid Chemical compound OC(=O)C1=CC=CC=C1OS(O)(=O)=O MOODSJOROWROTO-UHFFFAOYSA-N 0.000 description 1
- 229950001102 salicylsulfuric acid Drugs 0.000 description 1
- 229960000953 salsalate Drugs 0.000 description 1
- 229950010729 salverine Drugs 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- IMOLVSPMDGCLMB-UHFFFAOYSA-N simetride Chemical compound COC1=CC(CCC)=CC=C1OCC(=O)N1CCN(C(=O)COC=2C(=CC(CCC)=CC=2)OC)CC1 IMOLVSPMDGCLMB-UHFFFAOYSA-N 0.000 description 1
- 229950007670 simetride Drugs 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 229940126121 sodium channel inhibitor Drugs 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- 201000005671 spondyloarthropathy Diseases 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 1
- 229960004739 sufentanil Drugs 0.000 description 1
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 229960004492 suprofen Drugs 0.000 description 1
- 229960003755 suxibuzone Drugs 0.000 description 1
- ONWXNHPOAGOMTG-UHFFFAOYSA-N suxibuzone Chemical compound O=C1C(CCCC)(COC(=O)CCC(O)=O)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 ONWXNHPOAGOMTG-UHFFFAOYSA-N 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 229960005262 talniflumate Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- 229960003676 tenidap Drugs 0.000 description 1
- LXIKEPCNDFVJKC-QXMHVHEDSA-N tenidap Chemical compound C12=CC(Cl)=CC=C2N(C(=O)N)C(=O)\C1=C(/O)C1=CC=CS1 LXIKEPCNDFVJKC-QXMHVHEDSA-N 0.000 description 1
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- 229950002207 terofenamate Drugs 0.000 description 1
- 210000004357 third molar Anatomy 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- 229960001312 tiaprofenic acid Drugs 0.000 description 1
- HTJXMOGUGMSZOG-UHFFFAOYSA-N tiaramide Chemical compound C1CN(CCO)CCN1C(=O)CN1C(=O)SC2=CC=C(Cl)C=C21 HTJXMOGUGMSZOG-UHFFFAOYSA-N 0.000 description 1
- 229950010302 tiaramide Drugs 0.000 description 1
- 229960001402 tilidine Drugs 0.000 description 1
- PFENFDGYVLAFBR-UHFFFAOYSA-N tinoridine Chemical compound C1CC=2C(C(=O)OCC)=C(N)SC=2CN1CC1=CC=CC=C1 PFENFDGYVLAFBR-UHFFFAOYSA-N 0.000 description 1
- 229950010298 tinoridine Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229960002905 tolfenamic acid Drugs 0.000 description 1
- YEZNLOUZAIOMLT-UHFFFAOYSA-N tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
- UVITTYOJFDLOGI-KEYYUXOJSA-N trimeperidine Chemical compound C=1C=CC=CC=1[C@]1(OC(=O)CC)C[C@H](C)N(C)C[C@H]1C UVITTYOJFDLOGI-KEYYUXOJSA-N 0.000 description 1
- 229950009395 trimeperidine Drugs 0.000 description 1
- FYZXEMANQYHCFX-UHFFFAOYSA-K tripotassium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [K+].[K+].[K+].OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O FYZXEMANQYHCFX-UHFFFAOYSA-K 0.000 description 1
- UCCJWNPWWPJKGL-UHFFFAOYSA-N tropesin Chemical compound CC1=C(CC(=O)OCC(C(O)=O)C=2C=CC=CC=2)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 UCCJWNPWWPJKGL-UHFFFAOYSA-N 0.000 description 1
- 229950002470 tropesin Drugs 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229960002825 viminol Drugs 0.000 description 1
- ZILPIBYANAFGMS-UHFFFAOYSA-N viminol Chemical compound CCC(C)N(C(C)CC)CC(O)C1=CC=CN1CC1=CC=CC=C1Cl ZILPIBYANAFGMS-UHFFFAOYSA-N 0.000 description 1
- IYEPZNKOJZOGJG-UHFFFAOYSA-N xenbucin Chemical compound C1=CC(C(C(O)=O)CC)=CC=C1C1=CC=CC=C1 IYEPZNKOJZOGJG-UHFFFAOYSA-N 0.000 description 1
- 229950000707 ximoprofen Drugs 0.000 description 1
- 229950004227 zaltoprofen Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- 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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- 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
- A61K31/415—1,2-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
- A61K31/42—Oxazoles
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- 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
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Pyridine Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pyrane Compounds (AREA)
- Furan Compounds (AREA)
Abstract
本发明提供一种粉剂形式的药用组合物,其包含:(a)治疗有效量的至少一种水溶性治疗药物,所述治疗药物选自选择性COX-2抑制药物及其前体药物和盐,例如帕瑞考昔钠,所述水溶性治疗药物的总量占所述组合物的约30%至约90%(重量),(b)一种胃肠外可接受的缓冲剂,所述缓冲剂量为所述组合物的约5%至约60%(重量),以及任选(c)其它胃肠外可接受的赋形剂成分,所述赋形剂成分的总量不超过所述组合物的约10%(重量)。所述组合物可以用胃肠外可接受的溶剂液体稀释配制成注射溶液。提供一种用于制备所述组合物的冷冻干燥方法。
Description
发明领域
本发明涉及水溶性选择性环加氧酶-2(COX-2)抑制药物及其盐和前体药物,尤其是帕瑞考昔,例如其钠盐(帕瑞考昔钠)形式。帕瑞考昔是选择性COX-2抑制药物伐地考昔的水溶性前体药物。更具体地说,本发明涉及水溶性选择性COX-2抑制药物及其盐和前体药物的胃肠外给药制剂,例如注射制剂。甚至更具体地说,本发明涉及制备成为粉剂、胃肠外给药前在水性载体中稀释配制的所述制剂。本发明还涉及制备所述可稀释配制制剂的方法、应用所述制剂的治疗方法以及所述制剂在生产药物中的应用。
发明背景
环加氧酶(COX)的抑制作用据信至少是非甾体抗炎药(NSAID)通过抑制前列腺素合成而发挥其特征性抗炎、退热和镇痛效应的主要机制。治疗药物量的常规NSAID例如酮咯酸、双氯芬酸、萘普生及其盐既抑制组成型表达的COX-1,又抑制环加氧酶的炎症相关或诱导型COX-2同种型。COX-1产生正常细胞功能所需的前列腺素,抑制COX-1看起来引起与应用常规NSAID有关的某些毒副作用。与此不同,选择性抑制COX-2而基本上不抑制COX-1获得抗炎、退热、镇痛和其它有用的治疗效果,同时最小化或消除所述毒副作用。因此,在1999年首次进入市场的选择性COX-2抑制药物如塞来考昔和罗非考昔代表本领域内一大进步。这些药物配制成为多种口服给药剂型。
对于多种药物来说,胃肠外给药途径在具体情况下比口服给药提供许多好处,胃肠外给药途径包括皮下注射、肌内注射和静脉内注射。例如,胃肠外给药通常比口服给药在更短时间内获得治疗有效的药物血清浓度。静脉注射尤其如此,药物通过静脉注射直接进入血流。胃肠外给药因为消除了由于代谢、结合食物和其它原因引起的胃肠道损失,所以还导致预测性更好的药物血清浓度。出于相似原因,胃肠外给药常常允许减少剂量。胃肠外给药一般是紧急情况下的优选给药方法,并且也用于治疗不配合、昏迷或在其它情况下不能或不愿接受口服药物的患者。
市场上注射形式的NSAID相对较少。胃肠外应用的非选择性NSAID如酮咯酸氨丁三醇盐是有效的镇痛药,但与所述非选择性NSAID的典型副作用有关。这些副作用包括上胃肠道溃疡和出血,在老年患者中尤其如此;肾功能减退,这可能导致液体潴留和高血压加重;以及抑制血小板功能,这可能使患者倾向于出血增多,例如在手术期间。所述副作用已经严重限制非选择性NASID胃肠外制剂的应用。
因此,假如能够提供选择性COX-2抑制药物的胃肠外给药制剂,这将是本领域内的另一个显著进步。
已知通过真空冷冻干燥(冻干)治疗药物的水溶液的方法制备胃肠外制剂。参见例如
Remington:The Science and Practice of Pharmacy,第19版(1995),Mack Publishing,第1544-1546页,根据
Remington,当治疗药物的量非常少时,通常向治疗药物中加入赋形剂以增加固体量,以便使获得的粉剂更容易看到。“一些人认为理想情况是干燥产品填料占据与原始溶液基本相同的体积。为达到此目的,原始产品的固体含量必须在约5%到25%之间。为此,最有用的物质是磷酸钠或磷酸钾、柠檬酸、酒石酸、明胶和糖类如葡萄糖、甘露醇和葡聚糖,这些物质通常组合应用。”
Remington,在上述引文中。
在Talley等的美国专利第5,932,598号中公开的帕瑞考昔是选择性COX-2抑制药物的水溶性前体药物类中的一种。给予患者帕瑞考昔后,帕瑞考昔快速转化成为实质上水不溶性的选择性COX-2抑制药物伐地考昔。帕瑞考昔暴露于水时,例如溶解于水时,也转化为伐地考昔。帕瑞考昔尤其是帕瑞考昔的盐如钠盐的水溶解度比大多数选择性COX-2抑制药物如塞来考昔和伐地考昔要高,这引起人们开发帕瑞考昔用于胃肠外应用的兴趣。具有下面结构式(I)的帕瑞考昔,其本身显示对COX-1和COX-2的弱体外抑制活性,而伐地考昔(II)对COX-2有强抑制活性,但却是COX-1的弱抑制剂。
已知其它水溶性选择性COX-2抑制药物和前体药物。例如,Carter等的美国专利第6,034,256号公开了一系列据说可用作选择性COX-2抑制药物的水溶性苯并吡喃,包括化合物(S)-6,8-氯-2-(三氟甲基)-2H-1-苯并吡喃-3-羧酸(III)及其盐。
虽然已经概括地提议使用这些和其它选择性COX-2抑制药物和前体药物用于胃肠外给药,但至今还没有描述所述药物或前体药物的药学上可接受的注射制剂。如下面的公开内容以帕瑞考昔为例所清楚陈述的,许多问题困扰试图制备所述制剂的配方设计师。本发明提供这些问题的解决方案。
发明简述
在一个实施方案中,现在提供粉剂形式的药用组合物,所述药用组合物包含(a)治疗有效量的至少一种选自选择性COX-2抑制药物及它们的前体药物和盐的水溶性治疗药物,所述治疗药物的总量占所述组合物的约30%至约90%(重量),(b)胃肠外可接受的缓冲剂,所述缓冲剂量为所述组合物的约5%至约60%(重量),以及任选(c)其它胃肠外可接受的赋形剂成分,所述赋形剂成分的总量不超过所述组合物的约10%(重量)。所述组合物可以在胃肠外可接受的溶剂液体(优选水性液体)中稀释配制,形成注射溶液。
可以通过下述方法制备上述组合物,所述方法包括下述步骤:冻干包含所述治疗药物、所述缓冲剂以及任选的其它赋形剂成分的水溶液,形成可以容易地稀释配制的粉剂;所述方法代表本发明的另一个实施方案。
本发明的再一个实施方案是通过稀释配制所述组合物而制备的注射溶液。
本发明的又一个实施方案是一种制成品,该制成品包括在无菌条件下装入单位剂量的所述组合物的密封小瓶。
本发明的另一个实施方案是一种治疗或预防患者的COX-2介导的疾病或紊乱的方法,所述方法包括(a)在生理可接受体积的胃肠外可接受溶剂液体中稀释配制单位剂量所述组合物,形成注射溶液,和(b)将所述溶液通过胃肠外途径注射到患者体内。
在所有上面的实施方案中,尤其优选的治疗药物是帕瑞考昔的水溶性盐。惊人的是,发现帕瑞考昔在胃肠外给药时通过转化为伐地考昔而表现实质上与等剂量伐地考昔本身相等的抗炎和镇痛效果。因此,根据本发明的又一实施方案,提供一种治疗或预防患者的COX-2介导性疾病或紊乱的方法,所述方法包括胃肠外给予所述患者帕瑞考昔或其盐,所给予的帕瑞考昔剂量在摩尔量上等于伐地考昔的治疗有效剂量。
本发明的又一实施方案是制成品,所述制成品包括其中装有无菌、可胃肠外给药的组合物的密封小瓶,所述组合物包含帕瑞考昔或其盐,帕瑞考昔剂量等于伐地考昔的治疗有效剂量。
附图简述
图1陈述从实施例3的人体药物动力学研究获得的数据,数据显示在(a)静脉内(IV)注射1ml药团(bolus)内的20mg帕瑞考昔;以及(b)口服给予配制成为速释片剂的20mg伐地考昔后,从0小时到72小时的平均伐地考昔血浆浓度。
发明详述
本发明的药用组合物包含作为治疗药物的以下组分:
(a)水溶性选择性COX-2抑制药物;
(b)选择性COX-2抑制药物的水溶性盐,而不论所述药物本身是否是水溶性的;
(c)选择性COX-2抑制药物的水溶性前体药物,而不论所述药物本身是否是水溶性的;
(d)选择性COX-2抑制药物的前体药物的水溶性盐,而不论所述前体药物本身是否是水溶性的。
在所述组合物中可以存在一种以上所述治疗药物,但一般优选仅包括一种所述选择性COX-2抑制药物或其前体药物或盐。包含选择性COX-2抑制药物的前体药物或所述药物或前体药物的盐的组合物可以包含少量所述药物本身,例如在假如所述前体药物或盐在生产、贮存、处理或使用时容易地转化为所述药物的情况下。
术语“水溶性”当在本文中应用于治疗药物时,指在患者体内治疗有效量的所述试剂在20-25℃和胃肠外可接受的pH下可溶于水,所述水的体积少于胃肠外给予患者单一剂量可接受的最大体积。优选治疗药物的溶解度在20℃和pH 7.4的水中溶解度大于约0.1mg/ml。更优选的治疗药物在20℃和pH 7.4的水中溶解度大于约0.5mg/ml。
本文应用的选择性COX-2抑制药物或者本文应用的前体药物或盐在体内所转化成为的选择性COX-2抑制药物表现相对于COX-1对COX-2的选择性抑制,选择性系数至少50,优选至少100。所述药物包括但不限于下面所列专利和出版物中公开的化合物,下面所列的每项专利和出版物都单独通过引用结合到本文中。
Reitz和Li的美国专利第5,344,991号。
Norman等的美国专利第5,380,738号。
Reitz等的美国专利第5,393,790号。
Lee的美国专利第5,401,765号。
Huang和Reitz的美国专利第5,418,254号。
Koszyk和Weier的美国专利第5,420,343号。
Talley和Rogier的美国专利第5,434,178号。
Black等的美国专利第5,436,265号。
Talley等的美国专利第5,466,823号。
Ducharme等的美国专利第5,474,995号。
Lee和Bertenshaw的美国专利第5,475,018号。
Lee等的美国专利第5,486,534号。
Lau等的美国专利第5,510,368号。
Prasit等的美国专利第5,521,213号。
Ducharme等的美国专利第5,536,752号。
Cromlish等的美国专利第5,543,297号。
Talley等的美国专利第5,547,975号。
Ducharme等的美国专利第5,550,142号。
Gauthier等的美国专利第5,552,422号。
Desmond等的美国专利第5,585,504号。
Adams等的美国专利第5,593,992号。
Lee的美国专利第5,596,008号。
Lau等的美国专利第5,604,253号。
Guay和Li的美国专利第5,604,260号。
Lipsky等的美国专利第5,616,458号。
Khanna等的美国专利第5,616,601号。
Weier等的美国专利第5,620,999号。
Talley等的美国专利第5,633,272号。
Lau等的美国专利第5,639,780号。
Talley等的美国专利第5,643,933号。
Adams等的美国专利第5,658,903号。
Talley等的美国专利第5,668,161号。
Huang和Reitz的美国专利第5,670,510号。
Lau的美国专利第5,677,318号。
Dellaria和Gane的美国专利第5,681,842号。
Nicolai等的美国专利第5,686,460号。
Weier等的美国专利第5,686,470号。
Talley等的美国专利第5,696,143号。
Ducharme等的美国专利第5,710,140号。
Adams等的美国专利第5,716,955号。
Güngr和Teulon的美国专利第5,723,485号。
Reitz等的美国专利第5,739,166号。
Lazer等的美国专利第5,741,798号。
Adams等的美国专利第5,756,499号。
Isakson和Talley的美国专利第5,756,529号。
Kreft等的美国专利第5,776,967号。
Beers和Wachter的美国专利第5,783,597号。
Black等的美国专利第5,789,413号。
Nicolai和Teulon的美国专利第5,807,873号。
Dube等的美国专利第5,817,700号。
Failli等的美国专利第5,830,911号。
Atkinson和Wang的美国专利第5,849,943号。
Sartori等的美国专利第5,859,036号。
Dube等的美国专利第5,861,419号。
Sartori和Teulon的美国专利第5,866,596号。
Failli的美国专利第5,869,524号。
Adams等的美国专利第5,869,660号。
Rossen等的美国专利第5,883,267号。
Zhi等的美国专利第5,892,053号。
Black等的美国专利第5,922,742号。
Adams和Garigipati的美国专利第5,929,076号。
上面引用的美国专利第5,932,598号
Khanna等的美国专利第5,935,990号。
Haruta等的美国专利第5,945,539号。
Yamazaki等的美国专利第5,958,978号。
Guay等的美国专利第5,968,958号。
Nicolai和Teulon的美国专利第5,972,950号。
Mamett和Kalgutkar的美国专利第5,973,191号。
Belley等的美国专利第5,981,576号。
Haruta等的美国专利第5,994,381号。
Haruta等的美国专利第6,002,014号。
Li等的美国专利第6,004,960号。
Hopper等的美国专利第6,005,000号。
Belley等的美国专利第6,020,343号。
DeLaszlo和Hagmann的美国专利第6,020,347号。
上面引用的美国专利第6,034,256。
Corley等的美国专利第6,040,319号。
Davies等的美国专利第6,040,450号。
Adams等的美国专利第6,046,208号。
Friesen等的美国专利第6,046,217号。
Black等的美国专利第6,057,319号。
De Nanteuil等的美国专利第6,063,804号。
Chabrier de Lassauniere和Broquet的美国专利第6,063,807号。
LeBlanc等的美国专利第6,071,954号。
Cook等的美国专利第6,077,868号。
Sui和Wachter的美国专利第6,077,869号。
Ferro等的美国专利第6,083,969号。
Spohr等的美国专利第6,096,753号。
Wang等的美国专利第6,133,292号。
国际专利公布号WO 94/15932。
国际专利公布号WO 96/19469。
国际专利公布号WO 96/26921。
国际专利公布号WO 96/31509。
国际专利公布号WO 96/36623。
国际专利公布号WO 96/38418。
国际专利公布号WO 97/03953。
国际专利公布号WO 97/10840。
国际专利公布号WO 97/13755。
国际专利公布号WO 97/13767。
国际专利公布号WO 97/25048。
国际专利公布号WO 97/30030。
国际专利公布号WO 97/34882。
国际专利公布号WO 97/46524。
国际专利公布号WO 98/04527。
国际专利公布号WO 98/06708。
国际专利公布号WO 98/07425。
国际专利公布号WO 98/17292。
国际专利公布号WO 98/21195。
国际专利公布号WO 98/22457。
国际专利公布号WO 98/32732。
国际专利公布号WO 98/41516。
国际专利公布号WO 98/43966。
国际专利公布号WO 98/45294。
国际专利公布号WO 98/47871。
国际专利公布号WO 99/01130。
国际专利公布号WO 99/01131。
国际专利公布号WO 99/01452。
国际专利公布号WO 99/01455。
国际专利公布号WO 99/10331。
国际专利公布号WO 99/10332。
国际专利公布号WO 99/11605。
国际专利公布号WO 99/12930。
国际专利公布号WO 99/14195。
国际专利公布号WO 99/14205。
国际专利公布号WO 99/15505。
国际专利公布号WO 99/23087。
国际专利公布号WO 99/24404。
国际专利公布号WO 99/25695。
国际专利公布号WO 99/35130。
国际专利公布号WO 99/61016。
国际专利公布号WO 99/61436。
国际专利公布号WO 99/62884。
国际专利公布号WO 99/64415。
国际专利公布号WO 00/01380。
国际专利公布号WO 00/08024。
国际专利公布号WO 00/10993。
国际专利公布号WO 00/13684。
国际专利公布号WO 00/18741。
国际专利公布号WO 00/18753。
国际专利公布号WO 00/23426。
国际专利公布号WO 00/24719。
国际专利公布号WO 00/26216。
国际专利公布号WO 00/31072。
国际专利公布号WO 00/40087。
国际专利公布号WO 00/56348。
欧洲专利申请号0 799 823。
欧洲专利申请号0 846 689。
欧洲专利申请号0 863 134。
欧洲专利申请号0 985 666。
本文使用的优选选择性COX-2抑制药物、或本文使用的前体药物或盐在体内被转化成为的选择性COX-2抑制药物是式(IV)的化合物:
其中:
A是取代基,选自部分不饱和或不饱和的杂环基以及部分不饱和或不饱和的碳环,优选杂环基选自吡唑基、呋喃酮基、异噁唑基、吡啶基、环戊烯酮基和哒嗪酮基;
X是O、S或CH2;
n是0或1;
R1是至少一个取代基,选自杂环基、环烷基、环烯基和芳基,并任选在可取代位置上被一个或多个基团取代,所述基团选自烷基、卤烷基、氰基、羧基、烷氧羰基、羟基、羟烷基、卤烷氧基、氨基、烷基氨基、芳基氨基、硝基、烷氧基烷基、烷基亚硫酰基、卤、烷氧基和烷硫基;
R2是甲基、氨基或氨羰基烷基;
R3是一个或多个选自以下的基团:氢基(hydrido)、卤、烷基、链烯基、链炔基、氧代基、氰基、羧基、氰烷基、杂环氧基、烷氧基、烷硫基、烷羰基、环烷基、芳基、卤烷基、杂环基、环烯基、芳烷基、杂环基烷基、酰基、烷硫基烷基、羟烷基、烷氧羰基、芳羰基、芳烷羰基、芳链烯基(aralkenyl)、烷氧基烷基、芳基硫代烷基、芳氧基烷基、芳烷基硫代烷基、芳烷氧基烷基、烷氧基芳烷氧基烷基、烷氧羰基烷基、氨羰基、氨基羰基烷基、烷基氨基羰基、N-芳基氨基羰基、N-烷基-N-芳基氨基羰基、烷基氨基羰基烷基、羧基烷基、烷基氨基、N-芳基氨基、N-芳烷基氨基、N-烷基-N-芳烷基氨基、N-烷基-N-芳基氨基、氨基烷基、烷基氨基烷基、N-芳基氨基烷基、N-芳烷基氨基烷基、N-烷基-N-芳烷基氨基烷基、N-烷基-N-芳基氨基烷基、芳氧基、芳烷氧基、芳基硫代、芳烷基硫代、烷基亚硫酰基、烷基磺酰基、氨基磺酰基、烷基氨基磺酰基、N-芳基氨基磺酰基、芳基磺酰基和N-烷基-N-芳基氨基磺酰基,R3任选地在可取代位置上被一个或多个选自以下的基团取代:烷基、卤烷基、氰基、羧基、烷氧基羰基、羟基、羟烷基、卤烷氧基、氨基、烷基氨基、芳基氨基、硝基、烷氧基烷基、烷基亚硫酰基、卤、烷氧基和烷硫基;和
R4选自氢基和卤。
本发明的组合物尤其用于具有式(V)的选择性COX-2抑制药物的水溶性盐、前体药物和前体药物的盐、或其同分异构体或互变异构体:
其中R5是甲基或氨基,R6是氢或C1-4烷基或烷氧基,X′是N或CR7,其中R7是氢或卤素,而Y和Z独立地是碳原子或氮原子,它们限定五元环或六元环的相邻原子,所述五元环或六元环任选地在一个或多个位置上被氧代基、卤、甲基或卤甲基取代。优选的所述五元环或六元环是仅在一个位置上取代的环戊烯酮、呋喃酮、甲基吡唑、异噁唑和吡啶环。
例如,本发明的组合物适于塞来考昔、地拉考昔、伐地考昔、罗非考昔、艾托考昔、2-(3,5-二氟苯基)-3-[4-(甲磺酰基)苯基]-2-环戊烯-1-酮和2-(3,4-二氟苯基)-4-(3-羟基-3-甲基-1-丁氧基)-5-[4-(甲磺酰基)苯基]-3-(2H)-哒嗪酮,最优选伐地考昔。可用于本发明组合物的尤其有用的伐地考昔的前体药物是帕瑞考昔,更优选其水溶性盐,例如帕瑞考昔钠。
在本发明的组合物和方法中使用的帕瑞考昔可以用例如上面引用的美国专利第5,932,598中陈述的方法制备。
本发明的组合物也可用于具有式(VI)的化合物及其药学上可接受的盐:
其中X″是O、S或N-低级烷基;R8是低级卤烷基;R9是氢或卤素;R10是氢、卤素、低级烷基、低级烷氧基或卤烷氧基、低级芳烷基羰基、低级二烷基氨基磺酰基、低级烷基氨基磺酰基、低级芳烷基氨基磺酰基、低级杂芳烷基氨基磺酰基或5元或6元含氮杂环磺酰基;R11和R12独立地是氢、卤素、低级烷基、低级烷氧基或芳基。
尤其有用的式(VI)的化合物是(S)-6,8-二氯-2-(三氟甲基)-2H-1-苯并吡喃-3-羧酸,尤其是其水溶性盐形式,例如钠盐。该化合物可以用例如上面引用的美国专利第6,034,256中陈述的方法制备。
在本发明可稀释配制粉剂组合物中存在一种或多种选自以上的治疗药物,其总量以重量计占所述组合物的约30%至约90%,优选约40%至约85%,更优选约50%至约80%。
所述缓冲剂一般是主要的赋形剂成分,其量以重量计占所述组合物的约5%至约60%,优选约10%至约60%,更优选约20%至约50%。在本发明的一个实施方案中,所述可稀释配制粉剂组合物基本上由所述治疗药物和所述缓冲剂组成。
选择所述缓冲剂使得在用生理可接受体积的胃肠外可接受溶剂液体稀释配制时提供所述组合物的pH,所述缓冲剂(a)胃肠外可接受,(b)与完全在所述溶剂液体的溶液内的所述治疗药物一致,以及(c)提供介质,所述治疗药物在稀释配制后表现出可接受的化学稳定性至少约1小时。合适的缓冲剂例如可以选自磷酸钠和磷酸钾、柠檬酸钠和柠檬酸钾、乙醇胺、二乙醇胺和三乙醇胺、2-氨基-2-(羟甲基)-1,3-丙二醇(氨丁三醇)等以及它们的混合物。优选的缓冲剂是磷酸氢二钠和磷酸氢二钾以及氨丁三醇。特别优选的缓冲剂是磷酸氢二钠,例如无水磷酸氢二钠、七水合磷酸氢二钠、十二水合磷酸氢二钠等。
在一个实施方案中,所述组合物稀释配制后pH约7至约9,优选约7.5至约8.5,例如约8。如果需要,在所述组合物中除包括所述缓冲剂外,还可以包括少量酸(如磷酸)和/或碱(如氢氧化钠),以调节pH。
除所述缓冲剂(如果存在的话)外的赋形剂在稀释配制前占所述组合物的不超过约10%(重量),优选不超过约5%(重量)。本文的术语“赋形剂”包括除水外所述组合物的所有非治疗活性成分。在本发明的一个实施方案中,基本不存在除所述缓冲剂以外的赋形剂。
惊人的是,已经发现重要的是在所述组合物中包括不超过约10%(重量)、优选不超过约5%(重量)、最优选基本不包括除缓冲剂外通常在可稀释配制胃肠外制剂中用作膨胀剂的成分。尤其是优选所述组合物不包含广泛使用的膨胀剂甘露醇,或者如果包括甘露醇,其存在的量占所述组合物的不超过约10%(重量),优选不超过5%(重量)。根据本发明,相信通过最小化作为所述组合物成分的所述膨胀剂尤其是甘露醇的量,或者完全排除所述膨胀剂尤其是甘露醇用作所述组合物的成分,能够保证所述治疗药物可接受的化学稳定性。
任选地可以在所述组合物中包括至多约0.5%(重量)的一种或多种防腐剂。合适的防腐剂的例子包括羟苯甲酯、羟苯丙酯、苯酚和苯甲醇。
本发明的可稀释配制粉剂组合物优选包含少于约5%、更优选少于约2%、最优选少于约1%(重量)的水。通常水分含量约0.5%至约1%(重量)。在所述治疗药物有在水的存在下降解或转化为较不可溶形式的趋势的情况下,保持水分含量在该低水平特别重要。本发明的粉剂组合物在封口小瓶内贮存于室温(约20-25℃)时所述治疗药物可接受的化学稳定性至少约30天,优选至少约6个月,最优选至少约2年。
本文中“可接受的化学稳定性”指所述组合物在确定时间长度(如约30天、约6个月或约2年)后,通过所述治疗药物化学纯度的标准试验,例如管理当局批准所需的测试。所述测试的一个例子是“总共5%,单一杂质1%的规则”,即候选药物的制备物必须不含有超过总共5%的杂质,并且任一单一杂质不超过1%。
在所述治疗药物是帕瑞考昔的情况下,例如采取帕瑞考昔钠的形式,过一段时间后组合物内可能出现部分转化为伐地考昔。因为伐地考昔本身在治疗上是有活性的选择性COX-2抑制药物(事实上帕瑞考昔的治疗功效依赖于在体内转化为伐地考昔),所以所述转化并不导致治疗效果的损失。然而,因为伐地考昔在水中溶解度非常低,所以需要在稀释配制前最小化所述转化,以便能够保证所述治疗药物的完全溶解。在计划用于胃肠外给药的溶液中,通常不希望存在颗粒,例如由于存在相当大数量的伐地考昔而产生的颗粒。
惊人的是,发现通过从所述组合物中减少或优选排除膨胀剂如甘露醇,可以极大减少可稀释配制粉剂组合物内帕瑞考昔到伐地考昔的转化。这在下面的实施例1和2中举例说明。如实施例1所述,除缓冲剂外具有不超过10%(重量)赋形剂的本发明的组合物表现出非常高水平的帕瑞考昔化学稳定性,而如实施例2所述,除缓冲剂外含有较高水平赋形剂的组合物表现出更大程度的帕瑞考昔到伐地考昔的转化。
本发明的另一实施方案是注射溶液组合物,通过用胃肠外可接受的溶剂稀释配制如本文提供的粉剂组合物而制备所述注射溶液组合物,所述溶剂优选水性溶剂。在所述溶液组合物中,所述治疗药物的化学稳定性有限,在这种情况下优选给药前在短时间内稀释配制所述组合物,例如给药前约1小时内。在其它情况下所述治疗药物可能在溶液中表现出相对高水平的化学稳定性,在这样的情况下,稀释配制后在短时间内给药不是关键的。
在所述治疗药物是帕瑞考昔的情况下,例如采取帕瑞考昔钠的形式,在水溶液内一段时间后可能出现部分转化为高度不溶性的伐地考昔,导致形成固体颗粒。如上文指出的,在注射制剂中一般不希望存在固体颗粒;因此,在本发明帕瑞考昔组合物的具体情况下,优选稀释配制后在短时间内给予注射溶液,例如在稀释配制后约1小时内。
通过维持水性介质处于约7或更高的pH,可以极大降低所述介质中帕瑞考昔到伐地考昔的转化率。此外,帕瑞考昔钠本身在水中的溶解度受到pH的强烈影响。例如,20℃下平衡溶解度从pH 7.3的1.0mg/ml升到pH 7.8的18mg/ml,然后升到pH 8.2的220mg/ml。在更高浓度下也可以制备帕瑞考昔钠的过饱和溶液。提供生理可接受性、良好的短期化学稳定性以及良好的帕瑞考昔钠溶解度的优选pH范围是约7.5至约8.5,更优选约7.8至约8.2,例如约8.0。
可以使用任何已知的胃肠外可接受的溶剂液体稀释配制本发明的粉剂组合物。注射用水适用,但通常提供低渗溶液。因此,通常优选法使用包含如葡萄糖或氯化钠等溶质的水性液体。举例来说,适用的有0.9%注射用氯化钠USP、制菌性0.9%注射用氯化钠USP、5%注射用葡萄糖USP以及注射用5%葡萄糖和0.45%氯化钠USP。乳酸化林格氏注射液USP较不合适,至少在所述治疗药物是帕瑞考昔钠的情况下如此,因为有形成晶体的趋势。
用于稀释配制的所述溶剂液体的合适体积取决于患者的年龄和体重、所述治疗药物的溶解度和给药量以及其它因素,但合适的体积一般从约0.25ml至约5ml,优选约0.5ml至约2ml。例如,在帕瑞考昔钠的情况下,20mg剂量一般能够在约1ml任何上述溶剂液体中方便地稀释配制,而40mg剂量通常适用2ml所述溶剂液体体积。
本发明的粉剂组合物最好具有足够的空隙度,以允许所述治疗药物在所述溶剂液体中稀释配制时能够快速溶解。使用如下文所述制备所述粉剂的方法,能够获得高度空隙度。所述方法是本发明的另一实施方案,在本文中专门就帕瑞考昔钠和七水合磷酸氢二钠进行描述;然而,技术人员知道可以按照本发明容易地将所述方法应用于其它治疗药物和/或其它缓冲剂。
在该方法中,将帕瑞考昔钠和作为缓冲剂的七水合磷酸氢二钠溶于水中,形成水溶液。最好使用注射用水作为溶剂。帕瑞考昔钠和所述缓冲剂在所述溶液中相互之间的相对浓度与这些成分在最终组合物中的所需相对浓度一致。这些成分的绝对浓度并不是关键的;然而,考虑到工艺效率,通常优选帕瑞考昔钠的浓度尽量高到可以方便制备并且没有超过溶解度限制的风险。如果需要,可以在该步骤中加入其它制剂成分。加入顺序不是关键的,但强烈优选最后加入帕瑞考昔钠以保证快速而完全的溶解。
任选但优选将所述溶液除菌,例如通过一个或多个除菌滤器,然后定量分装进一个或多个小瓶。每个小瓶容纳定量容积的溶液,所述溶液包含所需单位剂量帕瑞考昔钠。在小瓶上放置冷冻干燥塞子,所述冷冻干燥塞子上有允许升华的开口。最好所述小瓶和塞子是无菌的,并且在无菌操作条件下进行灌注。
然后将所述塞上塞子的小瓶置于冷冻干燥室内,并冷冻干燥所述小瓶的内容物,最好以三个阶段循环进行冷冻干燥。
在所述冷冻干燥循环的第一阶段,冷冻每个小瓶内的溶液到低于所述溶液玻璃态化温度以下的温度。对于包含帕瑞考昔钠和磷酸氢二钠的本发明组合物,玻璃态化温度是约-20℃。可以通过本领域已知的任何技术测量玻璃态化温度,例如通过应用冻干显微镜或通过测量电阻。该冷冻阶段的合适温度一般是约-30℃至约-60℃,例如约-40℃至约-50℃。从室温逐渐降低温度到所需冷冻温度,一般在约1小时至约5小时的时间内,更一般约2小时至约4小时。然后保持温度在所述冷冻温度,一般保持约0.5小时至约24小时的时间,更一般约0.75小时至约3小时。
在优选冷冻干燥过程的冷冻阶段中,温度首先从室温相当快速地降至约-20℃,例如在约0.25小时至约1小时、更优选约0.5小时至约0.75小时的时间内完成降温。然后更进一步将温度逐渐从约-20℃降至约-30℃,例如在约1小时至约4小时、更优选约1.5小时至约3小时的时间内完成降温。虽然不希望受理论的束缚,但是相信这种逐渐降温保证溶液完全冷冻。然后相当快速地将温度从约-30℃降到最终的冷冻温度,所述最终冷冻温度最好是约-40℃,例如在约0.1小时至约1小时、更优选约0.25小时至约0.5小时的时间内完成降温。已经发现如上所述的分步冷冻阶段往往提供看起来没有裂缝的固体的冻干终产品。
在所述冷冻干燥循环的第二阶段中,在所述冷冻干燥室内抽真空,实现冻干。该阶段在本文中被描述为“第一个干燥”阶段。一般合适的真空是约25至约500μmHg(约25至约500毫托),优选约50至约300μmHg。在该第一个干燥阶段期间,逐渐升高温度,任选在温度保持恒定的各个时间段之间升高温度。优选用氮气吹扫维持真空。在该阶段期间冰从冷冻溶液中升华,形成部分干燥的饼状物。
在优选冷冻干燥过程的第一个干燥阶段内,首先在约1小时至约5小时、优选约2小时至约4小时的时间内将温度从冷冻温度(如约-40℃)升至约0℃,然后在约0℃保持相当长的一段时间,例如约6小时至约12小时,优选约8小时至约10小时。最好在所述第一个干燥阶段期间使用约150至约300μmHg的真空。
在所述冷冻干燥循环的第三阶段,在真空下完成干燥。该阶段在本文中被描述为“第二个干燥阶段”。同样通常适用约25至约500μmHg、优选约50至约300μmHg的真空,最好在氮气吹扫下维持真空。在该第二个干燥阶段期间升高温度,最好升高到室温以上水平,例如约40℃,去除剩余的水分,提供水分含量低于约5%、优选低于约2%、更优选低于约1%(重量)的粉剂。
在优选冷冻干燥过程的第二干燥阶段中,在约1小时至约4小时、优选约1.5小时至约3小时的时间内将温度从约0℃升高至约40℃,然后在约40℃保持约3小时至约12小时,优选约4小时至约8小时。在所述第二干燥阶段期间最好使用约150至约300μmHg的真空。任选在所述第二干燥阶段的最后阶段,当温度维持在约40℃时,将真空降低至约25至约75μmHg。
全部冷冻干燥循环时间一般是约18小时至约36小时。延长循环时间通常不损害对终产品的质量,但增加工艺成本。根据本文提供的信息,通过常规测试能够发现产品质量和工艺经济学的最佳组合,所述最佳组合根据几个因素而有所不同,这些因素包括使用的具体冷冻干燥设备、冻干溶液内成分的准确组成和浓度、选定的治疗药物和缓冲剂等等。然而,一般而言,发现适用约18小时至约24小时的循环时间。在使用磷酸氢二钠作为缓冲剂的帕瑞考昔钠组合物的情况下,已经发现缩短循环时间到实质上少于约18小时(例如到16.5小时)导致终产品收缩的发生率增加,而这不利于稀释配制时所需的快速溶解。
完成所述冷冻干燥循环后,释放真空,并使温度回到室温。随后为所述小瓶加盖、封口,防止从空气中再吸收水分并且维持无菌。
本发明的再一实施方案是一种制成品,所述制成品包括密封小瓶,最好是玻璃小瓶,所述小瓶在无菌条件下装入单位剂量的本文所述粉剂组合物。在一个具体实施方案中,提供用上文所述方法制备的所述制成品。所述小瓶最好具有足以允许原位稀释配制所述组合物的容积。一般而言,方便使用约1ml至约10ml、优选约2ml至约5ml的容积。
本文术语“小瓶”用来指任何小容器,所述小容器有盖,适于包装单位剂量的可稀释配制的粉剂,最好是在无菌条件下包装。技术人员知道本发明的该实施方案包括包装的等同形式,例如安瓿、一次性注射器和注射器药筒。
任选地所述小瓶包括两个区室,一个区室容纳所述可稀释配制粉剂,一个区室容纳足以溶解所述粉剂的溶剂液体。在所述小瓶中,通过一个孔相互连接所述两个区室,在所述孔上可以使用一个塞子,防止所述粉剂与所述溶剂液体的接触直到准备使用所述小瓶。当使用时,通过任何合适的工具分开或刺穿所述塞子,使所述液体接触所述粉剂。所述合适的工具例如一种装置,例如施加压力或驱动针头穿过所述塞子的柱塞。所述多区室小瓶的例子包括用于注射器的双室药筒或例如使用Pharmacia Corporation的以商标Act-O-Vial销售的双室小瓶。
适于制备和或置于小瓶内、形成本发明制成品的本发明粉剂组合物的单位剂量是这样的量:当胃肠外给予患有COX-2介导的病症或疾病的患者所述量治疗药物时,足以提供治疗益处。例如,在本发明帕瑞考昔钠组合物的情况下,合适的单位剂量一般包含约1mg至约200mg、优选约5mg至约120mg、更优选约10mg至约100mg、例如约20mg、约40mg或约80mg帕瑞考昔。当所述治疗药物不是帕瑞考昔时,合适单位剂量是在治疗上等同于上面指示剂量范围内的帕瑞考昔的量。
本发明的组合物用于治疗和预防各种各样的由COX-2介导性疾病,包括但不限于特征为炎症、疼痛和/或发热的疾病。所述组合物尤其可用作抗炎药,例如用于治疗关节炎,其额外的好处是有害副作用明显少于缺乏对COX-2的选择性优于对COX-1的选择性的常规NSAID组合物。具体地说,本发明组合物与常规NSAID组合物相比,胃肠毒性和胃肠刺激的潜力降低,所述胃肠毒性和胃肠刺激包括胃肠上部溃疡和出血。因此,在禁忌常规NSAID的情况下,本发明组合物尤其可用作所述NSAID的替代物,所述禁忌常规NSAID的情况例如患有消化性溃疡、胃炎、局限性肠炎、溃疡性结肠炎、憩室炎或有胃肠损害复发史的患者;患有胃肠出血、凝结疾病的患者,所述胃肠出血、凝结疾病包括贫血,例如血凝血酶原过少、血友病或其它出血问题;肾病患者;或手术前患者或摄入抗凝药的患者。
设想的组合物用于治疗多种关节炎疾病,包括但不限于类风湿性关节炎、脊椎关节病、痛风性关节炎、骨关节炎、系统性红斑狼疮以及青少年关节炎。
所述组合物用于治疗哮喘、支气管炎、月经性痉挛、早产、腱炎、粘液囊炎、变应性神经炎、巨细胞病毒感染、细胞凋亡(包括HIV诱导的细胞凋亡)、腰痛、肝病(包括肝炎)、皮肤相关疾病(例如银屑病、湿疹、痤疮、烧伤、皮炎和紫外辐射损伤(包括晒斑))以及术后炎症(包括眼科手术后的炎症,所述眼科手术例如白内障手术或屈光手术)。
所述组合物用于治疗胃肠病症,例如炎性肠病、局限性回肠炎、胃炎、过敏性肠综合征和溃疡性结肠炎。
所述组合物用于治疗下面疾病中的炎症:偏头痛、动脉外膜炎结节、甲状腺炎、再生障碍性贫血、霍奇金病、硬皮病(sclerodoma)、风湿性发热、I型糖尿病、神经肌肉接头病(包括重症肌无力)、白质病(包括多发性硬化)、结节病、肾病综合征、贝赫切特综合征、多肌炎、龈炎、肾炎、过敏反应、损伤后出现的肿胀包括脑浮肿、心肌缺血等等。
所述组合物用于治疗眼病,包括但不限于下面炎症疾病:眼内炎、巩膜外层炎、视网膜炎、虹膜炎、睫状体炎、脉络膜炎、角膜炎、结膜炎和睑炎,眼睛一个部分以上的炎症疾病,如视网膜脉络膜炎、虹膜睫状体炎、虹膜睫状体脉络膜炎(也称为眼色素层炎)、角结膜炎、睑结膜炎等;其它COX-2介导的视网膜病,包括糖尿病性视网膜病;眼畏光;眼睛任何组织的急性损伤,包括术后损伤,如白内障手术或角膜移植手术后的急性损伤;术后眼部炎症;手术中的瞳孔缩小;角膜移植物排斥;眼的新血管形成,例如视网膜新血管形成,包括在损伤或感染后出现的新血管形成;黄斑变性;囊状黄斑水肿;晶状体后纤维组织形成;新血管形成性青光眼(neovascularglaucoma);以及眼痛。
所述组合物用于治疗肺部炎症,例如与病毒感染和囊性纤维变性有关的肺部炎症,以及用于骨吸收,例如与骨质疏松有关的骨吸收。
所述组合物用于治疗某些中枢神经系统疾病,例如皮质痴呆包括阿尔茨海默病、神经变性以及由于中风、局部缺血和创伤导致的中枢神经系统损害。术语“治疗”在本文中包括对痴呆的部分或完全抑制,所述痴呆包括阿尔茨海默病、血管性痴呆、多梗死性痴呆、早老性痴呆、酒精性痴呆和老年性痴呆。
所述组合物用于治疗过敏性鼻炎、呼吸窘迫综合征、内毒素休克综合征和肝病。
所述组合物用于治疗疼痛,包括但不限于术后疼痛、牙痛、肌肉痛和癌症引起的疼痛。例如,所述组合物用于缓解多种病症中的疼痛、发热和炎症,所述病症包括风湿性发热、流感和其它病毒感染包括普通感冒、腰背痛和颈痛(low back and neck pain)、痛经、头痛、牙痛、扭伤和劳损、肌炎、神经痛、滑膜炎、关节炎包括类风湿性关节炎、退化性关节病(骨关节炎)、痛风和强直性脊椎炎、粘液囊炎、烧伤以及外科和牙科手术后的损伤。
所述组合物用于治疗和预防炎症相关心血管病,包括血管病、冠状动脉病、动脉瘤、血管排斥、动脉硬化、动脉粥样硬化包括心脏移植物动脉粥样硬化、心肌梗塞、栓塞、中风、血栓形成包括静脉血栓形成、心绞痛包括不稳定心绞痛、冠状动脉斑炎症、细菌引起的炎症包括衣原体引起的炎症、病毒引起的炎症以及与外科手术有关的炎症,所述外科手术例如血管移植包括冠状动脉旁路手术、换血管术手术包括血管成形术、放置斯滕特印模(stent placement)、动脉内膜切除术或其它涉及动脉、静脉和毛细管的侵袭性手术。
所述组合物用于治疗患者的血管生成相关性疾病,例如用于抑制肿瘤血管生成。所述组合物用于治疗瘤形成,包括转移癌;眼科病症例如角膜移植排斥、眼新血管形成、视网膜新血管形成包括损伤或感染后的新血管形成、糖尿病性视网膜病、黄斑变性、晶状体后纤维组织形成和新血管性青光眼;溃疡性疾病如胃溃疡;病理性但非恶性的病症,例如血管瘤,包括幼稚型血管瘤、鼻咽的血管纤维瘤以及骨的无血管性坏死;以及雌性生殖系统的疾病如子宫内膜异位。
所述组合物用于预防和治疗良性和恶性肿瘤以及瘤形成,包括癌症,例如结肠直肠癌、脑癌、骨癌、上皮细胞衍生的瘤形成(上皮细胞癌)如基底细胞癌、腺癌、胃肠癌如唇癌、口腔癌、食管癌、小肠癌、胃癌、结肠癌、肝癌、膀胱癌、胰腺癌、卵巢癌、宫颈癌、肺癌、乳腺癌、皮肤癌如鳞状细胞癌和基底细胞癌、前列腺癌、肾细胞癌以及其它已知的影响全身上皮细胞的癌症。设想本发明组合物特别有用的瘤形成是胃肠癌、巴特雷食管、肝癌、膀胱癌、胰癌、卵巢癌、前列腺癌、宫颈癌、肺癌、乳腺癌和皮肤癌。所述组合物也可用于治疗放射疗法引起的纤维变性。所述组合物也可用于治疗患有腺瘤性息肉的患者,包括患有家族性腺瘤性息肉病(FAP)的患者。此外,所述组合物可用于预防有FAP风险的患者体内形成息肉。
所述组合物通过抑制收缩性前列腺素类合成而抑制前列腺素类引起的平滑肌收缩,并因此可用于治疗痛经、早产、哮喘和嗜酸粒细胞相关性疾病。它们也可用于减少骨丢失,尤其是经绝后妇女的骨丢失(即治疗骨质疏松),以及用于治疗青光眼。
本发明组合物的优选应用是用于治疗类风湿性关节炎和骨关节炎,用于一般性地控制疼痛(特别是口腔手术后疼痛、全身性手术后疼痛、矫形外科手术后疼痛以及骨关节炎的急性突发),用于治疗阿尔茨海默病以及用于化学预防结肠癌。
本发明组合物除可以用于人类治疗外,还可用于兽医治疗宠物(companion animal)、不同寻常的动物、家畜等等,尤其是哺乳动物。更具体地说,本发明组合物可用于治疗马、狗和猫的COX-2介导性疾病。
本发明还涉及治疗其中需要使用COX-2抑制药物进行治疗的病症或疾病的方法,所述方法包括胃肠外给予本发明的稀释配制组合物到需要所述组合物的患者。用于预防、减轻或缓解病症或疾病的给药方案最好对应于一日一次或一日两次的治疗,但可以根据多种因素改变。这些因素包括患者的类型、年龄、体重、性别、饮食状况和医学病症以及疾病的性质和严重性。因此,实际使用的给药方案可以变化很大,并因此可以偏离上面所述的优选给药方案。
可以用上面指示的给药方案开始初始治疗。治疗一般根据需要持续几周到几个月或几年的时间,直到已经控制或消除所述病症或疾病。可以通过本领域熟知的任何方法常规监测接受本发明稀释配制组合物治疗的患者,以确定治疗的有效性。从所述监测获得的连续数据分析允许在治疗期间修改治疗方案,以便在任何时间点给予最佳有效剂量,并且以便可以确定治疗时间。这样,可以在疗程内合理地改变治疗方案和给药计划,以便给予表现出满意有效性的最少量所述组合物,并且使得给药仅持续成功治疗所述病症或疾病的时间。
本文术语“胃肠外给药”包括注射和/或输注组合物进入或穿透患者的皮肤,并且包括真皮内给药、皮下给药、肌内给药、静脉内给药、髓内给药、关节内给药、滑膜内给药、脊柱内给药、鞘内给药和心内给药。可以使用任何已知用于胃肠外注射或输注药物的装置实现所述给药。
已经发现:当胃肠外给予人类患者帕瑞考昔时,帕瑞考昔快速完全地转化为伐地考昔。因此,惊人的是,甚至在需要快速开始治疗效果的情况下,帕瑞考昔(采取帕瑞考昔钠的形式)的治疗有效剂量等于口服给予的伐地考昔治疗有效剂量。本文中术语“等于”指在摩尔量或绝对量(即重量)上相等。根据分子量,1mg帕瑞考昔的完全转化产生约0.85mg伐地考昔。为实用目的,在考虑1mg帕瑞考昔等同于1mg伐地考昔时不产生大的误差。
因此,根据本发明的实施方案,提供治疗人类患者的COX-2介导性疾病的方法,所述方法包括胃肠外给予所述患者帕瑞考昔或其盐,给予的帕瑞考昔剂量等同于伐地考昔的治疗有效剂量。最好按约1mg至约200mg的日剂量给予帕瑞考昔或其盐例如钠盐。更优选的日剂量是约5mg至约120mg,更优选约10mg至约100mg,例如约20mg、约40mg或约80mg帕瑞考昔。
在图1举例说明的一个特别惊人的发现中,帕瑞考昔到伐地考昔的转化如此迅速和完全,以致胃肠外给予(例如静脉内给予)人类患者帕瑞考昔与口服给予速释形式相等剂量的伐地考昔本身相比,提供显著更早的伐地考昔血浆浓度峰值。
在本发明的另一实施方案中,提供包含封口小瓶、最好是玻璃小瓶的制成品,所述封口小瓶容纳有无菌的可胃肠外给药的组合物,所述组合物包含等于治疗有效剂量伐地考昔的帕瑞考昔剂量的帕瑞考昔或其盐。帕瑞考昔的剂量最好是约1mg至约200mg,更优选约5mg至约120mg,最优选约10mg至约100mg,例如约20mg、约40mg或约80mg。所述帕瑞考昔最好作为帕瑞考昔钠存在。任选所述小瓶是如上文所述的多区室小瓶。
本发明的治疗方法还包括帕瑞考昔或本发明组合物与选自阿片类物质和其它镇痛药的一种或多种药物的联合治疗,所述其它镇痛药其中包括麻醉性镇痛药、μ受体拮抗剂、κ受体拮抗剂、非麻醉性(即非成瘾性)镇痛剂、单胺摄取抑制剂、腺苷调节剂、大麻素衍生物、P物质拮抗剂、神经激肽-1受体拮抗剂和钠通道阻滞剂。优选的联合治疗包括应用本发明组合物以及一种或多种选自以下的化合物:醋氯芬酸、阿西美辛、e-乙酰氨基己酸、对乙酰氨基苯酚、醋氨沙洛、乙酰苯胺、乙酰水杨酸(阿司匹林)、S-腺苷甲硫氨酸、阿氯芬酸、阿芬太尼、烯丙罗定、阿明洛芬、阿洛普令、阿法罗定、二乙酰水杨酸铝、氨芬酸、氨氯苯噁嗪、3-氨基-4-羟丁酸、2-氨基-4-甲吡啶、氨丙吡酮、氨基比林、阿米西群、水杨酸铵、安吡昔康、呱氨托美丁、阿尼利定、安替比林、水杨酸安替比林、安曲非宁、阿扎丙宗、苄达酸、贝诺酯、苯噁洛芬、苄哌立隆、苄达明、苄吗啡、柏莫洛芬、贝齐米特、α-没药醇、溴芬酸、p-溴乙酰苯胺、5-溴水杨酸乙酸酯、溴水杨醇、布西丁、布氯酸、布可隆、丁苯羟酸、布马地宗、丁丙诺啡、布他西丁、丁布芬、布托啡诺(butophanol)、乙酰水杨酸钙、卡马西平、卡比芬、卡洛芬、卡沙兰、三氯叔丁醇、氯西诺嗪、水杨酸胆碱、辛可芬、桂美辛、西拉马多、环氯茚酸、氯美辛、氯尼他秦、氯尼辛、氯吡酸、丁香(cloVe)、可待因、溴甲可待因、磷酸可待因、硫酸可待因、克罗丙胺、克罗乙胺、地索吗啡、右奥沙屈、右吗拉胺、地佐辛、地恩丙胺、双氯芬酸钠、二苯米唑、联苯吡胺、二氯尼柳、双氢可待因、盐酸二氢可待因酮烯醇、双氢吗啡、乙酰水杨酸二羟铝、地沙美多、地美庚醇、二甲噻丁、吗苯丁酯、地匹哌酮、diprocetyl、安乃近、地他唑、屈噁昔康、依莫法宗、恩芬那酸、依匹唑、依他佐辛、依特柳酯、乙水杨胺、依索庚嗪、依托沙秦、乙甲噻丁、乙基吗啡、依托度酸、依托芬那酯、依托尼秦、丁香酚、联苯乙酸、芬布芬、芬克洛酸、芬度柳、非诺洛芬、芬太尼、芬替酸、非普地醇、非普拉宗、夫洛非宁、氟芬那酸、氟诺洛芬、氟苯乙砜、氟吡汀、氟丙喹宗、氟比洛芬、磷柳酸、龙胆酸、格拉非宁、葡美辛、水杨酸乙二醇酯、愈创蓝油烃、氢可酮、氢吗啡酮、羟哌替啶、异丁芬酸、布洛芬、异丁普生、水杨酸咪唑、吲哚美辛、吲哚洛芬、三苯唑酸、isoladol、异美沙酮、异尼辛、伊索克酸、伊索昔康、凯托米酮、酮洛芬、酮咯酸、p-乳酰N-酰乙氧基苯胺、来苯胺、左啡诺、洛芬太尼、氯那唑酸、氯诺昔康、洛索洛芬、赖氨酸乙酰水杨酸、乙酰水杨酸镁、甲氧芬那酸、甲芬那酸、哌替啶、美普他酚、5-氨基水杨酸、美他佐辛、盐酸美沙酮、左美丙嗪、甲嗪酸、甲氧夫啉、美托酮、莫非布宗、莫苯唑酸、吗拉宗、吗啡、盐酸吗啡、硫酸吗啡、水杨吗啉、麦罗啡、萘丁美酮、纳布啡、水杨酸1-萘酯、萘普生、那碎因、奈福泮、尼可吗啡、尼芬那宗、尼氟酸、尼美舒利、5′-硝基-2′-丙氧基乙酰苯胺、去甲左啡诺、去甲美沙酮、去甲吗啡、诺匹哌酮、奥沙拉秦、阿片、奥沙西罗、奥沙美辛、噁丙嗪、羟考酮、羟吗啡酮、羟布宗、阿片全碱、瑞尼托林、帕沙米特、喷他佐辛、哌立索唑、非那西丁、苯吗庚酮、非那佐辛、盐酸非那吡啶、非诺可、苯哌利定、非诺吡酮、乙酰水杨酸苯酯、保泰松、水杨酸苯酯、非尼拉朵、吡酮洛芬、匹米诺定、哌布宗、哌立酮、piprofen、吡拉唑酸、哌腈米特、吡罗昔康、普拉洛芬、丙谷美辛、普罗庚嗪、γ-二甲哌替啶、丙帕他莫、丙吡兰、右丙氧芬、异丙安替比林、普罗喹宗、丙替嗪酸、雷米那酮、瑞芬太尼、甲硫利马唑、醋水杨胺、水杨苷、水杨酰胺、水杨酰胺o-醋酸、水杨基硫酸、双水杨酯、沙维林、西美曲特、水杨酸钠、舒芬太尼、柳氮磺吡啶、舒林酸、过氧化物歧化酶、舒洛芬、琥布宗、他尼氟酯、替尼达普、替诺昔康、特罗芬那酯、粉防已碱、噻唑丁炎酮、噻洛芬酸、噻拉米特、替利定、替诺立定、托芬那酸、托美丁、曲马多、tropesin、维米醇、联苯丁酸、希莫洛芬、扎托洛芬和佐美酸(参见
The Merck Index,第12版,Therapeutic Category and Biological ActivityIndex,S.Budavari编辑(1996),页码:Ther-2到Ther-3和Ther-12(镇痛药(牙科)、镇痛药(麻醉性)、镇痛药(非麻醉性)、消炎药(非甾类))。
尤其优选的联合治疗包括应用帕瑞考昔或本发明组合物以及阿片样物质,更具体地说其中所述阿片样物质是可待因、哌替啶、吗啡或它们的衍生物。
可以通过任何途径给予在与帕瑞考昔或本发明组合物的联合疗法中使用的药物,所述途径例如胃肠外途径、口服途径、局部途径等。
实施例
下面实施例举例说明本发明的各个方面,但不应当认为下面的
实施例是限制本发明。
实施例1
如下所述制备可稀释配制粉剂组合物,所述粉剂组合物本文命名为制剂A-D,分别包含5、10、20和40mg剂量帕瑞考昔钠形式的帕瑞考昔。
首先,制备具有表1所示组合物的用于冷冻干燥的溶液。用于冷冻干燥的溶液A-D分别对应于制剂A-D。
表1.用于冷冻干燥的溶液A-D的组成
成分 | A | B | C | D |
帕瑞考昔钠(mg) | 5.30 | 10.59 | 21.18 | 42.36 |
七水合磷酸氢二钠(mg) | 0.67 | 1.34 | 2.68 | 5.36 |
磷酸,1M | 如调整pH所需 | |||
氢氧化钠,1N | 如调整pH所需 | |||
注射用水USP,至定制容积(ml) | 1 | 1 | 1 | 2 |
在制备上述每种用于冻干的溶液时,将七水合磷酸氢二钠溶于合适体积的注射用水中,用1M磷酸将所得溶液的pH调到8.1。将帕瑞考昔钠溶于该溶液中。检查pH,如果需要,就用1M磷酸或1N氢氧化钠再次调整pH,加入水,将体积调整到目标体积,形成用于冻干的溶液。每种制备溶液的体积都足以制备几个单位剂量的组合物(如表1所指出的每单位剂量1ml或2ml溶液)。
所述用于冻干的溶液通过两个0.2μm Durapore除菌滤器,将1ml或2ml所述溶液在无菌条件下分别灌入2ml或5ml I型未处理的无热原透明玻璃小瓶中。按重量计量所述灌注。每种溶液几批的平均密度是1.005g/ml。在一个独立的测试中,发现帕瑞考昔钠不结合除菌滤器。
用无菌冷冻干燥塞子(有一个开口允许升华)部分塞住所述小瓶,将所述小瓶置于预先除菌的冷冻干燥室内,进行冷冻干燥循环。使用的典型循环如表2所述。使用无菌氮气充满所述小瓶的顶部空间,并在循环完成时打破真空。当所述小瓶还在所述室内时,用塞子完全塞住所述小瓶。当从所述室取出所述小瓶时,立即用咬边的(crimpinto place)揭开式(flip-off)铝封盖封住所述小瓶,室温贮存,避光。
表2.典型冷冻干燥循环
阶段 | 描述 |
冷冻阶段 | 在1.75h内从室温到-50℃在-50℃保持7.0h |
第一干燥阶段 | 在1.5h内从-50℃到15℃在15℃保持2.25h在1.0h内从15℃到45℃在45℃保持16.5h真空300μmHg |
第二干燥阶段 | 在5.0h内从45℃到室温真空300μmHg |
总循环时间 | 36h |
得到的制剂A-D在所述小瓶内形成外观良好的饼状物,即所述饼状物没有裂缝或收缩。粉剂X射线衍射(PXRD)分析指出:所述饼状物是无定形的。甚至在70℃贮存12周后,PXRD分析显示所述饼状物的物理性状没有改变,并且没有观察到收缩的迹象。
分析制剂A、B和C(5、10和20mg帕瑞考昔)内的残余水分含量,并分析伐地考昔,作为化学稳定性的指标。对新鲜制备的样品和在70℃贮存12周的样品通过HPLC进行伐地考昔分析。如表3所示的,数据显示极好的化学稳定性,甚至在高温下贮存12周后仅有少于0.5%的伐地考昔。
表3.制剂A-C的稳定性
参数 | A | B | C |
水(%),新鲜样品 | 1.6 | 1.4 | 0.8 |
伐地考昔(%),新鲜样品 | 0.06 | 0.07 | 0.03 |
伐地考昔(%),在70℃贮存12周 | 0.45 | 0.37 | 0.36 |
测试制剂D(40mg帕瑞考昔)的pH和残余水分含量,并在新鲜制备以及在不同温度下贮存4、8和12周后通过HPLC分析帕瑞考昔和伐地考昔。如表4所示的数据,显示极好的化学稳定性,甚至在高温下贮存12周后仅有少于0.5%的伐地考昔。帕瑞考昔和伐地考昔百分率以不含赋形剂为准表示。
表4.制剂D的稳定性
贮存温度和取样时间 | 帕瑞考昔% | 伐地考昔% | 水% | pH |
新鲜制备 | 97.4 | 0.03 | 1.00 | 7.9 |
40℃,4周 | 97.1 | 0.03 | 1.06 | 8.0 |
40℃,8周 | 96.4 | 0.03 | 1.08 | 7.8 |
40℃,12周 | 96.9 | 0.04 | 1.29 | 7.8 |
55℃,4周 | 96.8 | 0.05 | 1.03 | 8.0 |
55℃,8周 | 96.8 | 0.07 | 0.84 | 7.8 |
55℃,12周 | 95.4 | 0.09 | 0.87 | 7.9 |
70℃,4周 | 97.3 | 0.14 | 0.90 | 8.0 |
70℃,8周 | 96.6 | 0.20 | 0.77 | 7.8 |
70℃,12周 | 无数据 | 0.36 | 无数据 | 无数据 |
在1ml注射用0.9%氯化钠USP内稀释配制制剂A-C,在2ml注射用0.9%氯化钠USP内稀释配制制剂D。所述饼状物立即溶解。
实施例2
如下所述制备本文称为制剂E-J的可稀释配制粉剂组合物,制剂E-J每种都包含帕瑞考昔钠形式的20mg帕瑞考昔。首先制备具有如表5所示组成的冷冻干燥用溶液。用于冷冻干燥的溶液E-J分别对应于制剂E-J。制备所述溶液和所述冻干粉剂组合物采用类似于制备实施例1制剂A-D所采用的程序。
可以注意到制剂E-J分别包含超过约10%除缓冲剂(磷酸氢二钠或氨丁三醇)以外的赋形剂成分。为比较目的在本文中陈述这些制剂。
表5.用于冷冻干燥的溶液E-J的组成
成分 | E | F | G | H | I | J |
帕瑞考昔钠(mg) | 21.18 | 21.18 | 21.18 | 21.18 | 21.18 | 21.18 |
七水合磷酸氢二钠(mg) | 2.68 | 2.68 | 2.68 | 2.68 | ||
氨丁三醇(mg) | 1.2 | 1.2 | ||||
甘露醇(mg) | 30 | 30 | 30 | 30 | ||
甘氨酸(mg) | 13.5 | 13.5 | ||||
聚乙二醇4000(mg) | 200 | |||||
磺基丁基-β-环糊精(mg) | 15 | |||||
盐酸,1N | 如调整pH所需 | |||||
氢氧化钠,1N | 如调整pH所需 | |||||
注射用水USP,至定制容积(ml) | 1 | 1 | 1 | 1 | 1 | 1 |
分析新鲜制备以及在不同温度下贮存4周后的制剂E-J内的帕瑞考昔和伐地考昔。帕瑞考昔和伐地考昔百分率以不含赋形剂为准表示,示于表6。
表6.制剂E-J的稳定性
参数 | E | F | G | H | I | J |
帕瑞考昔(%),新制备 | 99.00 | 99.40 | 104.3 | 102.2 | 90.46 | 99.86 |
帕瑞考昔(%),5℃,4周 | 95.71 | 95.76 | 100.0 | 98.04 | 90.17 | 98.76 |
帕瑞考昔(%),55℃,4周 | 98.79 | 99.00 | 98.37 | 98.03 | 87.57 | 97.41 |
帕瑞考昔(%),70℃,4周 | 87.60 | 98.00 | 82.77 | 92.81 | 85.58 | 90.00 |
伐地考昔(%),新制备 | 0.19 | 0.17 | 0.25 | 0.26 | 0.16 | 0.20 |
伐地考昔(%),5℃,4周 | 0.20 | 0.12 | 0.19 | 0.19 | 0.13 | 0.14 |
伐地考昔(%),55℃,4周 | 1.43 | 0.26 | 1.72 | 1.38 | 0.43 | 1.04 |
伐地考昔(%),70℃,4周 | 9.03 | 0.89 | 15.08 | 5.26 | 0.95 | 8.81 |
可以注意到,制剂E-J的化学稳定性比本发明的制剂A-D要差。制剂F和I除磷酸氢二钠外各包含30mg甘露醇,它们在该实施例测试的制剂中显示最高的稳定性,但在55℃或70℃贮存4周后仍然比制剂A-D显示更高水平的帕瑞考昔到伐地考昔的转化。制剂E、G、H和J的化学稳定性差得难以接受。
此外,制剂E-J没有一种在稀释配制时立即溶解。制剂I除甘露醇和磷酸氢二钠外含200mg聚乙二醇4000,在试图稀释配制制剂时溶解尤其缓慢和困难。
实施例3
在药代动力学研究中确定人类受试者体内的伐地考昔血浆浓度。在11名健康成人受试者中,一次静脉内(IV)给予1ml药团内的20mg剂量采用帕瑞考昔钠形式的帕瑞考昔,或者用240ml水口服给予速释片剂形式的一次20mg剂量伐地考昔。受试者在服药后1小时、2小时和3小时饮用180ml水。
使用经过验证的高效液相色谱(HPLC)程序测定伐地考昔血浆浓度。图1显示服药后0到24小时的平均伐地考昔血浆浓度。
静脉内给予帕瑞考昔钠比口服给予伐地考昔更早达到最大伐地考昔血浆浓度。
实施例4
在一个单一中心、单一剂量、随机化、双盲、使用安慰剂作对照的平行组24小时研究中,一组224名患者(每个治疗组54名患者),该组患者需要拔除两颗同侧嵌塞性第三磨牙并进行骨切除,患者包括18到45岁的男性和女性,将该组患者随机化,接受4ml体积0.9%氯化钠内的单一优先静脉内剂量20mg、40mg或80mg帕瑞考昔或安慰剂。
手术结束30分钟后开始,每两小时评价疼痛水平直到24小时,除非作疼痛评价的患者没有苏醒。患者按照0-3等级并在有从“无疼痛”到“极度疼痛”的连续区的表上评价疼痛。患者一经要求即给予药物止痛。在最后一次安排好的评价或在给予抢救药物之前,要求患者评价所述研究药物延缓疼痛的有效性。
使用存活率分析技术分析抢救药物时间(TRM)。使用如Miller(1981)在
Survival Analysis,第74-75页.New York:John Wiley & Sons中所述调整过的Kaplan-Meier产物限度估计量,计算每个治疗组该事件的中值时间。使用Simon和Lee(1982),
Cancer Treat.Rep66,37-42的方法,计算该事件中值时间的百分之九十五(95%)置信区间。对于TRM,直到24小时评价都不需要抢救药物的患者被认为在24小时经过审查。因为除给予抢救药物而放弃研究的患者在他们放弃研究的时候接受审查。
在中值TRM(表7)的基础上,单一剂量帕瑞考昔20mg、40mg和80mg导致比安慰剂显著更长的TRM。帕瑞考昔40mg和80mg的中值TRM值相互之间没有显著性差异,但它们比帕瑞考昔20mg的TRM都显著更长。
帕瑞考昔治疗组内接受抢救药物的患者比例(也示于表7)比安慰剂治疗组显著更低;在该参数上,帕瑞考昔40mg和80mg治疗组之间没有显著性差异。
表7.抢救药物的时间(TRM)
治疗组 | 中值TRM | 95%置信区间 | 接受抢救药物的患者 |
安慰剂 | 2h51m | 2h16m到3h16m | 93% |
帕瑞考昔20mg | 6h17m | 4h04m到11h17m | 78% |
帕瑞考昔40mg | >24h | 11h04m到>24h | 48% |
帕瑞考昔80mg | 12h00m | 6h24m到16h37m | 59% |
关于患者对于所述研究药物有效性的评价,每个帕瑞考昔治疗组内患者的分数都显著高于安慰剂治疗组内的患者分数;在帕瑞考昔40mg和80mg治疗组之间没有显著性差异。在帕瑞考昔40mg治疗组的患者中,92%评价研究药物为“好”或“极好”。
Claims (40)
1.一种粉剂形式的药用组合物,所述组合物包含:
(a)至少一种水溶性治疗药物,所述水溶性治疗药物选自选择性COX-2抑制药物及其前体药物和盐,所述水溶性治疗药物的治疗有效性总量占所述组合物的约30%至约90%(重量),
(b)一种胃肠外可接受的缓冲剂,所述缓冲剂量为所述组合物的约5%至约60%(重量),
(c)其它胃肠外可接受的赋形剂成分,所述赋形剂成分总量为所述组合物的零至约10%(重量);
所述组合物可以用胃肠外可接受的溶剂液体稀释配制成注射溶液。
2.权利要求1的组合物,其中所述治疗药物包括选择性COX-2抑制药物的水溶性盐、前体药物或前体药物的盐,所述选择性COX-2抑制药物选自以下:塞来考昔、地拉考昔、伐地考昔、罗非考昔、艾托考昔、2-(3,5-二氟苯基)-3-[4-(甲磺酰基)苯基]-2-环戊烯-酮和2-(3,4-(二氟苯基)-4-(3-羟基-3-甲基-1-丁氧基)-5-[4-(甲磺酰基)苯基]-3-(2H)-哒嗪酮。
3.权利要求1的组合物,其中所述治疗药物包括伐地考昔的水溶性盐、前体药物或前体药物的盐。
4.权利要求1的组合物,其中所述治疗药物包括帕瑞考昔或其盐。
5.权利要求1的组合物,其中所述治疗药物包括帕瑞考昔钠。
6.权利要求1的组合物,其中所述治疗药物包括(S)-6,8-二氯-2-(三氟甲基)-2H-1-苯并吡喃-3-羧酸或其水溶性盐。
7.权利要求1-6中任一项的组合物,其中所述治疗药物量为所述组合物的约40%至约85%(重量),优选约50%至约80%(重量)。
8.权利要求1-6中任一项的组合物,其中所述缓冲剂量为所述组合物的约10%至约60%(重量),优选约20%至约50%(重量)。
9.权利要求1-6中任一项的组合物,所述组合物基本上由所述治疗药物和所述缓冲剂组成。
10.权利要求1-6中任一项的组合物,其中所述缓冲剂选自磷酸钠、磷酸钾、柠檬酸钠、柠檬酸钾、单乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇和它们的混合物。
11.权利要求1-6中任一项的组合物,其中所述缓冲剂选自磷酸氢二钠、磷酸氢二钾以及氨丁三醇。
12.权利要求1-6中任一项的组合物,其中所述缓冲剂是磷酸氢二钠。
13.权利要求1-6中任一项的组合物,所述组合物稀释配制后pH为约7至约9。
14.权利要求1-6中任一项的组合物,所述组合物具有足够空隙度以稀释配制时快速溶解所述治疗药物。
15.一种注射溶液,所述注射溶液通过用胃肠外可接受的溶剂稀释配制权利要求1-6中任一项的组合物制得。
16.权利要求15的溶液,其中所述溶剂是水性溶剂。
17.权利要求16的溶液,所述溶液的pH为约7.5至约8.5。
18.权利要求16的溶液,其中所述水性溶剂包含葡萄糖和/或氯化钠。
19.一种制成品,所述制成品包括密封小瓶,所述小瓶中装有单位剂量的权利要求1-6中任一项的无菌组合物。
20.权利要求19的制成品,其中所述组合物包含治疗药物帕瑞考昔钠,其剂量为约1mg至约200mg帕瑞考昔,优选约5mg至约120mg帕瑞考昔,更优选约10mg至约100mg帕瑞考昔。
21.权利要求19的制成品,其中所述小瓶是多区室小瓶。
22.一种制备可稀释配制的选择性COX-2抑制组合物的方法,所述方法包括冷冻干燥一种水性溶液的步骤,所述水性溶液除水以外,还包含:
(a)至少一种治疗药物,所述治疗药物选自选择性COX-2抑制药物及其前体药物和盐,所述治疗药物的治疗有效性总量占所述组合物的约30%至约90%(重量),
(b)一种胃肠外可接受的缓冲剂,所述缓冲剂量为所述组合物的约5%至约60%(重量),
(c)其它胃肠外可接受的赋形剂成分,所述赋形剂成分总量为所述组合物的零至约10%(重量);
所述冷冻干燥步骤形成一种容易稀释配制的粉剂。
23.权利要求22的方法,其中所述治疗药物是帕瑞考昔钠。
24.权利要求23的方法,其中所述缓冲剂是磷酸氢二钠。
25.权利要求24的方法,其中在所述冷冻干燥步骤前,所述溶液是通过用注射用水溶解帕瑞考昔钠和磷酸氢二钠制得,所述溶液除菌后定量分装到小瓶中,每支小瓶装有一定体积的单位剂量帕瑞考昔钠溶液,然后将所述小瓶放入冷冻干燥室内。
26.权利要求25的方法,其中在制备所述溶液的步骤中,最后加入帕瑞考昔钠。
27.权利要求24-26中任一项的方法,其中所述冷冻干燥步骤包括一个冷冻阶段、一个第一干燥阶段和一个第二干燥阶段。
28.权利要求27的方法,其中:
(a)在所述冷冻阶段中,温度在约1小时至约5小时的时间内降低至约-30℃至约-60℃的冷冻温度,然后在所述冷冻温度下保持约0.5小时至约24小时;
(b)在所述第一干燥阶段中,抽真空约25至约500μmHg,并在约1小时至约5小时的时间内将温度从冷冻温度升高至约0℃;
(c)在所述第二干燥阶段中,在约25至约500μmHg的真空下,在约1小时至约4小时的时间内将温度从约0℃升高到室温以上的水平,并在该温度下保持约3小时至约12小时;结果获得水分含量低于约2%(重量)的粉剂。
29.权利要求27的方法,其中总冷冻干燥循环时间约18小时至约24小时。
30.一种治疗或预防患者COX-2介导性疾病的方法,所述方法包括用生理可接受量的胃肠外可接受的溶剂液体稀释配制单位剂量的权利要求1-6中任一项的组合物,形成注射溶液,然后将所述溶液胃肠外给予所述患者。
31.权利要求30的方法,其中所述胃肠外给药是通过真皮内、皮下、肌内、静脉内、髓内、关节内、滑膜内、脊柱内、鞘内或心内注射或输注。
32.权利要求30的方法,其中所述胃肠外给药是通过静脉内注射或输注给药。
33.权利要求32的方法,其中静脉内大剂量注射所述组合物。
34.一种治疗或预防人类患者COX-2介导性疾病的方法,所述方法包括胃肠外给予所述患者帕瑞考昔或其盐,所述帕瑞考昔或其盐的剂量相当于治疗有效剂量的伐地考昔。
35.权利要求34的方法,其中给予帕瑞考昔或其盐的日剂量为约1mg至约200mg帕瑞考昔,优选约5mg至约120mg帕瑞考昔,更优选约10mg至约100mg帕瑞考昔。
36.权利要求34或权利要求35的方法,其中静脉内大剂量注射帕瑞考昔或其盐。
37.一种制成品,所述制成品包括密封小瓶,所述小瓶中装有可胃肠外给药的无菌组合物,所述组合物包含帕瑞考昔或其盐,所述帕瑞考昔或其盐的剂量相当于治疗有效剂量的伐地考昔。
38.权利要求37的制成品,其中所述帕瑞考昔剂量是约1mg至约200mg,优选约5mg至约120mg,更优选约10mg至约100mg。
39.权利要求37或权利要求38的制成品,其中所述帕瑞考昔为帕瑞考昔钠。
40.权利要求37或权利要求38的制成品,其中所述小瓶是多区室小瓶。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710474394.8A CN107115302A (zh) | 2001-04-03 | 2002-04-02 | 包含cox‑2抑制剂的可稀释配制的胃肠外组合物 |
CN201710514915.8A CN107213121A (zh) | 2001-04-03 | 2002-04-02 | 包含cox‑2抑制剂的可稀释配制的胃肠外组合物 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US28105801P | 2001-04-03 | 2001-04-03 | |
US60/281,058 | 2001-04-03 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710514915.8A Division CN107213121A (zh) | 2001-04-03 | 2002-04-02 | 包含cox‑2抑制剂的可稀释配制的胃肠外组合物 |
CN201710474394.8A Division CN107115302A (zh) | 2001-04-03 | 2002-04-02 | 包含cox‑2抑制剂的可稀释配制的胃肠外组合物 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1512882A true CN1512882A (zh) | 2004-07-14 |
Family
ID=23075770
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710474394.8A Pending CN107115302A (zh) | 2001-04-03 | 2002-04-02 | 包含cox‑2抑制剂的可稀释配制的胃肠外组合物 |
CN201710514915.8A Pending CN107213121A (zh) | 2001-04-03 | 2002-04-02 | 包含cox‑2抑制剂的可稀释配制的胃肠外组合物 |
CNA028107659A Pending CN1512882A (zh) | 2001-04-03 | 2002-04-02 | 包含cox-2抑制剂的可稀释配制的胃肠外组合物 |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710474394.8A Pending CN107115302A (zh) | 2001-04-03 | 2002-04-02 | 包含cox‑2抑制剂的可稀释配制的胃肠外组合物 |
CN201710514915.8A Pending CN107213121A (zh) | 2001-04-03 | 2002-04-02 | 包含cox‑2抑制剂的可稀释配制的胃肠外组合物 |
Country Status (46)
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102512383A (zh) * | 2011-12-25 | 2012-06-27 | 天津市嵩锐医药科技有限公司 | 供注射用的帕瑞昔布钠药物组合物 |
CN104771370A (zh) * | 2014-01-14 | 2015-07-15 | 南京圣和药业股份有限公司 | 帕瑞昔布钠冻干粉针剂及其制备方法 |
CN105125506A (zh) * | 2015-08-18 | 2015-12-09 | 上海秀新臣邦医药科技有限公司 | 一种注射用帕瑞昔布钠及其制备方法 |
CN105168152A (zh) * | 2015-08-27 | 2015-12-23 | 上海华源药业(宁夏)沙赛制药有限公司 | 一种帕瑞昔布钠冻干粉及其制备方法 |
CN105726496A (zh) * | 2014-12-12 | 2016-07-06 | 四川科伦药物研究院有限公司 | 一种帕瑞昔布钠冻干粉剂、其制备方法及其粉剂产品 |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6929954B2 (en) | 2000-11-02 | 2005-08-16 | Chromaceutical Advanced Technologies, Inc. | Method for producing purified hematinic iron-saccharidic complex and product produced |
EP2275075A3 (en) * | 2000-11-02 | 2011-08-10 | Chromaceutical Advanced Technologies, Inc. | Method of measuring an iron-saccharidic complex |
KR20050044459A (ko) * | 2001-11-13 | 2005-05-12 | 파마시아 코포레이션 | 파레콕시브 등의 설폰아미드 선구약물의 경구 투여 형태 |
KR100763045B1 (ko) * | 2002-03-15 | 2007-10-04 | 파마시아 코포레이션 | 파레콕시브 나트륨 결정체 |
US7964568B2 (en) * | 2003-05-30 | 2011-06-21 | Chromaceutical Advanced Technologies, Inc. | Synthesis of high molecular weight iron-saccharidic complexes |
DE10327674A1 (de) * | 2003-06-20 | 2005-01-05 | Awd.Pharma Gmbh & Co. Kg | Injizierbare Darreichungsform von Flupirtin |
CN101217939A (zh) * | 2005-05-27 | 2008-07-09 | 灵药生物技术有限公司 | 可注射组合物及制备这类组合物的方法 |
NZ572007A (en) * | 2006-05-09 | 2010-12-24 | Astrazeneca Ab | Parenteral formulation comprising proton pump inhibitor sterilized in its final container by ionizing radiation |
EP2061749B1 (en) * | 2006-09-03 | 2018-02-21 | Techfields Biochem Co. Ltd | Positively charged water-soluble prodrugs of acetaminophen and related compounds with very fast skin penetration rate |
US20080279930A1 (en) * | 2007-05-07 | 2008-11-13 | Bernd Terhaag | Controlled-Release Flupirtine Compositions, Compacts, Kits and Methods of Making and Use Thereof |
MX2010005932A (es) * | 2007-11-29 | 2010-06-15 | Alltranz Inc | Metodos y composiciones para mejorar la viabilidad de poros de microaguja. |
KR100967490B1 (ko) * | 2009-11-21 | 2010-07-07 | 곽철호 | 하수구의 배출 처리 구조 |
CA2854160A1 (en) | 2011-11-02 | 2013-05-10 | Halscion, Inc. | Methods and compositions for wound treatment |
US8940317B2 (en) | 2011-12-23 | 2015-01-27 | Pioneer Surgical Technology | Continuous matrix with osteoconductive particles dispersed therein, method of forming thereof, and method of regenerating bone therewith |
JP2017505349A (ja) | 2014-02-11 | 2017-02-16 | ドクター レディズ ラボラトリーズ リミテッド | セレコキシブの非経口組成物 |
US11243028B2 (en) * | 2018-12-14 | 2022-02-08 | Fortunata, LLC | Systems and methods of cryo-curing |
CA3132227A1 (en) | 2019-03-01 | 2020-09-10 | Eurofarma Laboratorios S.A. | Non-steroid anti-inflammatory pharmaceutical composition |
CN110960493B (zh) * | 2019-12-30 | 2022-03-11 | 山东罗欣药业集团股份有限公司 | 一种帕瑞昔布钠冻干制剂及其制备方法 |
CN113456597B (zh) * | 2020-03-30 | 2023-02-14 | 石药集团欧意药业有限公司 | 一种注射用帕瑞昔布钠及其制备方法 |
CN116421569B (zh) * | 2023-06-15 | 2023-09-05 | 四川尚锐生物医药有限公司 | 一种注射用帕瑞昔布钠药物组合物及其制备方法 |
Family Cites Families (105)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4434163A (en) * | 1981-06-01 | 1984-02-28 | Pfizer Inc. | Water-soluble benzothiazine dioxide salts |
US4797388A (en) * | 1984-05-21 | 1989-01-10 | Cetus Corporation | Pharmaceutical compositions with galactitol as carrier |
US4677195A (en) * | 1985-01-11 | 1987-06-30 | Genetics Institute, Inc. | Method for the purification of erythropoietin and erythropoietin compositions |
US5036060A (en) * | 1988-07-25 | 1991-07-30 | Fujisawa Usa, Inc. | Cyclophosphamide |
US5616458A (en) | 1990-03-14 | 1997-04-01 | Board Of Regents, University Of Tx System | Tripterygium wilfordii hook F extracts and components, and uses thereof |
US5604260A (en) | 1992-12-11 | 1997-02-18 | Merck Frosst Canada Inc. | 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2 |
US5543297A (en) | 1992-12-22 | 1996-08-06 | Merck Frosst Canada, Inc. | Human cyclooxygenase-2 cDNA and assays for evaluating cyclooxygenase-2 activity |
WO1994015932A1 (en) | 1993-01-15 | 1994-07-21 | G.D. Searle & Co. | Novel 3,4-diaryl thiophenes and analogs thereof having use as antiinflammatory agents |
US5380738A (en) | 1993-05-21 | 1995-01-10 | Monsanto Company | 2-substituted oxazoles further substituted by 4-fluorophenyl and 4-methylsulfonylphenyl as antiinflammatory agents |
US5474995A (en) | 1993-06-24 | 1995-12-12 | Merck Frosst Canada, Inc. | Phenyl heterocycles as cox-2 inhibitors |
US5436265A (en) | 1993-11-12 | 1995-07-25 | Merck Frosst Canada, Inc. | 1-aroyl-3-indolyl alkanoic acids and derivatives thereof useful as anti-inflammatory agents |
US5593992A (en) | 1993-07-16 | 1997-01-14 | Smithkline Beecham Corporation | Compounds |
US5344991A (en) | 1993-10-29 | 1994-09-06 | G.D. Searle & Co. | 1,2 diarylcyclopentenyl compounds for the treatment of inflammation |
US5434178A (en) | 1993-11-30 | 1995-07-18 | G.D. Searle & Co. | 1,3,5 trisubstituted pyrazole compounds for treatment of inflammation |
US5466823A (en) | 1993-11-30 | 1995-11-14 | G.D. Searle & Co. | Substituted pyrazolyl benzenesulfonamides |
US5401765A (en) | 1993-11-30 | 1995-03-28 | G. D. Searle | 1,4,5-triphenyl pyrazolyl compounds for the treatment of inflammation and inflammation-related disorders |
US5475018A (en) | 1993-11-30 | 1995-12-12 | G. D. Searle & Co. | 1,5-diphenyl pyrazole compounds for treatment of inflammation |
US5393790A (en) | 1994-02-10 | 1995-02-28 | G.D. Searle & Co. | Substituted spiro compounds for the treatment of inflammation |
AU2424895A (en) | 1994-05-04 | 1995-11-29 | G.D. Searle & Co. | Substituted spirodienes for the treatment of inflammation |
US5418254A (en) | 1994-05-04 | 1995-05-23 | G. D. Searle & Co. | Substituted cyclopentadienyl compounds for the treatment of inflammation |
BE1008307A3 (fr) | 1994-06-16 | 1996-04-02 | Europharmaceuticals Sa | Sel de nimesulide hydrosoluble, solution aqueuse le contenant, sa preparation et son utilisation. |
US5486534A (en) | 1994-07-21 | 1996-01-23 | G. D. Searle & Co. | 3,4-substituted pyrazoles for the treatment of inflammation |
EP1125932A3 (en) | 1994-07-27 | 2001-08-29 | G.D. Searle & Co. | Substituted thiazoles for the treatment of inflammation |
US5616601A (en) | 1994-07-28 | 1997-04-01 | Gd Searle & Co | 1,2-aryl and heteroaryl substituted imidazolyl compounds for the treatment of inflammation |
US5620999A (en) | 1994-07-28 | 1997-04-15 | Weier; Richard M. | Benzenesulfonamide subtituted imidazolyl compounds for the treatment of inflammation |
US5521213A (en) | 1994-08-29 | 1996-05-28 | Merck Frosst Canada, Inc. | Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2 |
US5420343A (en) | 1994-08-31 | 1995-05-30 | G. D. Searle & Co. | Derivatives of aromatic cyclic alkylethers |
US5585504A (en) | 1994-09-16 | 1996-12-17 | Merck & Co., Inc. | Process of making cox-2 inhibitors having a lactone bridge |
US5696143A (en) | 1994-09-20 | 1997-12-09 | Talley; John J. | Benz G! indazolyl derivatives for the treatment of inflammation |
US5547975A (en) | 1994-09-20 | 1996-08-20 | Talley; John J. | Benzopyranopyrazolyl derivatives for the treatment of inflammation |
ES2139959T3 (es) | 1994-10-27 | 2000-02-16 | Merck Frosst Canada Inc | Derivados de estilbeno utiles como inhibidores de la ciclooxigenasa-2. |
US5739166A (en) | 1994-11-29 | 1998-04-14 | G.D. Searle & Co. | Substituted terphenyl compounds for the treatment of inflammation |
JP2636819B2 (ja) | 1994-12-20 | 1997-07-30 | 日本たばこ産業株式会社 | オキサゾール系複素環式芳香族化合物 |
JP3181190B2 (ja) | 1994-12-20 | 2001-07-03 | 日本たばこ産業株式会社 | オキサゾール誘導体 |
JPH10511089A (ja) | 1994-12-21 | 1998-10-27 | メルク フロスト カナダ インコーポレーテツド | Cox−2阻害剤としてのジアリール−2−(5h)−フラノン |
US5552422A (en) | 1995-01-11 | 1996-09-03 | Merck Frosst Canada, Inc. | Aryl substituted 5,5 fused aromatic nitrogen compounds as anti-inflammatory agents |
CA2211320C (en) | 1995-01-31 | 2007-03-20 | Merck Frosst Canada Inc. | 5-methanesulfonamido-3h-isobenzofuran-1-ones as inhibitors of cyclooxygenase-2 |
US5596008A (en) | 1995-02-10 | 1997-01-21 | G. D. Searle & Co. | 3,4-Diaryl substituted pyridines for the treatment of inflammation |
US5686470A (en) | 1995-02-10 | 1997-11-11 | Weier; Richard M. | 2, 3-substituted pyridines for the treatment of inflammation |
US5633272A (en) | 1995-02-13 | 1997-05-27 | Talley; John J. | Substituted isoxazoles for the treatment of inflammation |
JP3802581B2 (ja) | 1995-03-01 | 2006-07-26 | 富山化学工業株式会社 | 新規なビフェニル誘導体またはその塩およびそれらを含有する抗炎症剤 |
JPH11501049A (ja) | 1995-04-04 | 1999-01-26 | グラクソ、グループ、リミテッド | イミダゾ〔1,2−a〕ピリジン誘導体 |
US5691374A (en) | 1995-05-18 | 1997-11-25 | Merck Frosst Canada Inc. | Diaryl-5-oxygenated-2-(5H) -furanones as COX-2 inhibitors |
US5604253A (en) | 1995-05-22 | 1997-02-18 | Merck Frosst Canada, Inc. | N-benzylindol-3-yl propanoic acid derivatives as cyclooxygenase inhibitors |
US5510368A (en) | 1995-05-22 | 1996-04-23 | Merck Frosst Canada, Inc. | N-benzyl-3-indoleacetic acids as antiinflammatory drugs |
US5639780A (en) | 1995-05-22 | 1997-06-17 | Merck Frosst Canada, Inc. | N-benzyl indol-3-yl butanoic acid derivatives as cyclooxygenase inhibitors |
CN1174970C (zh) | 1995-05-25 | 2004-11-10 | G·D·瑟尔公司 | 3-卤代烷基-1h-吡唑的制备方法 |
US5643933A (en) | 1995-06-02 | 1997-07-01 | G. D. Searle & Co. | Substituted sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors |
US5739143A (en) | 1995-06-07 | 1998-04-14 | Smithkline Beecham Corporation | Imidazole compounds and compositions |
US5658903A (en) | 1995-06-07 | 1997-08-19 | Smithkline Beecham Corporation | Imidazole compounds, compositions and use |
GB9514518D0 (en) | 1995-07-15 | 1995-09-13 | Sod Conseils Rech Applic | Guanidine salt inhibitors of NO synthase and cyclooxygenase |
JPH0977664A (ja) | 1995-09-13 | 1997-03-25 | Yakult Honsha Co Ltd | シクロオキシゲナーゼ−2特異的阻害剤及び抗炎症剤 |
US5756529A (en) | 1995-09-29 | 1998-05-26 | G.D. Searle & Co. | Substituted pyrazolyl benzenesulfonamides for use in veterinary therapies |
US5981576A (en) | 1995-10-13 | 1999-11-09 | Merck Frosst Canada, Inc. | (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors |
US6020343A (en) | 1995-10-13 | 2000-02-01 | Merck Frosst Canada, Inc. | (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors |
US6057319A (en) | 1995-10-30 | 2000-05-02 | Merck Frosst Canada & Co. | 3,4-Diaryl-2-hydroxy-2,5-dihydrofurans as prodrugs to cox-2 inhibitors |
NZ327044A (en) | 1996-01-11 | 2000-01-28 | Smithkline Beecham Corp | Substituted imidazole compounds |
US6046208A (en) | 1996-01-11 | 2000-04-04 | Smithkline Beecham Corporation | Substituted imidazole compounds |
ZA97175B (en) | 1996-01-11 | 1997-11-04 | Smithkline Beecham Corp | Novel substituted imidazole compounds. |
US5746546A (en) * | 1996-01-24 | 1998-05-05 | Stabilizer, Inc. | Soil stabilization composition and method |
US5789413A (en) | 1996-02-01 | 1998-08-04 | Merck Frosst Canada, Inc. | Alkylated styrenes as prodrugs to COX-2 inhibitors |
GB9607503D0 (en) | 1996-04-11 | 1996-06-12 | Merck Frosst Canada Inc | Bisaryl cyclobutenes derivatives as cyclooxygenase inhibitors |
US5807873A (en) | 1996-04-04 | 1998-09-15 | Laboratories Upsa | Diarylmethylidenefuran derivatives and their uses in therapeutics |
US5908858A (en) | 1996-04-05 | 1999-06-01 | Sankyo Company, Limited | 1,2-diphenylpyrrole derivatives, their preparation and their therapeutic uses |
DE69739003D1 (de) * | 1996-04-12 | 2008-10-30 | Searle Llc | Substituierte Benzensulfonamid-Derivate als Wirkstoff-Vorläufer von COX-2 Inhibitoren |
US5922742A (en) | 1996-04-23 | 1999-07-13 | Merck Frosst Canada | Pyridinyl-2-cyclopenten-1-ones as selective cyclooxygenase-2 inhibitors |
US5883267A (en) | 1996-05-31 | 1999-03-16 | Merck & Co., Inc. | Process for making phenyl heterocycles useful as cox-2 inhibitors |
US5741798A (en) | 1996-06-03 | 1998-04-21 | Boehringer Ingelheim Pharmaceuticals, Inc. | 2-benzyl-4-sulfonyl-4H-isoquinolin-1,3-diones and their use as antiinflammatory agents |
US5677318A (en) | 1996-07-11 | 1997-10-14 | Merck Frosst Canada, Inc. | Diphenyl-1,2-3-thiadiazoles as anti-inflammatory agents |
US5861419A (en) | 1996-07-18 | 1999-01-19 | Merck Frosst Canad, Inc. | Substituted pyridines as selective cyclooxygenase-2 inhibitors |
US5776967A (en) | 1996-07-26 | 1998-07-07 | American Home Products Corporation | Pyranoindole inhibitors of COX--2 |
FR2751964B1 (fr) | 1996-08-01 | 1998-10-30 | Union Pharma Scient Appl | Nouveaux derives diarylmethylene carbocycliques, leurs procedes de preparation, et leurs utilisations en therapeutique |
FR2751966B1 (fr) | 1996-08-01 | 1998-10-30 | Union Pharma Scient Appl | Nouveaux derives 1,2-diarylindoles, leurs procedes de preparation, et leurs utilisations en therapeutique |
US5830911A (en) | 1996-08-14 | 1998-11-03 | American Home Products Corporation | Pyranoindole and tetrahydrocarbazole inhibitors of COX-2 |
US6005000A (en) | 1996-08-22 | 1999-12-21 | Oxis International, Inc. | 5,5-Disubstituted-3, 4-dihydroxy-2(5H)-furanones and methods of use therefor |
FR2753449B1 (fr) | 1996-09-13 | 1998-12-04 | Union Pharma Scient Appl | Nouveaux derives 3,4-diaryloxazolone, leurs procedes de preparation, et leurs utilisations en therapeutique |
US5972950A (en) | 1996-10-08 | 1999-10-26 | Laboratories Upsa | 1,2-diarylmethylene derivatives, their methods of preparation and their uses in therapeutics |
US5681842A (en) | 1996-11-08 | 1997-10-28 | Abbott Laboratories | Prostaglandin synthase-2 inhibitors |
US5869524A (en) | 1996-11-12 | 1999-02-09 | American Home Products Corporation | Indene inhibitors of COX-2 |
US6096753A (en) | 1996-12-05 | 2000-08-01 | Amgen Inc. | Substituted pyrimidinone and pyridone compounds and methods of use |
DE69727199T2 (de) | 1996-12-09 | 2004-11-18 | Pfizer Inc. | Benzimidazol-Verbindungen |
ATE250576T1 (de) | 1996-12-10 | 2003-10-15 | Searle & Co | Substituierte pyrrolylverbindungen zur behandlung von entzündungen |
US5973191A (en) | 1996-12-30 | 1999-10-26 | Vanderbilt University | Selective inhibitors of prostaglandin endoperoxide synthase-2 |
US5929076A (en) | 1997-01-10 | 1999-07-27 | Smithkline Beecham Corporation | Cycloalkyl substituted imidazoles |
US5783597A (en) | 1997-03-04 | 1998-07-21 | Ortho Pharmaceutical Corporation | 2,5-disubstituted thiophenes: inhibitors of 5-lipoxygenase and inducible cyclooxygenase (COX-2) enzymes, composition and use |
EP0863134A1 (en) | 1997-03-07 | 1998-09-09 | Merck Frosst Canada Inc. | 2-(3,5-difluorophenyl)-3-(4-(methyl-sulfonyl)phenyl)-2-cyclopenten-1-one useful as an inhibitor of cyclooxygenase-2 |
US6004960A (en) | 1997-03-14 | 1999-12-21 | Merck Frosst Canada, Inc. | Pyridazinones as inhibitors of cyclooxygenase-2 |
US6071954A (en) | 1997-03-14 | 2000-06-06 | Merk Frosst Canada, Inc. | (methylsulfonyl)phenyl-2-(5H)-furanones with oxygen link as COX-2 inhibitors |
US6034256A (en) | 1997-04-21 | 2000-03-07 | G.D. Searle & Co. | Substituted benzopyran derivatives for the treatment of inflammation |
US6046217A (en) | 1997-09-12 | 2000-04-04 | Merck Frosst Canada & Co. | 2,3,5-trisubstituted pyridines as inhibitors of cyclooxygenase-2 |
RS49982B (sr) * | 1997-09-17 | 2008-09-29 | Euro-Celtique S.A., | Sinergistička analgetička kombinacija analgetičkog opijata i inhibitora ciklooksigenaze-2 |
US6040450A (en) | 1997-09-25 | 2000-03-21 | Merck & Co., Inc. | Process for making diaryl pyridines useful as cox-2-inhibitors |
FR2769311B1 (fr) | 1997-10-07 | 1999-12-24 | Union Pharma Scient Appl | Nouveaux derives 3,4-diarylthiazolin-2-one ou -2-thione, leurs procedes de preparation et leurs utilisations en therapeutique |
US6133292A (en) | 1997-10-30 | 2000-10-17 | Merck Frosst Canada & Co. | Diaryl-5-alkyl-5-methyl-2-(5H)-furanones as selective cyclooxygenase-2-inhibitors |
US6020347A (en) | 1997-11-18 | 2000-02-01 | Merck & Co., Inc. | 4-substituted-4-piperidine carboxamide derivatives |
FR2771412B1 (fr) | 1997-11-26 | 2000-04-28 | Adir | Nouveaux derives de pyrrole, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
PT1071745E (pt) | 1998-04-24 | 2004-11-30 | Merck & Co Inc | Processo para sintetizar inibidores cox-2 |
WO1999059583A1 (en) * | 1998-05-18 | 1999-11-25 | Merck & Co., Inc. | Method for treating or preventing chronic nonbacterial prostatitis and prostatodynia |
KR100295206B1 (ko) * | 1998-08-22 | 2001-07-12 | 서경배 | 디아릴벤조피란유도체및이를함유하는시클로옥시게네이즈-2저해제조성물 |
US6277878B1 (en) | 1998-09-07 | 2001-08-21 | Pfizer Inc | Substituted indole compounds as anti-inflammatory and analgesic agents |
US6077869A (en) | 1998-10-29 | 2000-06-20 | Ortho-Mcneil Pharmaceutical, Inc. | Aryl phenylhydrazides as selective COX-2 inhibitors for treatment of inflammation |
US6077868A (en) | 1999-07-20 | 2000-06-20 | Wisconsin Alumni Research Foundation | Selective inhibition of cyclooxygenase-2 |
US6083969A (en) | 1999-10-20 | 2000-07-04 | Ortho-Mcneil Pharaceutical, Inc. | 1,3- and 2,3-diarylcycloalkano and cycloalkeno pyrazoles as selective inhibitors of cyclooxygenase-2 and antiinflammatory agents |
AU2001247745B2 (en) * | 2000-03-24 | 2006-08-31 | Pharmacia Corporation | Amidino compounds useful as nitric oxide synthase inhibitors |
AR031135A1 (es) * | 2000-10-10 | 2003-09-10 | Upjohn Co | Composiciones de antibiotico topico para el tratamiento de infecciones oculares |
-
2002
- 2002-04-01 US US10/113,281 patent/US7695736B2/en not_active Expired - Lifetime
- 2002-04-01 MY MYPI20021178A patent/MY137736A/en unknown
- 2002-04-01 PE PE2002000258A patent/PE20021017A1/es active IP Right Grant
- 2002-04-02 MX MXPA03009013A patent/MXPA03009013A/es active IP Right Grant
- 2002-04-02 PL PL368597A patent/PL205658B1/pl unknown
- 2002-04-02 ES ES02725471T patent/ES2252448T3/es not_active Expired - Lifetime
- 2002-04-02 AT AT02725471T patent/ATE310516T1/de active
- 2002-04-02 JP JP2002578951A patent/JP4511792B2/ja not_active Expired - Lifetime
- 2002-04-02 CN CN201710474394.8A patent/CN107115302A/zh active Pending
- 2002-04-02 SK SK1228-2003A patent/SK287754B6/sk unknown
- 2002-04-02 IL IL15820902A patent/IL158209A0/xx unknown
- 2002-04-02 WO PCT/US2002/010252 patent/WO2002080912A1/en active IP Right Grant
- 2002-04-02 CN CN201710514915.8A patent/CN107213121A/zh active Pending
- 2002-04-02 AU AU2002256031A patent/AU2002256031B2/en not_active Expired
- 2002-04-02 AP APAP/P/2003/002879A patent/AP1776A/en active
- 2002-04-02 NZ NZ528547A patent/NZ528547A/en not_active IP Right Cessation
- 2002-04-02 KR KR1020037013043A patent/KR100980685B1/ko active IP Right Grant
- 2002-04-02 RS YUP-858/03A patent/RS50430B/sr unknown
- 2002-04-02 BR BRPI0208652A patent/BRPI0208652B8/pt not_active IP Right Cessation
- 2002-04-02 OA OA1200300254A patent/OA12498A/en unknown
- 2002-04-02 EA EA200301004A patent/EA006554B1/ru not_active IP Right Cessation
- 2002-04-02 DK DK02725471T patent/DK1372645T3/da active
- 2002-04-02 ME MEP-569/08A patent/MEP56908A/xx unknown
- 2002-04-02 HU HU0303750A patent/HU229264B1/hu unknown
- 2002-04-02 CZ CZ20032651A patent/CZ299623B6/cs not_active IP Right Cessation
- 2002-04-02 SI SI200230231T patent/SI1372645T1/sl unknown
- 2002-04-02 UA UA2003108945A patent/UA77173C2/xx unknown
- 2002-04-02 CA CA002442906A patent/CA2442906C/en not_active Expired - Fee Related
- 2002-04-02 GE GE5312A patent/GEP20063775B/en unknown
- 2002-04-02 CN CNA028107659A patent/CN1512882A/zh active Pending
- 2002-04-02 DE DE60207535T patent/DE60207535T2/de not_active Expired - Lifetime
- 2002-04-02 EP EP02725471A patent/EP1372645B1/en not_active Expired - Lifetime
- 2002-04-03 TW TW091106757A patent/TWI314867B/zh not_active IP Right Cessation
- 2002-04-03 PA PA20028542701A patent/PA8542701A1/es unknown
- 2002-04-03 EG EG2002040352A patent/EG24345A/xx active
- 2002-04-03 TN TNTNSN02039A patent/TNSN02039A1/en unknown
- 2002-04-03 GT GT200200065A patent/GT200200065A/es unknown
- 2002-04-03 JO JO200231A patent/JO2337B1/en active
- 2002-04-03 SV SV2002000969A patent/SV2002000969A/es active IP Right Grant
- 2002-04-03 AR ARP020101224A patent/AR033688A1/es not_active Application Discontinuation
-
2003
- 2003-07-08 TN TNPCT/US2002/010252A patent/TNSN03085A1/fr unknown
- 2003-09-30 ZA ZA200307630A patent/ZA200307630B/en unknown
- 2003-09-30 IS IS6972A patent/IS2408B/is unknown
- 2003-10-01 IL IL158209A patent/IL158209A/en active IP Right Grant
- 2003-10-01 BG BG108221A patent/BG66367B1/bg unknown
- 2003-10-01 HR HRP20030793AA patent/HRP20030793B1/hr not_active IP Right Cessation
- 2003-10-02 MA MA27332A patent/MA27008A1/fr unknown
- 2003-10-02 NO NO20034415A patent/NO333381B1/no not_active IP Right Cessation
- 2003-10-03 EC EC2003004789A patent/ECSP034789A/es unknown
-
2018
- 2018-02-28 HK HK18102864.9A patent/HK1243338A1/zh unknown
- 2018-03-27 HK HK18104186.6A patent/HK1244690A1/zh unknown
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102512383A (zh) * | 2011-12-25 | 2012-06-27 | 天津市嵩锐医药科技有限公司 | 供注射用的帕瑞昔布钠药物组合物 |
CN104771370A (zh) * | 2014-01-14 | 2015-07-15 | 南京圣和药业股份有限公司 | 帕瑞昔布钠冻干粉针剂及其制备方法 |
CN105726496A (zh) * | 2014-12-12 | 2016-07-06 | 四川科伦药物研究院有限公司 | 一种帕瑞昔布钠冻干粉剂、其制备方法及其粉剂产品 |
CN105125506A (zh) * | 2015-08-18 | 2015-12-09 | 上海秀新臣邦医药科技有限公司 | 一种注射用帕瑞昔布钠及其制备方法 |
CN105168152A (zh) * | 2015-08-27 | 2015-12-23 | 上海华源药业(宁夏)沙赛制药有限公司 | 一种帕瑞昔布钠冻干粉及其制备方法 |
CN105168152B (zh) * | 2015-08-27 | 2018-06-01 | 上海华源药业(宁夏)沙赛制药有限公司 | 一种帕瑞昔布钠冻干粉及其制备方法 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1512882A (zh) | 包含cox-2抑制剂的可稀释配制的胃肠外组合物 | |
CN1292746C (zh) | 含具有氨基磺酰基的活性化合物、聚乙二醇和抗氧化剂的口服传递的药用组合物 | |
CN100335136C (zh) | 具有降低的药物结晶趋势的药物组合物 | |
CN1305470C (zh) | 制备细自乳化的药物组合物的方法 | |
CN1287768C (zh) | 稳定的口服悬浮液配方 | |
CN1547474A (zh) | 含选择性环加氧酶-2抑制剂及一元醇的可渗透皮肤的组合物 | |
ES2536191T3 (es) | Derivados de sulfonamida | |
US7999006B2 (en) | Methods of using MEK inhibitors | |
CN1230167C (zh) | 环加氧酶-2抑制剂的二元释放组合物 | |
US8470811B2 (en) | Substituted heterocyclylbenzylpyrazoles and use thereof | |
CN1516601A (zh) | 含低水溶性药物(cox-2抑制剂)、溶剂、脂肪酸和有机胺的口服传递的药用组合物 | |
CN1642544A (zh) | 包含过氧化物酶体增殖物激活受体-γ激动剂和环加氧酶-2选择性抑制剂的组合物及治疗方法 | |
CN101743241A (zh) | 哒嗪酮衍生物 | |
CN1434713A (zh) | 环加氧酶-2抑制剂的缓释制剂 | |
US20130150325A1 (en) | 3-(Fluorovinyl)pyrazoles and their use | |
CN1049116C (zh) | 血管紧张素受体阻滞剂在制造治疗心、血管肥大或增生药物中的应用 | |
CN1681501A (zh) | 作为转化生长因子(tgf)抑制剂的吡唑衍生物 | |
JP5602230B2 (ja) | スフィンゴシン−1−リン酸受容体アゴニスト | |
US20110301122A1 (en) | Heteroaromatic compounds for use as hif inhibitors | |
RU2014107000A (ru) | Производные 3-гетероароиламинопропионовой кислоты и их применение в качестве лекарственных средств | |
CN101060832A (zh) | 非水液体肠胃外醋氯芬酸配方 | |
CN1615135A (zh) | 磺酰胺前药如帕瑞考昔的口服剂型 | |
WO2011141325A1 (de) | Hydroxyalkylbenzyl- pyrazole und ihre verwendung zur behandlung von hyperproliferativen und angiogenen erkrankungen | |
CN1642556A (zh) | 醛固酮受体拮抗剂与胆汁酸多价螯合剂的联合 | |
CN1433308A (zh) | 能迅速开始治疗作用的环氧合酶-2抑制剂组合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1067554 Country of ref document: HK |
|
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20040714 |
|
RJ01 | Rejection of invention patent application after publication | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1067554 Country of ref document: HK |