CN102088975A - 基于激肽b2受体拮抗剂和皮质类固醇的药物组合物及其用途 - Google Patents
基于激肽b2受体拮抗剂和皮质类固醇的药物组合物及其用途 Download PDFInfo
- Publication number
- CN102088975A CN102088975A CN200980126795.8A CN200980126795A CN102088975A CN 102088975 A CN102088975 A CN 102088975A CN 200980126795 A CN200980126795 A CN 200980126795A CN 102088975 A CN102088975 A CN 102088975A
- Authority
- CN
- China
- Prior art keywords
- acid
- methyl
- receptor antagonist
- arg
- corticosteroid
- 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.)
- Granted
Links
- 239000003246 corticosteroid Substances 0.000 title claims abstract description 37
- 239000002464 receptor antagonist Substances 0.000 title claims abstract description 37
- 229940044551 receptor antagonist Drugs 0.000 title claims abstract description 34
- 108010093008 Kinins Proteins 0.000 title claims abstract description 26
- 102000002397 Kinins Human genes 0.000 title claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 23
- 229960001334 corticosteroids Drugs 0.000 title 1
- 238000011282 treatment Methods 0.000 claims abstract description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 21
- 239000000203 mixture Substances 0.000 claims abstract description 16
- 208000006673 asthma Diseases 0.000 claims abstract description 11
- 206010003246 arthritis Diseases 0.000 claims abstract description 9
- QIAWOUUTKDMGTE-UJXPALLWSA-M [(4s)-4-amino-5-[4-[4-[[2,4-dichloro-3-[(2,4-dimethylquinolin-8-yl)oxymethyl]phenyl]sulfonylamino]oxane-4-carbonyl]piperazin-1-yl]-5-oxopentyl]-trimethylazanium;chloride;hydrochloride Chemical compound Cl.[Cl-].C12=NC(C)=CC(C)=C2C=CC=C1OCC(C=1Cl)=C(Cl)C=CC=1S(=O)(=O)NC1(C(=O)N2CCN(CC2)C(=O)[C@@H](N)CCC[N+](C)(C)C)CCOCC1 QIAWOUUTKDMGTE-UJXPALLWSA-M 0.000 claims description 32
- 201000008482 osteoarthritis Diseases 0.000 claims description 31
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 26
- 230000004054 inflammatory process Effects 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- 206010061218 Inflammation Diseases 0.000 claims description 21
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 18
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 18
- QURWXBZNHXJZBE-SKXRKSCCSA-N icatibant Chemical compound NC(N)=NCCC[C@@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2SC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@H](CC3=CC=CC=C3C2)C(=O)N2[C@@H](C[C@@H]3CCCC[C@@H]32)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C[C@@H](O)C1 QURWXBZNHXJZBE-SKXRKSCCSA-N 0.000 claims description 18
- 229960001062 icatibant Drugs 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 239000001301 oxygen Substances 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 18
- 229960003957 dexamethasone Drugs 0.000 claims description 17
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 17
- 108700023918 icatibant Proteins 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 201000004624 Dermatitis Diseases 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229960000890 hydrocortisone Drugs 0.000 claims description 9
- 239000007924 injection Substances 0.000 claims description 9
- 238000002347 injection Methods 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 206010010741 Conjunctivitis Diseases 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 claims description 6
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 claims description 6
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 6
- 229960004544 cortisone Drugs 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- -1 n-pro-pyl Chemical group 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 6
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical group OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 5
- 239000000443 aerosol Substances 0.000 claims description 5
- 239000005557 antagonist Substances 0.000 claims description 5
- 230000002421 anti-septic effect Effects 0.000 claims description 5
- 229960002537 betamethasone Drugs 0.000 claims description 5
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 claims description 5
- 230000001684 chronic effect Effects 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 claims description 4
- 206010006811 Bursitis Diseases 0.000 claims description 4
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 claims description 4
- 208000012659 Joint disease Diseases 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 208000027418 Wounds and injury Diseases 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 201000008937 atopic dermatitis Diseases 0.000 claims description 4
- 229960004495 beclometasone Drugs 0.000 claims description 4
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 4
- 229960001810 meprednisone Drugs 0.000 claims description 4
- PIDANAQULIKBQS-RNUIGHNZSA-N meprednisone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)CC2=O PIDANAQULIKBQS-RNUIGHNZSA-N 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 239000002674 ointment Substances 0.000 claims description 4
- 239000001117 sulphuric acid Substances 0.000 claims description 4
- 235000011149 sulphuric acid Nutrition 0.000 claims description 4
- 201000004595 synovitis Diseases 0.000 claims description 4
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 claims description 4
- 239000005711 Benzoic acid Substances 0.000 claims description 3
- 208000014181 Bronchial disease Diseases 0.000 claims description 3
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 claims description 3
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 206010020751 Hypersensitivity Diseases 0.000 claims description 3
- 206010023204 Joint dislocation Diseases 0.000 claims description 3
- 206010024453 Ligament sprain Diseases 0.000 claims description 3
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 claims description 3
- MKPDWECBUAZOHP-AFYJWTTESA-N Paramethasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O MKPDWECBUAZOHP-AFYJWTTESA-N 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 206010041591 Spinal osteoarthritis Diseases 0.000 claims description 3
- 208000010040 Sprains and Strains Diseases 0.000 claims description 3
- 208000004760 Tenosynovitis Diseases 0.000 claims description 3
- 230000001154 acute effect Effects 0.000 claims description 3
- 208000026935 allergic disease Diseases 0.000 claims description 3
- 230000007815 allergy Effects 0.000 claims description 3
- 150000001412 amines Chemical group 0.000 claims description 3
- 208000010668 atopic eczema Diseases 0.000 claims description 3
- 230000001363 autoimmune Effects 0.000 claims description 3
- 235000010233 benzoic acid Nutrition 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 208000010217 blepharitis Diseases 0.000 claims description 3
- 201000005668 blepharoconjunctivitis Diseases 0.000 claims description 3
- 229960004436 budesonide Drugs 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 3
- 230000007850 degeneration Effects 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 229960003469 flumetasone Drugs 0.000 claims description 3
- WXURHACBFYSXBI-GQKYHHCASA-N flumethasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O WXURHACBFYSXBI-GQKYHHCASA-N 0.000 claims description 3
- 229960000676 flunisolide Drugs 0.000 claims description 3
- 229960003973 fluocortolone Drugs 0.000 claims description 3
- GAKMQHDJQHZUTJ-ULHLPKEOSA-N fluocortolone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)CO)[C@@]2(C)C[C@@H]1O GAKMQHDJQHZUTJ-ULHLPKEOSA-N 0.000 claims description 3
- 229960002714 fluticasone Drugs 0.000 claims description 3
- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 229960004584 methylprednisolone Drugs 0.000 claims description 3
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 229960002858 paramethasone Drugs 0.000 claims description 3
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- 229960005205 prednisolone Drugs 0.000 claims description 3
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 claims description 3
- 206010039083 rhinitis Diseases 0.000 claims description 3
- 208000005801 spondylosis Diseases 0.000 claims description 3
- 239000001384 succinic acid Substances 0.000 claims description 3
- 229960005137 succinic acid Drugs 0.000 claims description 3
- 229960005294 triamcinolone Drugs 0.000 claims description 3
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 claims description 3
- 229940005605 valeric acid Drugs 0.000 claims description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- 208000036487 Arthropathies Diseases 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- 201000009859 Osteochondrosis Diseases 0.000 claims description 2
- 230000002159 abnormal effect Effects 0.000 claims description 2
- 230000004075 alteration Effects 0.000 claims description 2
- 239000000872 buffer Substances 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- 230000006378 damage Effects 0.000 claims description 2
- 238000011161 development Methods 0.000 claims description 2
- 239000003889 eye drop Substances 0.000 claims description 2
- 239000007922 nasal spray Substances 0.000 claims description 2
- 229940097496 nasal spray Drugs 0.000 claims description 2
- 230000000414 obstructive effect Effects 0.000 claims description 2
- 230000000241 respiratory effect Effects 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 239000012929 tonicity agent Substances 0.000 claims description 2
- 208000027866 inflammatory disease Diseases 0.000 abstract description 2
- 239000004480 active ingredient Substances 0.000 abstract 1
- 150000001887 cortisones Chemical class 0.000 description 20
- 108010025252 Kassinin Proteins 0.000 description 18
- 208000002193 Pain Diseases 0.000 description 17
- 230000000694 effects Effects 0.000 description 17
- 230000036407 pain Effects 0.000 description 17
- 201000010099 disease Diseases 0.000 description 13
- 235000010418 carrageenan Nutrition 0.000 description 11
- 229920001525 carrageenan Polymers 0.000 description 11
- 210000003127 knee Anatomy 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000002158 endotoxin Substances 0.000 description 8
- 230000001939 inductive effect Effects 0.000 description 8
- 229920006008 lipopolysaccharide Polymers 0.000 description 8
- 206010030113 Oedema Diseases 0.000 description 7
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 7
- 230000002757 inflammatory effect Effects 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- 239000002253 acid Substances 0.000 description 6
- 239000007853 buffer solution Substances 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 101800004538 Bradykinin Proteins 0.000 description 5
- 102400000967 Bradykinin Human genes 0.000 description 5
- 206010048768 Dermatosis Diseases 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 208000017520 skin disease Diseases 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 4
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 4
- 239000003152 bradykinin antagonist Substances 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 230000008961 swelling Effects 0.000 description 4
- 208000006820 Arthralgia Diseases 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 150000001450 anions Chemical class 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 3
- 229960002986 dinoprostone Drugs 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 229940071643 prefilled syringe Drugs 0.000 description 3
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 3
- 150000003180 prostaglandins Chemical class 0.000 description 3
- 210000002345 respiratory system Anatomy 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 101710085045 B2 bradykinin receptor Proteins 0.000 description 2
- 229940123765 Bradykinin B2 receptor antagonist Drugs 0.000 description 2
- 206010006482 Bronchospasm Diseases 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- 206010012442 Dermatitis contact Diseases 0.000 description 2
- 206010061818 Disease progression Diseases 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 2
- 206010065952 Hyperpathia Diseases 0.000 description 2
- 206010023215 Joint effusion Diseases 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 229940114079 arachidonic acid Drugs 0.000 description 2
- 235000021342 arachidonic acid Nutrition 0.000 description 2
- 210000001188 articular cartilage Anatomy 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000003359 bradykinin B2 receptor antagonist Substances 0.000 description 2
- 239000000679 carrageenan Substances 0.000 description 2
- 229940113118 carrageenan Drugs 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 208000010247 contact dermatitis Diseases 0.000 description 2
- 230000005750 disease progression Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229960001484 edetic acid Drugs 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 201000001819 hydrarthrosis Diseases 0.000 description 2
- 210000004969 inflammatory cell Anatomy 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000011866 long-term treatment Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 239000008299 semisolid dosage form Substances 0.000 description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 210000001179 synovial fluid Anatomy 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 2
- IYKLZBIWFXPUCS-VIFPVBQESA-N (2s)-2-(naphthalen-1-ylamino)propanoic acid Chemical compound C1=CC=C2C(N[C@@H](C)C(O)=O)=CC=CC2=C1 IYKLZBIWFXPUCS-VIFPVBQESA-N 0.000 description 1
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 102000000412 Annexin Human genes 0.000 description 1
- 108050008874 Annexin Proteins 0.000 description 1
- 206010003062 Apraxia Diseases 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- 206010011732 Cyst Diseases 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 206010012434 Dermatitis allergic Diseases 0.000 description 1
- 206010016228 Fasciitis Diseases 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 206010017577 Gait disturbance Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 208000004575 Infectious Arthritis Diseases 0.000 description 1
- 102000001399 Kallikrein Human genes 0.000 description 1
- 108060005987 Kallikrein Proteins 0.000 description 1
- 108010077861 Kininogens Proteins 0.000 description 1
- 102000010631 Kininogens Human genes 0.000 description 1
- 208000003947 Knee Osteoarthritis Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 102000003820 Lipoxygenases Human genes 0.000 description 1
- 108090000128 Lipoxygenases Proteins 0.000 description 1
- 102100037611 Lysophospholipase Human genes 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- SCIFESDRCALIIM-UHFFFAOYSA-N N-Me-Phenylalanine Natural products CNC(C(O)=O)CC1=CC=CC=C1 SCIFESDRCALIIM-UHFFFAOYSA-N 0.000 description 1
- LWLSVNFEVKJDBZ-UHFFFAOYSA-N N-[4-(trifluoromethoxy)phenyl]-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide Chemical compound FC(OC1=CC=C(C=C1)NC(=O)N1CCC(CC1)CC1=CC(=CC=C1)OC1=NC=C(C=C1)C(F)(F)F)(F)F LWLSVNFEVKJDBZ-UHFFFAOYSA-N 0.000 description 1
- SCIFESDRCALIIM-VIFPVBQESA-N N-methyl-L-phenylalanine Chemical compound C[NH2+][C@H](C([O-])=O)CC1=CC=CC=C1 SCIFESDRCALIIM-VIFPVBQESA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 108010058864 Phospholipases A2 Proteins 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 208000036688 Radicular syndrome Diseases 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 208000007156 Spondylarthritis Diseases 0.000 description 1
- 201000002661 Spondylitis Diseases 0.000 description 1
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 210000004404 adrenal cortex Anatomy 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 208000037883 airway inflammation Diseases 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000007885 bronchoconstriction Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- XEKAUTDWPYQNFU-UHFFFAOYSA-N chlorane Chemical compound Cl.Cl.Cl XEKAUTDWPYQNFU-UHFFFAOYSA-N 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- 208000031513 cyst Diseases 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- 229940084973 dexamethasone 4 mg Drugs 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- ZJJQKGOLULBDGX-LWCNAHDDSA-N disodium (8S,9R,10S,11S,13S,14S,16S,17R)-9-fluoro-11-hydroxy-10,13,16-trimethyl-17-(2-oxidoacetyl)-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-olate Chemical compound [Na+].[Na+].[H][C@@]12C[C@H](C)[C@]([O-])(C(=O)C[O-])[C@@]1(C)C[C@H](O)[C@@]1(F)[C@@]2([H])CCC2=CC(=O)C=C[C@]12C ZJJQKGOLULBDGX-LWCNAHDDSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 230000037189 immune system physiology Effects 0.000 description 1
- 230000001524 infective effect Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 210000000281 joint capsule Anatomy 0.000 description 1
- 208000018934 joint symptom Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- CQYBNXGHMBNGCG-RNJXMRFFSA-N octahydroindole-2-carboxylic acid Chemical compound C1CCC[C@H]2N[C@H](C(=O)O)C[C@@H]21 CQYBNXGHMBNGCG-RNJXMRFFSA-N 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 210000004417 patella Anatomy 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical group [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000011833 salt mixture Substances 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 201000001223 septic arthritis Diseases 0.000 description 1
- 208000013363 skeletal muscle disease Diseases 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 210000001258 synovial membrane Anatomy 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000006208 topical dosage form Substances 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/14—Decongestants or antiallergics
-
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Dermatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Ophthalmology & Optometry (AREA)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicinal Preparation (AREA)
Abstract
本文公开的是含有作为活性成分的皮质类固醇和激肽B2受体拮抗剂的混合物的药物组合物。所述的组合物已经被证明特别有效，尤其在炎症疾病如哮喘、眼科疾病或皮肤疾病、并尤其是与关节相关的炎性疾病(关节炎)的治疗中特别有效。
Description
技术领域
本发明公开了含有作为活性成分的皮质类固醇和激肽B2受体拮抗剂的混合物的药物组合物。所述的组合物已经被证明特别有效，尤其在炎症疾病如哮喘、眼科疾病或皮肤疾病、并尤其是与关节相关的炎性疾病(关节炎)的治疗中特别有效。
现有技术水平
骨关节炎(OA)，也称作退行性关节疾病，是一种疼痛的、进行性的关节退行性疾病。OA的主要病理生理学特征是关节软骨破坏和损失、肥大、滑膜的炎症和随后的关节肿胀。这些效应产生例如疼痛、僵硬和功能丧失的症状。与平均预期寿命的增长有关的OA在老年人群中的高发病率表明受此种疾病影响的患者的数量在不久的将来可能极大地增长。OA患者认为减轻疼痛对他们的生活质量很重要。
当前没有能够阻止此种疾病恶化的药物。现有的治疗主要是减轻疼痛症状和恢复关节功能。扑热息痛和非甾体抗炎药(NSAIDs)被普遍开处用于治疗骨关节炎疼痛。但是，长期使用所述药物可能伴随有主要的副作用，尤其是在胃肠道水平(溃疡)和血小板聚集方面。
缓激肽(BK)是激肽的成员，激肽是在被有肽酶活性的酶(激肽释放酶)攻击后来源于高分子量的前体(激肽原)的小肽(8-11个氨基酸)家族。激肽形成在各种情况包括炎症、缺血和免疫过程或细菌和病毒感染下被激活。
两种激肽受体已被药理鉴定：B1受体，其在正常条件下极少表达，但被上面所列的刺激诱导表达；和B2受体，其被许多细胞类型组成性表达。缓激肽，通过B2受体的刺激，是炎症和疼痛最重要的介质之一，并与促炎和痛觉过敏介质的释放有关。
已经证实缓激肽(BK)在各种水平上参与OA的病理生理学。
长期已知激肽被释放于OA患者的滑液中。而且，在这些患者中，已在内衬地滑液腔的细胞、成纤维细胞和血管内皮细胞中发现B2受体。
各种临床前模型的许多研究表明BK，当通过关节内途径给药时，比其他炎症介质如P物质、组胺和降钙素基因相关的肽更有效地诱导大鼠的滑液中浆液外渗和中性粒细胞聚集。而且，BK减少关节软骨中的蛋白聚糖含量并在鼠OA模型中引起前列腺素的释放。
已证明一些缓激肽B2受体拮抗剂各种动物滑膜炎模型中有效抑制炎症事件和痛觉过敏。
释放后，BK刺激和敏化分布于关节囊的感觉神经纤维。
BK的临床重要性已经被在58名膝盖有OA症状的患者中进行的II期临床试验证实，其中B2受体拮抗剂艾替班特(90μg/1ml)单剂量关节内给药比安慰剂更大程度地减少膝盖中的疼痛强度(55名患者)。赛诺菲-安万特(Sanofi-Aventis)最近报道在患有膝盖OA的患者中，艾替班特关节内浸润(每隔一周3×500μg注射)引起强烈的镇痛反应，在治疗后持续达3个月，并且在有略微的或无副作用的情况下获得此种显著的镇痛作用。
激肽在呼吸道和其它地方是强效的炎症物质。呼吸道中局部应用缓激肽或内源性释放的激肽在哮喘患者中产生炎症作用和支气管收缩，但在健康的志愿者中几乎没有作用。激肽拮抗剂，尤其是激肽B2受体拮抗剂，可用于治疗过敏性哮喘。
许多缓激肽B2受体拮抗剂已经描述在文献中：Steward，J.M.等免疫药理学(Immunopharmacology)，1999，43，155-61(化合物B10056、B9430)。
Pruneau，D等.英国药理学杂志(Br.J.Pharmacol)1998，125，365-72(化合物FR167344、FR173657、LF160687、Bradizide、LF160335)。
EP370453描述了一些作为缓激肽拮抗剂的具有肽结构的化合物，并且所述的化合物包括艾替班特。艾替班特还构成专利EP1594520的主题，其中公开了它在骨关节炎的预防和治疗中的用途。
WO03103671描述了一组很强效的非肽缓激肽拮抗剂。WO2006040004中报道了特别强效的拮抗剂的选择，包括化合物MEN16132；这些拮抗剂也已被证明在骨关节炎的预防和治疗中、尤其在膝盖的关节内治疗中具有高效。
天然可的松类(cortisones)(糖皮质激素或皮质类固醇)、可的松和皮质醇产生于肾上腺皮质中，并且具有甾体分子结构。
它们的抗炎和抗过敏作用主要通过诱导酶脂皮质蛋白(其抑制磷脂酶A2)的合成而产生。此酶将膜磷脂转化成花生四烯酸，花生四烯酸接着，经环氧合酶和脂氧酶，转化成炎症介质如前列腺素和白三烯。而且，可的松类干扰蛋白质和酶的合成，并稳定细胞膜。
皮质类固醇抑制炎症反应，无论引起炎症反应的刺激物质是化学的、感染性的或免疫的。虽然可的松给药具有症状治疗的性质，因为可的松类不作用于疾病的起因、炎症的抑制及其后果，使得这些药物在临床实践中非常有用。可的松类不仅抑制炎症过程的早期症状(水肿，以及血液和淋巴微循环的改变)，还抑制随后的症状如发红和疼痛。
衍生自胆酸的合成的皮质类固醇，与天然皮质类固醇稍有不同；引入的修饰被设计用于增加所述物质的半衰期，保持天然化合物的生物化学活性不变。
可的松类一般不通过口服途径用于退行性或炎性骨关节疾病，这是因为它们的低效和特别是在长期治疗中出现的潜在的严重系统性副作用，长期治疗在慢性炎症疾病中经常是必要的。
通过局部浸润给药近年来在骨关节疾病和骨骼肌疾病的治疗中变得日益重要。此种治疗方法被推荐用于与疼痛和功能限制相关的急性炎症过程，和退行性关节疾病如骨关节炎、非感染性关节炎、肌腱炎、滑囊炎、筋膜炎、纤维肌痛和根综合征中。
用可的松类浸润的目的是减少或消除关节或关节周围的炎症并阻止系统性扩散。具有长溶出时间的微晶混悬剂延长作用的持续时间，其用于此目的。引入关节中的微晶的存在可引起浸润后疼痛；它们因此与局部麻醉剂共同给药以减少疼痛。患者被建议使关节休息至少24小时以阻止药物的系统性吸收。高剂量的可的松类，即使局部应用，必须被避免以阻止药物的系统性吸收，其禁用于一系列常见疾病如溃疡、糖尿病、心力衰竭、骨质疏松症和高血压。
对于关节内或囊内给药和注射至腱鞘以及腱囊肿形成内，可的松类的剂量当时评价，取决于症状的严重程度和关节的大小或其他将被治疗的局部区域(剂量一般在1和100mg之间)。在具有多关节症状的进展型(evolving forms)中给与高剂量，有时通过在不同位点同时进行单次注射。
任何情况中，可的松类的无数的副作用，在系统和局部水平上，已致使寻找旨在减少可的松类的剂量或使用的替代的解决方案。
两类化合物(B2受体拮抗剂和可的松类)的抗炎和镇痛活性是科学文献中众所周知的。根据现有技术水平，认为可的松类和缓激肽B2受体拮抗剂均以类似的机理产生镇痛和抗炎作用是完全合理的。具体地讲，二者均抑制前列腺素合成以及对其他促炎化合物(细胞因子)的合成有抑制作用。基于这些因素，当一起给药时所述的两类化合物将有叠加作用是不可预期的。但是，我们的实验观察已经证实缓激肽B2受体拮抗剂和可的松类之间不仅有叠加作用还具有出乎意料的协同作用，在抑制所研究的模型中的炎症和疼痛反应中有显著的增强作用，并且此发现构成了本发明的核心。
还众所周知的是合成的皮质类固醇，尤其是重复、长期给药后，引起严重的副作用，并被禁用于如上所述的一些疾病中，因为这些药可使所述的疾病恶化。而且，正如例如在使用实验性膝盖骨关节炎模型的临床前研究中证实的那样，可的松类的作用是部分的，而没有解决50％以上的被炎症过程如疼痛、促炎细胞增加和水肿改变的参数。
从治疗的角度看，在更低剂量完全抑制炎症的含有可的松类的制剂将因此是合乎需要的。
现在已经发现源于激肽B2受体拮抗剂和皮质类固醇的联用在减少炎症过程中的出乎意料的和令人惊讶的活性。由于所述两类化合物的显著的叠加和协同作用，该活性对于各种疾病如骨关节炎、类风湿性关节炎、哮喘、COPD、或炎性眼科疾病和皮肤疾病是非常有用的。
例如，在膝盖的骨关节炎中，B2拮抗剂和可的松类的联用产生1)完全的抗炎治疗作用，2)持续更长时间的作用，和3)皮质类固醇的剂量减少最高达十倍。
这种出乎意料的叠加性质，并且尤其是两类化合物的相互促进，适用于激肽发挥重要作用的所有其他形式的炎症，如哮喘，其中皮质类固醇的效力是众所周知的。总的来说，用较低量的皮质类固醇即能够获得显著的作用是在炎症过程的治疗中的重要的和创新的前景。
发明详述
现在已经令人惊讶地发现天然或合成的可的松类与激肽B2受体拮抗剂联合给药的应用在炎症疾病的治疗中令人惊讶地有效，所述炎症疾病例如但不限于骨关节炎和退行性关节疾病、关节炎、类风湿性关节炎、哮喘和COPD、眼科疾病和皮肤疾病。
本发明涉及药物组合物，其含有作为活性成分的：
-a)天然或合成的皮质类固醇
-b)激肽B2受体拮抗剂
和药学上可接受的载体和赋形剂，以及
所述的活性成分用于制备所述的组合物的用途。
所述的活性成分不仅可以以其中两种活性成分同时存在的组合物给药，还可以以独立的形式同时或顺序给药，其中用含有激肽B2受体拮抗剂的组合物的治疗可先于或后于用含有皮质类固醇的组合物的治疗，两种治疗之间的间隔时间为1分钟至高达8小时，优选为1至30分钟。
在皮质类固醇中，特别优选的为：
可的松、氢化可的松、倍氯米松、倍他米松、布地奈德、地塞米松、氟米松、氟尼缩松、氟可龙(Fluocortone)、氟替卡松、甲泼尼龙、甲基强的松(Methylprednisone)、帕拉米松、泼尼松龙、曲安西龙，
它们为其本身的形式，或者为与乙酸、苯甲酸、己酸、琥珀酸、磷酸、丙酸或戊酸形成的酯的形式，或为丙酮化合物(acetonides)的形式；
B2激肽受体拮抗剂可选自：
H-D-Arg-Arg-Pro-Hyp-Gly-Igl-Ser-D-F5F-Igl-Arg-OH(B10056)，
H-Arg-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic-Arg-OH(B9430)，
H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH(艾替班特)，
4-[2-[([[3-(3-溴-2-甲基-咪唑并[1.2-a]吡啶-8-基氧基甲基)-2.4-二氯-苯基]-甲基-氨基甲酰基]-甲基)-氨基甲酰基]-乙烯基]-N，N-二甲基-苯甲酰胺(FR167344)
3-(6-乙酰氨基-吡啶-3-基)-N-([[2.4-二氯-3-(2-甲基-喹啉-8-基氧基甲基)-苯基]-甲基-氨基甲酰基]-甲基)-丙烯酰胺，(FR173657 op.FK3657)
1-[2.4-二氯-3-(2.4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基]-吡咯烷-2-甲酸[3-(4-甲脒基-苯甲酰基氨基)-丙基]-酰胺(LF160687，阿替班特)
Bradizide，
4-(4-[1-[2.4-二氯-3-(2.4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基]-吡咯烷-2-羰基]-哌嗪-1-羰基)-苄脒(LF160335)
2-[5-(4-氰基-苯甲酰基)-1-甲基-1H-吡咯-2-基]-N-[2.4-二氯-3-(2-甲基-喹啉-8-基氧基甲基)-苯基]-N-甲基-乙酰胺，
或者WO2006/04004中公开的具有通式(I)的化合物之一，
其中
-R为氢或甲基；
-W代表单键或氧原子；
-n＝3、4；
-X为氢或胺基团-NR1R2，其中R1和R2相互独立地为氢或选自甲基、乙基、正丙基、异丙基；
-Y为季铵-NR3R4R5，其中R3、R4、R5相互独立地为甲基、乙基、正丙基、异丙基、丁基、异丁基、正戊基；
-且A-是形式上衍生自药学上可接受的酸的阴离子；
以及其药学上可接受的盐、对映异构体和对映异构体的混合物。
对于本发明的目的，药学上可接受的酸是选自盐酸、氢溴酸、磷酸、碳酸、乙酸、硫酸、三氟乙酸、甲磺酸(methansulphuric acid)、琥珀酸、马来酸、苹果酸、丙二酸、拘橼酸、依地酸；其中所述阴离子带有两个或更多个负电荷，A-应为部分值(fractional value)。
本发明特别涉及药物组合物，其中激肽B2受体拮抗剂选自：
-艾替班特或具有通式(I)的化合物。
在具有通式(I)的化合物中，特别优选下列化合物：与形式上衍生自选自盐酸、乙酸、硫酸、三氟乙酸、甲磺酸、琥珀酸和依地酸的酸的离子形成的盐形式的(4-(S)-氨基-5-(4-{4-[2，4-二氯-3-(2，4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基氨基]-四氢-吡喃-4-羰基}-哌嗪-1-基)-5-氧代-戊基]-三甲基-铵；氯化物双盐酸盐是称为MEN16132的化合物(MW 871.5)。
其中每单剂量单位B2激肽受体拮抗剂的量为6×10-5至2×10-2、优选1×10-4至1×10-2、更优选3×10-4至6×10-3毫摩尔，相当于每单剂量单位MEN16132的量分别为0.05至17mg、0.09至9mg以及0.26至5mg。
根据本发明的组合物每剂量包含缓激肽拮抗剂的量在6×10-5至2×10-2毫摩尔之间(就MEN16132而言，它们相当于大约0.05至17mg的量)，优选在1×10-4至1×10-2毫摩尔之间(就MEN16132而言，它们相当于大约0.09至9mg的量)，甚至更优选在3×10-4和6×10-3毫摩尔之间(就MEN16132而言，它们相当于大约0.26至5mg的量)。
而且，所述的组合物每剂量包含0.05至100mg、优选0.1至10mg的皮质类固醇。
根据本发明的药物制剂还可包含一种或多种药学上可接受的载体/赋形剂。
适合局部给药的液体和半固体剂型例如溶液剂、乳膏剂、凝胶剂或透皮贴剂是优选的；特别是，适合关节内或囊内注射的剂型，例如溶液剂，和透皮应用，例如像乳膏剂或凝胶剂和透皮贴剂的半固体剂型。药物剂型也可由其中一些或所有成分是干燥形式的形式构成，所述干燥形式可能是冷冻干燥的，并待在使用前用水溶液或其他合适的载体重构。
所述的制剂可采用赋形剂如粘合剂、崩解剂、填充剂、稳定剂、稀释剂和着色剂通过现有技术中众所周知的方法来制备。它们还可包括用制技术中公知的合适的聚合物制成的延迟释放或缓慢释放的剂型。
对于制备适合注射用的液体剂型，优选药学上可接受的载体/赋形剂例如溶剂、防腐剂例如抗氧化剂和/或螯合剂和抗菌剂、等渗调节剂，以及缓冲系统。
优选水作溶剂，可能含有共溶剂如二醇类或多元醇如乙二醇。
还可以使用防腐剂或螯合剂，优选依地酸钠和焦亚硫酸钠，并且还可使用抗菌剂，优选苯甲醇。
特别优选氯化钠或甘露醇作为等渗调节剂。
优选的缓冲系统可以是磷酸盐和枸橼酸盐缓冲剂的盐混合物，优选钠盐或钾盐形式。
在适合于喷雾的液体制剂的制备中，药学上可接受的载体/赋形剂优选为含有防腐剂如抗氧化剂和/或螯合剂和抗菌剂、等渗调节剂、和缓冲系统的溶剂。
在适合气雾给药用于在气道应用的剂型中，优选药学上可接受的载体/赋形剂和抛射剂，优选氢氟碳化合物。
对于鼻腔给药，优选用合适的装置给药的干粉剂型或喷雾剂型。
根据本发明的制剂的典型实例为：
1.皮质类固醇0.1-10mg、MEN16132 0.26-5mg，在盐水溶液(0.9％NaCl)中，用适量的0.1N HCl调节pH至4.5-6，加适量水调整至1ml。
2.皮质类固醇0.1-10mg、MEN16132 0.26-5mg，在盐水溶液(0.9％NaCl)中，pH 6-8的缓冲系统，加适量水调整至1ml。
3.通过将0.26-5mg冷冻干燥的MEN16132和0.1-10mg皮质类固醇溶液、及缓冲系统溶解于盐水溶液(0.9％NaCl)中、加适量水调整至1ml而获得的即用制剂。
4.皮质类固醇0.1-10mg、艾替班特(MW 1304.5)0.39-7.8mg，在盐水溶液(0.9％NaCl)中，pH在6-8的缓冲系统，加适量水调整至1ml。
根据本发明的药物组合物可用于预防和治疗关节的急性或慢性炎性、自身免疫性、创伤性和退行性疾病，例如：骨关节炎和创伤后骨关节炎、退行性骨关节炎(膝关节炎、椎关节炎)；椎关节强硬、滑膜炎、腱鞘炎、滑囊炎、挫伤、扭伤、脱臼和半脱位、痛风发作。
而且，所述的组合物对气道的炎症疾病，尤其是哮喘、鼻炎、慢性阻塞性肺病(COPD)、肺纤维症和其中支气管水肿或支气管痉挛起重要作用的疾病有效；并且对源于化学和物理因素或创伤的过敏和非过敏性炎性皮肤疾病和眼科疾病有效。在皮肤疾病中，主要治疗的适应症为烧伤(热或太阳灼伤)引起的皮炎、与过敏原性或刺激性物质接触引起的皮炎或湿疹、特应性皮炎和自身免疫性皮炎(银屑病)，而在眼科疾病的情况下，它主要应用于睑炎、结膜炎和睑结膜炎。
剂量可根据患者的年龄和一般健康状况、疾病或病症的性质和严重程度、以及给药途径和类型而改变。在成年人类患者关节内使用的情况下，根据本发明的药物组合物可以以3×10-4至6×10-3mmol的量的缓激肽拮抗剂(对于MEN16132，这相当于大约0.26至5mg)和0.1-10mg的皮质类固醇的周剂量(单次给药)来给药。
下列含有两种活性成分的组合物的实施例更详细地阐明了本发明：
实施例1
倍他米松1mg、MEN16132 0.5mg，在盐水溶液(0.9％NaCl)中，用适量0.1N HCl调至pH 4.5，加适量水调整至1ml。将溶液置于2.25ml预填充注射器中。
实施例2
倍氯米松0.25mg、MEN16132 0.5mg，在含有磷酸盐缓冲剂(Na2HPO40.16mg、NaH2PO4 0.04mg)的盐水溶液(0.9％NaCl)中，加适量水调整至1ml。将溶液置于2.25ml预填充注射器中。
实施例3
倍他米松1mg，在含有磷酸盐缓冲剂(Na2HPO4 0.16mg、NaH2PO40.04mg)的盐水溶液(0.9％NaCl)中，加适量水调整至1ml。将冷冻干燥形式的MEN16132用上述溶液溶解。
实施例4
地塞米松4mg、艾替班特0.5mg，在含有磷酸盐缓冲剂(Na2HPO4 0.16mg、NaH2PO4 0.04mg)的盐水溶液(0.9％NaCl)中，加适量水调整至1ml。将溶液置于2.25ml预填充注射器中。
实施例5
所述的两种活性成分顺序给药的典型实例包括以下类型的两种组合物的使用：
a)将MEN16132 0.5mg溶于NaCl等渗溶液(0.9％NaCl)中，用0.1NHCl调至pH 5，加100μmol/ml EDTA，用适量等渗溶液调整至2ml，置于2.25ml容量的注射器中；通过调节关节内途径给药的体积来调整剂量(0.5ml相当于0.125mg，1ml相当于0.250mg，1.5ml相当于0.375mg，以及2ml相当于0.500mg)。剂量超过0.5mg时，可注射两支注射器的内容物。
b)将倍他米松磷酸二钠1.97mg溶于含有作为稳定剂的苯酚、依地酸钠和焦亚硫酸钠的NaCl等渗溶液中，适量至2ml，置于2.25ml容量的注射器中；通过调节关节内途径给药的体积来调整剂量。
生物活性
在通过关节内注射引起强炎症作用的角叉菜胶诱导的关节炎实验模型中测量MEN16132、艾替班特和可的松类的生物活性。
将角叉菜胶(2％溶液，25μl)注射入大鼠的右膝盖的关节内位置，而对左膝盖给与25μl盐水以提供内部对照。
角叉菜胶的给药引起关节水肿、疼痛、行走困难以及在处理的膝盖相应的爪上不能负重，给药后6小时出现峰值作用；体重因此与右爪中感受的疼痛直接成正比地主要落在左爪上。用失用测试(incapacitance test)以非侵袭方式评价的两只负重爪上的重量失衡，测量关节炎症导致的疼痛。还通过测量膝关节的直径来测量水肿。
此试验的目的是评价激肽B2受体拮抗剂对角叉菜胶诱导的关节水肿和疼痛的保护作用以及明确皮质类固醇特别是地塞米松或氢化可的松共同给药产生的作用。
角叉菜胶给药前30分钟关节内给药(i.a.)MEN16132或艾替班特(100μg/25μl i.a.)，分别使刺激物诱导的水肿减少了45±3和48±5％(n＝6)，所述化合物给药后6小时达最大抑制作用。
给药地塞米松(100μg/25μl i.a.，角叉菜胶给药前30分钟)使水肿减少了57±3％，而证明其在10μg时无效。
MEN16132和地塞米松(100μg/25μl i.a.)共同给药显著增强了抗水肿作用，完全消除角叉菜胶引起的膝盖肿胀。甚至当地塞米松的剂量减少十倍至10μg/25μl i.a.时令人惊讶地观察到相似的结果。
MEN16132和地塞米松对关节疼痛的作用的结果定性和定量地与对水肿获得的那些结果类似。角叉菜胶给药前30分钟关节内给药MEN16132或地塞米松100μg，使关节疼痛在刺激物给药后6小时分别减少了38±4％和44±3％。地塞米松10μg关节内给药使疼痛减少了14±4％。MEN16132(100μg i.a.)和地塞米松(100和10μg i.a.)共同给药，使关节疼痛分别减少了92±2％和91±2％，甚至地塞米松的剂量低十倍时仍有显著的增强作用。
MEN16132和氢化可的松的联用对角叉菜胶诱导的大鼠膝盖肿胀获得类似的令人吃惊的结果，氢化可的松比地塞米松效力弱大约25倍。角叉菜胶之前30分钟关节内给药MEN16132 100μg，使膝盖肿胀减少了42±3％(n＝6)，而氢化可的松(100μg i.a.)被证明实际上无效(-4±3％)。所述的两种化合物同时给药使肿胀减少了85±6％，证实缓激肽B2受体拮抗剂和可的松类联用的强的增强作用，这不依赖于其化学结构。
在气道的炎症疾病(哮喘、过敏原或脂多糖诱导的呼吸道高敏性)、眼科疾病(由过敏原、碱性溶液和角叉菜胶引起的结膜炎)和皮肤疾病(过敏性皮炎)的实验模型中，激肽B2受体拮抗剂和可的松类的共同给药已经产生了与之前报道的在膝盖关节炎中的那些结果相类似的结果，表明两类化合物之间有明显的叠加和协同作用。
在由脂多糖(LPS)诱导的豚鼠气道炎症的模型中，通过支气管肺泡灌洗采集的白细胞的数目与对照组相比大约增加十倍。用MEN16132或艾替班特的治疗(1mg/ml溶液的气雾，15分钟)，使用LPS预处理后的气道中存在的炎症细胞的数量分别减少了6％和5％，而地塞米松(0.03mg/ml溶液的气雾，15分钟)使细胞浸润减少了8％。
激肽B2受体拮抗剂(MEN16132或艾替班特)和地塞米松以上面所示的剂量共同给药，通过两类化合物之间显著的、出乎意料的协同作用抑制了约50％的由LPS引起的豚鼠的气道中的细胞浸润。
通过体外模型获得了类似的研究结果，在以1μg/ml LPS刺激24小时的人气道肌细胞的培养物中，观察到与对照相比PGE2的产量大约增加16倍。
100nM的MEN16132或艾替班特使LPS诱导的PGE2的释放分别减少了39％和30％，而地塞米松(1μM)使其减少了45％。采用B2受体拮抗剂(MEN16132或艾替班特)和地塞米松的联合治疗消除了LPS诱导的PGE2的产生。
在本发明中，尤其在具有肽结构的化合物的描述中，下列缩写已被用于一些非天然的氨基酸：Nal＝萘基-丙氨酸；NMePhe＝N-甲基-苯基丙氨酸，Oic＝八氢吲哚-2-甲酸，Hyp＝羟基脯氨酸，Igl＝氨基茚满甲酸，Cpg＝1-氨基环戊烷甲酸，Tic＝1，2，3，4-四氢异喹啉-3-甲酸，F5F＝五氟苯基丙氨酸。
权利要求书(按照条约第19条的修改)
1.药物组合物，其包含作为活性成分的皮质类固醇和B2激肽受体拮抗剂、以及药学上可接受的载体和赋形剂，其中：
a)皮质类固醇为天然的或合成的，其选自：可的松、氢化可的松、倍氯米松、倍他米松、布地奈德、地塞米松、氟米松、氟尼缩松、氟可龙、氟替卡松、甲泼尼龙、甲基强的松、帕拉米松、泼尼松龙、曲安西龙，它们任选地为与乙酸、苯甲酸、己酸、琥珀酸、磷酸、丙酸或戊酸成酯的形式或为丙酮化合物的形式；
b)B2激肽受体拮抗剂选自：
-H-D-Arg-Arg-Pro-Hyp-Gly-Igl-Ser-D-F5F-Igl-Arg-OH；
-H-Arg-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic-Arg-OH；
-H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH(艾替班特)；
-4-[2-[([[3-(3-溴-2-甲基-咪唑并[1.2-a]吡啶-8-基氧基甲基)-2，4-二氯-苯基]-甲基-氨基甲酰基]-甲基)-氨基甲酰基]-乙烯基]-N，N-二甲基-苯甲酰胺；
-3-(6-乙酰氨基-吡啶-3-基)-N-([[2，4-二氯-3-(2-甲基-喹啉-8-基氧基甲基)-苯基]-甲基-氨基甲酰基]-甲基)-丙烯酰胺；
-1-[2，4-二氯-3-(2，4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基]-吡咯烷-2-甲酸[3-(4-甲脒基-苯甲酰基氨基)-丙基]-酰胺(阿替班特)；
-Bradizide；
-4-(4-[1-[2，4-二氯-3-(2，4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基]-吡咯烷-2-羰基]-哌嗪-1-羰基)-苄脒；
-2-[5-(4-氰基-苯甲酰基)-1-甲基-1H-吡咯-2-基]-N-[2，4-二氯-3-(2-甲基-喹啉-8-基氧基甲基)-苯基]-N-甲基-乙酰胺；
-通式(I)化合物：
其中
R为氢或甲基；
W代表单键或氧原子；
n＝3、4；
X为氢或胺基团-NR1R2，其中R1和R2相互独立地为氢或选自甲基、乙基、正丙基、异丙基的基团；
Y为季铵-NR3R4R5，其中R3、R4、R5相互独立地为甲基、乙基、正丙基、异丙基、丁基、异丁基、正戊基；
A-是形式上衍生自药学上可接受的酸的阴离子；
和其药学上可接受的盐、对映异构体和对映异构体的混合物。
2.根据权利要求1的药物组合物，其中B2激肽受体拮抗剂为艾替班特或通式(I)的化合物。
3.根据权利要求2的药物组合物，其中B2激肽受体拮抗剂是符合通式(I)的作为与盐酸、乙酸、硫酸、三氟乙酸、甲磺酸、琥珀酸或依地酸形成的盐的化合物(4-(S)-氨基-5-(4-{4-[2，4-二氯-3-(2，4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基氨基]-四氢-吡喃-4-羰基}-哌嗪-1-基)-5-氧代-戊基]-三甲基-铵，优选地为双盐酸氯化物的形式(MEN16132)。
4.根据权利要求1-3的药物组合物，其中每单剂量单位皮质类固醇的量为0.05-100mg，优选0.1-10mg。
5.根据权利要求1-4的药物组合物，其中每单剂量单位B2激肽受体拮抗剂的量为6×10-5至2×10-2、优选1×10-4至1×10-2、更优选3×10-4至6×10-3毫摩尔，相当于每单个单位剂量MEN16132的量分别为0.05至17mg、0.09至9mg和0.26至5mg。
6.根据权利要求1-5的药物组合物，其为关节内或囊内注射液的形式，或为选自乳膏剂、凝胶剂、透皮绷带、滴眼剂、喷雾剂或气雾剂溶液、鼻喷雾剂的透皮形式。
7.根据权利要求6的药物组合物，其中激肽拮抗剂为结晶的、无定形或冻干的固体形式，其待在使用前溶于含有皮质类固醇的溶液中以得到关节内或囊内注射液。
8.根据权利要求1-7的药物组合物，其进一步相互独立地含有作为缓冲剂的磷酸盐或枸橼酸盐、作为张度剂的氯化钠、作为防腐剂和螯合剂的依地酸钠。
9.根据权利要求1的皮质类固醇和B2激肽受体拮抗剂的组合在制备药物中的用途，所述药物用于预防或治疗关节炎症、损伤和退化，特别是骨关节炎和创伤后骨关节炎、骨关节病(膝关节病、椎关节病)、椎关节强硬、滑膜炎、腱鞘炎、滑囊炎、挫伤、扭伤、脱臼和半脱位，以及由生长改变引起的关节病例如骨软骨病、发育异常。
10.根据权利要求1的皮质类固醇和B2激肽受体拮抗剂的组合在制备药物中的用途，所述药物用于预防和治疗呼吸道炎症、皮肤疾患和眼科疾患，过敏或非过敏性、慢性或急性的，特别是哮喘、鼻炎、阻塞性慢性支气管病、灼伤皮炎(热或太阳灼伤)、暴露于过敏原物质或刺激性物质引起的皮炎或湿疹、特应性皮炎、自身免疫性皮炎(银屑病)、睑炎、结膜炎和睑结膜炎。
11.根据权利要求9或10的皮质类固醇和B2激肽受体拮抗剂的组合的用途，其中所述的B2激肽受体拮抗剂是MEN16132。
Claims (11)
1.药物组合物，其包含作为活性成分的皮质类固醇和B2激肽受体拮抗剂、以及药学上可接受的载体和赋形剂，其中：
a)皮质类固醇为天然的或合成的，其选自：可的松、氢化可的松、倍氯米松、倍他米松、布地奈德、地塞米松、氟米松、氟尼缩松、氟可龙、氟替卡松、甲泼尼龙、甲基强的松、帕拉米松、泼尼松龙、曲安西龙，它们任选地为与乙酸、苯甲酸、己酸、琥珀酸、磷酸、丙酸或戊酸成酯的形式或为丙酮化合物的形式；
b)B2激肽受体拮抗剂选自：
-H-D-Arg-Arg-Pro-Hyp-Gly-Igl-Ser-D-F5F-Igl-Arg-OH；
-H-Arg-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic-Arg-OH；
-H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH(艾替班特)；
-4-[2-[([[3-(3-溴-2-甲基-咪唑并[1.2-a]吡啶-8-基氧基甲基)-2，4-二氯-苯基]-甲基-氨基甲酰基]-甲基)-氨基甲酰基]-乙烯基]-N，N-二甲基-苯甲酰胺；
-3-(6-乙酰氨基-吡啶-3-基)-N-([[2，4-二氯-3-(2-甲基-喹啉-8-基氧基甲基)-苯基]-甲基-氨基甲酰基]-甲基)-丙烯酰胺；
-1-[2，4-二氯-3-(2，4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基]-吡咯烷-2-甲酸[3-(4-甲脒基-苯甲酰基氨基)-丙基]-酰胺(阿替班特)；
-Bradizide；
-4-(4-[1-[2，4-二氯-3-(2，4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基]-吡咯烷-2-羰基]-哌嗪-1-羰基)-苄脒；
-2-[5-(4-氰基-苯甲酰基)-1-甲基-1H-吡咯-2-基]-N-[2，4-二氯-3-(2-甲基-喹啉-8-基氧基甲基)-苯基]-N-甲基-乙酰胺；
-通式(I)化合物：
其中
R为氢或甲基；
W代表单键或氧原子；
n＝3、4；
X为氢或胺基团-NR1R2，其中R1和R2相互独立地为氢或选自甲基、乙基、正丙基、异丙基的基团；
Y为季铵-NR3R4R5，其中R3、R4、R5相互独立地为甲基、乙基、正丙基、异丙基、丁基、异丁基、正戊基；
其药学上可接受的盐、对映异构体和对映异构体的混合物。
2.根据权利要求1的药物组合物，其中B2激肽受体拮抗剂为艾替班特或通式(I)的化合物。
3.根据权利要求2的药物组合物，其中B2激肽受体拮抗剂是符合通式(I)的作为与盐酸、乙酸、硫酸、三氟乙酸、甲磺酸、琥珀酸或依地酸形成的盐的化合物(4-(S)-氨基-5-(4-{4-[2，4-二氯-3-(2，4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基氨基]-四氢-吡喃-4-羰基}-哌嗪-1-基)-5-氧代-戊基]-三甲基-铵，优选地为双盐酸氯化物的形式(MEN16132)。
4.根据权利要求1-3的药物组合物，其中每单剂量单位皮质类固醇的量为0.05-100mg，优选0.1-10mg。
5.根据权利要求1-4的药物组合物，其中每单剂量单位B2激肽受体拮抗剂的量为6×10-5至2×10-2、优选1×10-4至1×10-2、更优选3×10-4至6×10-3毫摩尔，相当于每单个单位剂量MEN16132的量分别为0.05至17mg、0.09至9mg和0.26至5mg。
6.根据权利要求1-5的药物组合物，其为关节内或囊内注射液的形式，或为选自乳膏剂、凝胶剂、透皮绷带、滴眼剂、喷雾剂或气雾剂溶液、鼻喷雾剂的透皮形式。
7.根据权利要求6的药物组合物，其中激肽拮抗剂为结晶的、无定形或冻干的固体形式，其待在使用前溶于含有皮质类固醇的溶液中以得到关节内或囊内注射液。
8.根据权利要求1-7的药物组合物，其进一步相互独立地含有作为缓冲剂的磷酸盐或枸橼酸盐、作为张度剂的氯化钠、作为防腐剂和螯合剂的依地酸钠。
9.根据权利要求1的皮质类固醇和B2激肽受体拮抗剂的组合在制备药物中的用途，所述药物用于预防或治疗关节炎症、损伤和退化，特别是骨关节炎和创伤后骨关节炎、骨关节病(膝关节病、椎关节病)、椎关节强硬、滑膜炎、腱鞘炎、滑囊炎、挫伤、扭伤、脱臼和半脱位，以及由生长改变引起的关节病例如骨软骨病、发育异常。
10.根据权利要求1的皮质类固醇和B2激肽受体拮抗剂的组合在制备药物中的用途，所述药物用于预防和治疗呼吸道炎症、皮肤疾患和眼科疾患，过敏或非过敏性、慢性或急性的，特别是哮喘、鼻炎、阻塞性慢性支气管病、灼伤皮炎(热或太阳灼伤)、暴露于过敏原物质或刺激性物质引起的皮炎或湿疹、特应性皮炎、自身免疫性皮炎(银屑病)、睑炎、结膜炎和睑结膜炎。
11.根据权利要求9或10的皮质类固醇和B2激肽受体拮抗剂的组合的用途，其中所述的B2激肽受体拮抗剂是MEN16132。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI2008A001264A IT1391236B1 (it) | 2008-07-11 | 2008-07-11 | Composizioni farmaceutiche a base di antagonisti del recettore b2 delle chinine e corticosteroidi e loro uso |
| ITMI2008A001264 | 2008-07-11 | ||
| PCT/EP2009/004847 WO2010003601A1 (en) | 2008-07-11 | 2009-07-03 | Pharmaceutical compositions based on kinin b2 receptor antagonists and corticosteroids, and their use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102088975A true CN102088975A (zh) | 2011-06-08 |
| CN102088975B CN102088975B (zh) | 2013-08-21 |
Family
ID=40466843
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009801267958A Expired - Fee Related CN102088975B (zh) | 2008-07-11 | 2009-07-03 | 基于激肽b2受体拮抗剂和皮质类固醇的药物组合物及其用途 |
Country Status (36)
| Country | Link |
|---|---|
| US (1) | US8476276B2 (zh) |
| EP (1) | EP2303268B1 (zh) |
| JP (1) | JP5791501B2 (zh) |
| KR (1) | KR101656324B1 (zh) |
| CN (1) | CN102088975B (zh) |
| AP (1) | AP2803A (zh) |
| AR (1) | AR072734A1 (zh) |
| AU (1) | AU2009267416B2 (zh) |
| BR (1) | BRPI0915866A2 (zh) |
| CA (1) | CA2730420A1 (zh) |
| CO (1) | CO6341556A2 (zh) |
| CR (1) | CR20110021A (zh) |
| CY (1) | CY1112900T1 (zh) |
| DK (1) | DK2303268T3 (zh) |
| EA (1) | EA019903B1 (zh) |
| EC (1) | ECSP11010752A (zh) |
| ES (1) | ES2389872T3 (zh) |
| GE (1) | GEP20135792B (zh) |
| HK (1) | HK1158547A1 (zh) |
| HN (1) | HN2011000089A (zh) |
| HR (1) | HRP20120678T1 (zh) |
| IL (1) | IL210554A0 (zh) |
| IT (1) | IT1391236B1 (zh) |
| MA (1) | MA32542B1 (zh) |
| MX (1) | MX2011000350A (zh) |
| MY (1) | MY150477A (zh) |
| NI (1) | NI201100014A (zh) |
| NZ (1) | NZ590427A (zh) |
| PL (1) | PL2303268T3 (zh) |
| PT (1) | PT2303268E (zh) |
| RS (1) | RS52418B (zh) |
| SI (1) | SI2303268T1 (zh) |
| TW (1) | TWI499419B (zh) |
| UA (1) | UA100060C2 (zh) |
| WO (1) | WO2010003601A1 (zh) |
| ZA (1) | ZA201100287B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104072585A (zh) * | 2014-07-21 | 2014-10-01 | 成都圣诺生物科技股份有限公司 | 一种合成艾替班特的方法 |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120190653A1 (en) * | 2011-01-20 | 2012-07-26 | Dow Pharmaceutical Sciences, Inc. | Therapeutic eye drop comprising doxycycline and a stabilizer |
| RU2015138443A (ru) * | 2013-03-14 | 2017-04-20 | Шир Хьюман Дженетик Терапис, Инк. | Способы лечения ангионевротического отека, опосредованного рецепторами брадикинина в2 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MXPA03011795A (es) * | 2001-06-26 | 2005-10-18 | Metaphore Pharmaceuticals Inc | Terapia de combinacion de una superoxido dismutasa mimetica y un corticosteroide para la prevencion y/o el tratamiento de una enfermedad inflamatoria. |
| ITMI20021247A1 (it) * | 2002-06-07 | 2003-12-09 | Menarini Ricerche Spa | Antagonisti basici non peptidici della bradichinina e loro impiego informulazioni farmaceutiche |
| DE10304994A1 (de) * | 2003-02-07 | 2004-09-02 | Aventis Pharma Deutschland Gmbh | Die Verwendung von Antagonisten des Bradykinin-B2 Rezeptors zur Behandlung von Osteoarthrose |
| ITMI20041963A1 (it) * | 2004-10-15 | 2005-01-15 | Luso Farmaco Inst | "antagonisti non-peptidici della bradichinina e loro composizioni farmaceutiche" |
| EP1741444A1 (en) * | 2005-07-05 | 2007-01-10 | Jerini AG | Kinin antagonists for treating bladder dysfunction |
| EP1894559A1 (en) * | 2006-09-01 | 2008-03-05 | PARI Pharma GmbH | Means to solubilise steroids for inhalation |
-
2008
- 2008-07-11 IT ITMI2008A001264A patent/IT1391236B1/it active
-
2009
- 2009-07-03 GE GEAP200912055A patent/GEP20135792B/en unknown
- 2009-07-03 JP JP2011517005A patent/JP5791501B2/ja not_active Expired - Fee Related
- 2009-07-03 AU AU2009267416A patent/AU2009267416B2/en not_active Ceased
- 2009-07-03 UA UAA201100312A patent/UA100060C2/uk unknown
- 2009-07-03 AP AP2011005572A patent/AP2803A/xx active
- 2009-07-03 RS RS20120360A patent/RS52418B/en unknown
- 2009-07-03 NZ NZ590427A patent/NZ590427A/xx not_active IP Right Cessation
- 2009-07-03 BR BRPI0915866A patent/BRPI0915866A2/pt not_active IP Right Cessation
- 2009-07-03 US US13/003,608 patent/US8476276B2/en not_active Expired - Fee Related
- 2009-07-03 CN CN2009801267958A patent/CN102088975B/zh not_active Expired - Fee Related
- 2009-07-03 SI SI200930330T patent/SI2303268T1/sl unknown
- 2009-07-03 ES ES09793880T patent/ES2389872T3/es active Active
- 2009-07-03 DK DK09793880.7T patent/DK2303268T3/da active
- 2009-07-03 EA EA201100013A patent/EA019903B1/ru not_active IP Right Cessation
- 2009-07-03 PL PL09793880T patent/PL2303268T3/pl unknown
- 2009-07-03 WO PCT/EP2009/004847 patent/WO2010003601A1/en active Application Filing
- 2009-07-03 PT PT09793880T patent/PT2303268E/pt unknown
- 2009-07-03 EP EP09793880A patent/EP2303268B1/en active Active
- 2009-07-03 KR KR1020117000761A patent/KR101656324B1/ko active IP Right Grant
- 2009-07-03 CA CA2730420A patent/CA2730420A1/en not_active Abandoned
- 2009-07-03 MX MX2011000350A patent/MX2011000350A/es active IP Right Grant
- 2009-07-03 MY MYPI20110133 patent/MY150477A/en unknown
- 2009-07-08 AR ARP090102611A patent/AR072734A1/es unknown
- 2009-07-09 TW TW098123207A patent/TWI499419B/zh not_active IP Right Cessation
-
2011
- 2011-01-10 HN HN2011000089A patent/HN2011000089A/es unknown
- 2011-01-10 EC EC2011010752A patent/ECSP11010752A/es unknown
- 2011-01-10 NI NI201100014A patent/NI201100014A/es unknown
- 2011-01-11 ZA ZA2011/00287A patent/ZA201100287B/en unknown
- 2011-01-11 CO CO11002068A patent/CO6341556A2/es active IP Right Grant
- 2011-01-11 IL IL210554A patent/IL210554A0/en not_active IP Right Cessation
- 2011-01-11 CR CR20110021A patent/CR20110021A/es unknown
- 2011-02-08 MA MA33588A patent/MA32542B1/fr unknown
- 2011-12-07 HK HK11113241.7A patent/HK1158547A1/xx not_active IP Right Cessation
-
2012
- 2012-07-10 CY CY20121100615T patent/CY1112900T1/el unknown
- 2012-08-27 HR HRP20120678AT patent/HRP20120678T1/hr unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104072585A (zh) * | 2014-07-21 | 2014-10-01 | 成都圣诺生物科技股份有限公司 | 一种合成艾替班特的方法 |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2773142T3 (es) | Nuevo tratamiento | |
| US9119777B2 (en) | Methods and compositions for administration of oxybutynin | |
| RU2003131178A (ru) | Агонисты никотиновых рецепторов для лечения воспалительных заболеваний | |
| CN102088975B (zh) | 基于激肽b2受体拮抗剂和皮质类固醇的药物组合物及其用途 | |
| US20080261932A1 (en) | Methods and compositions for the prevention and/or treatment of an exacerbation of asthma | |
| CA2827299A1 (en) | Liquid propellant-free formulation comprising an antimuscarinic drug | |
| AU2012265231B2 (en) | Nasal pharmaceutical formulation | |
| KR20100065360A (ko) | Ｄｈｅａｓ 흡입용 조성물 | |
| CN101868225B (zh) | 包含缓激肽拮抗剂和透明质酸的药物组合物及其应用 | |
| EA027831B1 (ru) | СПОСОБ ЛЕЧЕНИЯ ВОСПАЛИТЕЛЬНЫХ СОСТОЯНИЙ С ПРИМЕНЕНИЕМ S-[4-(3-ФТОР-3-МЕТИЛБУТИРИЛОКСИ)БУТ-2-ИНИЛ]6α,9α-ДИФТОР-17α-(ФУРАН-2-ИЛ)КАРБОНИЛОКСИ-11β-ГИДРОКСИ-16α-МЕТИЛ-3-ОКСОАНДРОСТА-1,4-ДИЕН-17β-КАРБОТИОАТА | |
| RU2006131788A (ru) | Микроэмульсионные композиции, включающие антагонисты вещества р | |
| JPH09157161A (ja) | 皮膚疾患治療剤 | |
| AU2013368298B2 (en) | Methods and compositions for administration of oxybutynin | |
| Krause | Therapeutic advances in the management of allergic rhinitis and urticaria | |
| CN111511359A (zh) | 非甾体选择性糖皮质激素受体激动调节剂(segram)及其用途 | |
| JPS6058726B2 (ja) | プリン誘導体を有効成分として含有する抗アレルギ−，鎮痛，鎮静剤 | |
| WO2021205341A1 (en) | 1-methylnicotinamide for the prevention/treatment of inflammatory airway diseases | |
| NZ616149B2 (en) | Nasal Pharmaceutical Formulation Comprising Fluticasone | |
| JP2005539058A (ja) | 選択的なホスホジエステラーゼ４−阻害物質による非アレルギー性鼻炎の治療 |
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: 1158547 Country of ref document: HK |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1158547 Country of ref document: HK |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130821 Termination date: 20170703 |