WO2012099479A1 - Compositions injectables utilisées pour traiter une mammite comprenant un médicament anti-inflammatoire non stéroïde (nsaid) et un antibiotique dans un solvant non aqueux - Google Patents
Compositions injectables utilisées pour traiter une mammite comprenant un médicament anti-inflammatoire non stéroïde (nsaid) et un antibiotique dans un solvant non aqueux Download PDFInfo
- Publication number
- WO2012099479A1 WO2012099479A1 PCT/NZ2012/000003 NZ2012000003W WO2012099479A1 WO 2012099479 A1 WO2012099479 A1 WO 2012099479A1 NZ 2012000003 W NZ2012000003 W NZ 2012000003W WO 2012099479 A1 WO2012099479 A1 WO 2012099479A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- antibiotic
- nsaid
- aqueous solvent
- concentration
- Prior art date
Links
- 230000003115 biocidal effect Effects 0.000 title claims abstract description 94
- 239000003125 aqueous solvent Substances 0.000 title claims abstract description 46
- 239000003242 anti bacterial agent Substances 0.000 title claims abstract description 31
- 239000007972 injectable composition Substances 0.000 title claims abstract description 8
- 208000004396 mastitis Diseases 0.000 title claims description 28
- 239000000203 mixture Substances 0.000 claims abstract description 219
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims abstract description 121
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims abstract description 121
- 241001465754 Metazoa Species 0.000 claims abstract description 37
- 208000015181 infectious disease Diseases 0.000 claims abstract description 33
- 238000011282 treatment Methods 0.000 claims abstract description 31
- 239000003120 macrolide antibiotic agent Substances 0.000 claims abstract description 21
- 239000003782 beta lactam antibiotic agent Substances 0.000 claims abstract description 19
- 239000002132 β-lactam antibiotic Substances 0.000 claims abstract description 19
- 230000000813 microbial effect Effects 0.000 claims abstract description 12
- 229940124586 β-lactam antibiotics Drugs 0.000 claims abstract description 12
- 210000005075 mammary gland Anatomy 0.000 claims abstract description 5
- 235000019375 tylosin Nutrition 0.000 claims description 62
- WBPYTXDJUQJLPQ-VMXQISHHSA-N tylosin Chemical compound O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 WBPYTXDJUQJLPQ-VMXQISHHSA-N 0.000 claims description 62
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 60
- 239000004182 Tylosin Substances 0.000 claims description 53
- 229930194936 Tylosin Natural products 0.000 claims description 53
- 229960004059 tylosin Drugs 0.000 claims description 53
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 46
- 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 claims description 33
- 229960000991 ketoprofen Drugs 0.000 claims description 33
- 238000002347 injection Methods 0.000 claims description 29
- 239000007924 injection Substances 0.000 claims description 29
- 238000009472 formulation Methods 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 23
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical class OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 20
- 238000004519 manufacturing process Methods 0.000 claims description 17
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 16
- NOOCSNJCXJYGPE-UHFFFAOYSA-N flunixin Chemical compound C1=CC=C(C(F)(F)F)C(C)=C1NC1=NC=CC=C1C(O)=O NOOCSNJCXJYGPE-UHFFFAOYSA-N 0.000 claims description 15
- 229960000588 flunixin Drugs 0.000 claims description 15
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 claims description 13
- 229960003184 carprofen Drugs 0.000 claims description 13
- 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 claims description 13
- 229960001929 meloxicam Drugs 0.000 claims description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 10
- 238000003860 storage Methods 0.000 claims description 10
- 239000003963 antioxidant agent Substances 0.000 claims description 9
- 230000003078 antioxidant effect Effects 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 235000011187 glycerol Nutrition 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 6
- 229960003276 erythromycin Drugs 0.000 claims description 5
- AFKRZUUZFWTBCC-WSTZPKSXSA-N 2-(diethylamino)ethyl (2s,5r,6r)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound N([C@H]1[C@@H]2N(C1=O)[C@H](C(S2)(C)C)C(=O)OCCN(CC)CC)C(=O)CC1=CC=CC=C1 AFKRZUUZFWTBCC-WSTZPKSXSA-N 0.000 claims description 4
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- RXZBMPWDPOLZGW-XMRMVWPWSA-N (E)-roxithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/OCOCCOC)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 RXZBMPWDPOLZGW-XMRMVWPWSA-N 0.000 claims description 2
- ACTOXUHEUCPTEW-BWHGAVFKSA-N 2-[(4r,5s,6s,7r,9r,10r,11e,13e,16r)-6-[(2s,3r,4r,5s,6r)-5-[(2s,4r,5s,6s)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[(2s,5s,6r)-5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-o Chemical compound O([C@H]1/C=C/C=C/C[C@@H](C)OC(=O)C[C@@H](O)[C@@H]([C@H]([C@@H](CC=O)C[C@H]1C)O[C@H]1[C@@H]([C@H]([C@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(O)C2)[C@@H](C)O1)N(C)C)O)OC)[C@@H]1CC[C@H](N(C)C)[C@@H](C)O1 ACTOXUHEUCPTEW-BWHGAVFKSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- UKXFZNMZXWBSGH-UHFFFAOYSA-N Carbomycin A Natural products COC1C(OC2OC(C)C(OC3CC(C)(O)C(OC(=O)CC(C)C)C(C)O3)C(C2O)N(C)C)C(CC=O)CC(C)C(=O)C=CC4OC4CC(C)OC(=O)CC1C(=O)C UKXFZNMZXWBSGH-UHFFFAOYSA-N 0.000 claims description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- 239000004104 Oleandomycin Substances 0.000 claims description 2
- RZPAKFUAFGMUPI-UHFFFAOYSA-N Oleandomycin Natural products O1C(C)C(O)C(OC)CC1OC1C(C)C(=O)OC(C)C(C)C(O)C(C)C(=O)C2(OC2)CC(C)C(OC2C(C(CC(C)O2)N(C)C)O)C1C RZPAKFUAFGMUPI-UHFFFAOYSA-N 0.000 claims description 2
- 239000004187 Spiramycin Substances 0.000 claims description 2
- FQVHOULQCKDUCY-OGHXVOSASA-N [(2s,3s,4r,6s)-6-[(2r,3s,4r,5r,6s)-6-[[(1s,3r,7r,8s,9s,10r,12r,14e,16s)-7-acetyloxy-8-methoxy-3,12-dimethyl-5,13-dioxo-10-(2-oxoethyl)-4,17-dioxabicyclo[14.1.0]heptadec-14-en-9-yl]oxy]-4-(dimethylamino)-5-hydroxy-2-methyloxan-3-yl]oxy-4-hydroxy-2,4-dimeth Chemical compound O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@H]1[C@@H](CC=O)C[C@@H](C)C(=O)/C=C/[C@@H]2O[C@H]2C[C@@H](C)OC(=O)C[C@H]([C@@H]1OC)OC(C)=O)[C@H]1C[C@@](C)(O)[C@@H](OC(=O)CC(C)C)[C@H](C)O1 FQVHOULQCKDUCY-OGHXVOSASA-N 0.000 claims description 2
- 229940022663 acetate Drugs 0.000 claims description 2
- 229960004099 azithromycin Drugs 0.000 claims description 2
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 claims description 2
- 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 2
- 229960000590 celecoxib Drugs 0.000 claims description 2
- 229960002626 clarithromycin Drugs 0.000 claims description 2
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 claims description 2
- 229960001259 diclofenac Drugs 0.000 claims description 2
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 claims description 2
- 229960004100 dirithromycin Drugs 0.000 claims description 2
- WLOHNSSYAXHWNR-NXPDYKKBSA-N dirithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H]2O[C@H](COCCOC)N[C@H]([C@@H]2C)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 WLOHNSSYAXHWNR-NXPDYKKBSA-N 0.000 claims description 2
- 229960005293 etodolac Drugs 0.000 claims description 2
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 claims description 2
- 229960001680 ibuprofen Drugs 0.000 claims description 2
- 229960004144 josamycin Drugs 0.000 claims description 2
- XJSFLOJWULLJQS-NGVXBBESSA-N josamycin Chemical compound CO[C@H]1[C@H](OC(C)=O)CC(=O)O[C@H](C)C\C=C\C=C\[C@H](O)[C@H](C)C[C@H](CC=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](N(C)C)[C@H](O[C@@H]2O[C@@H](C)[C@H](OC(=O)CC(C)C)[C@](C)(O)C2)[C@@H](C)O1 XJSFLOJWULLJQS-NGVXBBESSA-N 0.000 claims description 2
- 229950007634 kitasamycin Drugs 0.000 claims description 2
- XYJOGTQLTFNMQG-KJHBSLKPSA-N leucomycin V Chemical compound CO[C@H]1[C@H](O)CC(=O)O[C@H](C)C\C=C\C=C\[C@H](O)[C@H](C)C[C@H](CC=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](N(C)C)[C@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(O)C2)[C@@H](C)O1 XYJOGTQLTFNMQG-KJHBSLKPSA-N 0.000 claims description 2
- 229960002009 naproxen Drugs 0.000 claims 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 claims description 2
- 229960002351 oleandomycin Drugs 0.000 claims description 2
- 235000019367 oleandomycin Nutrition 0.000 claims description 2
- RZPAKFUAFGMUPI-KGIGTXTPSA-N oleandomycin Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](C)C(=O)O[C@H](C)[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@]2(OC2)C[C@H](C)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C RZPAKFUAFGMUPI-KGIGTXTPSA-N 0.000 claims description 2
- 229960002702 piroxicam Drugs 0.000 claims description 2
- 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 claims description 2
- 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 2
- 229960000371 rofecoxib Drugs 0.000 claims description 2
- 229960005224 roxithromycin Drugs 0.000 claims description 2
- VYGBQXDNOUHIBZ-UHFFFAOYSA-L sodium formaldehyde sulphoxylate Chemical compound [Na+].[Na+].O=C.[O-]S[O-] VYGBQXDNOUHIBZ-UHFFFAOYSA-L 0.000 claims description 2
- 229960001294 spiramycin Drugs 0.000 claims description 2
- 235000019372 spiramycin Nutrition 0.000 claims description 2
- 229930191512 spiramycin Natural products 0.000 claims description 2
- 229960003250 telithromycin Drugs 0.000 claims description 2
- LJVAJPDWBABPEJ-PNUFFHFMSA-N telithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)[C@@H](C)C(=O)O[C@@H]([C@]2(OC(=O)N(CCCCN3C=C(N=C3)C=3C=NC=CC=3)[C@@H]2[C@@H](C)C(=O)[C@H](C)C[C@@]1(C)OC)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O LJVAJPDWBABPEJ-PNUFFHFMSA-N 0.000 claims description 2
- 229960005041 troleandomycin Drugs 0.000 claims description 2
- LQCLVBQBTUVCEQ-QTFUVMRISA-N troleandomycin Chemical compound O1[C@@H](C)[C@H](OC(C)=O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](C)C(=O)O[C@H](C)[C@H](C)[C@H](OC(C)=O)[C@@H](C)C(=O)[C@@]2(OC2)C[C@H](C)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)OC(C)=O)[C@H]1C LQCLVBQBTUVCEQ-QTFUVMRISA-N 0.000 claims description 2
- 235000006708 antioxidants Nutrition 0.000 claims 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 2
- -1 Feracoxib Chemical compound 0.000 claims 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims 1
- 239000002904 solvent Substances 0.000 description 54
- 238000006243 chemical reaction Methods 0.000 description 30
- 230000036407 pain Effects 0.000 description 29
- 239000000243 solution Substances 0.000 description 21
- 230000002195 synergetic effect Effects 0.000 description 20
- 229940088710 antibiotic agent Drugs 0.000 description 18
- 238000012384 transportation and delivery Methods 0.000 description 17
- 230000008901 benefit Effects 0.000 description 16
- 230000000694 effects Effects 0.000 description 14
- 239000012669 liquid formulation Substances 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- 239000013543 active substance Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 206010061218 Inflammation Diseases 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 230000004054 inflammatory process Effects 0.000 description 9
- 208000035143 Bacterial infection Diseases 0.000 description 8
- 208000022362 bacterial infectious disease Diseases 0.000 description 8
- 230000009286 beneficial effect Effects 0.000 description 8
- 150000003952 β-lactams Chemical class 0.000 description 8
- 241000894006 Bacteria Species 0.000 description 7
- 241000283690 Bos taurus Species 0.000 description 7
- 229940012215 ketofen Drugs 0.000 description 7
- 235000013336 milk Nutrition 0.000 description 7
- 239000008267 milk Substances 0.000 description 7
- 210000004080 milk Anatomy 0.000 description 7
- 229940007392 tylan Drugs 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 238000007792 addition Methods 0.000 description 6
- 235000019445 benzyl alcohol Nutrition 0.000 description 6
- 229960004217 benzyl alcohol Drugs 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 206010037660 Pyrexia Diseases 0.000 description 4
- 210000000481 breast Anatomy 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 239000005018 casein Substances 0.000 description 3
- 235000013365 dairy product Nutrition 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000002158 endotoxin Substances 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 244000144980 herd Species 0.000 description 3
- 230000036512 infertility Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- CWERGRDVMFNCDR-UHFFFAOYSA-M thioglycolate(1-) Chemical compound [O-]C(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-M 0.000 description 3
- 230000014616 translation Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- 208000037487 Endotoxemia Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229960000469 flunixin meglumine Drugs 0.000 description 2
- MGCCHNLNRBULBU-WZTVWXICSA-N flunixin meglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.C1=CC=C(C(F)(F)F)C(C)=C1NC1=NC=CC=C1C(O)=O MGCCHNLNRBULBU-WZTVWXICSA-N 0.000 description 2
- 239000002085 irritant Substances 0.000 description 2
- 231100000021 irritant Toxicity 0.000 description 2
- 230000006651 lactation Effects 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 238000010979 pH adjustment Methods 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000001243 protein synthesis Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- AYIRNRDRBQJXIF-NXEZZACHSA-N (-)-Florfenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)C=C1 AYIRNRDRBQJXIF-NXEZZACHSA-N 0.000 description 1
- YHVUVJYEERGYNU-UHFFFAOYSA-N 4',8-Di-Me ether-5,7,8-Trihydroxy-3-(4-hydroxybenzyl)-4-chromanone Natural products COC1(C)CC(O)OC(C)C1O YHVUVJYEERGYNU-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 241000589877 Campylobacter coli Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 1
- ZOYWWAGVGBSJDL-UHFFFAOYSA-N D-desosamine Natural products CC1CC(N(C)C)C(O)C(O)O1 ZOYWWAGVGBSJDL-UHFFFAOYSA-N 0.000 description 1
- 241000186811 Erysipelothrix Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 241000237536 Mytilus edulis Species 0.000 description 1
- 239000004100 Oxytetracycline Substances 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241001180364 Spirochaetes Species 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 235000020244 animal milk Nutrition 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 239000003781 beta lactamase inhibitor Substances 0.000 description 1
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 1
- 125000003460 beta-lactamyl group Chemical group 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 150000001782 cephems Chemical class 0.000 description 1
- AJSDVNKVGFVAQU-BIIVOSGPSA-N cladinose Chemical compound O=CC[C@@](C)(OC)[C@@H](O)[C@H](C)O AJSDVNKVGFVAQU-BIIVOSGPSA-N 0.000 description 1
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 1
- 229960003324 clavulanic acid Drugs 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 150000008266 deoxy sugars Chemical class 0.000 description 1
- 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 description 1
- 229960003314 deracoxib Drugs 0.000 description 1
- VTJCSBJRQLZNHE-CSMHCCOUSA-N desosamine Chemical compound C[C@@H](O)C[C@H](N(C)C)[C@@H](O)C=O VTJCSBJRQLZNHE-CSMHCCOUSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000009513 drug distribution Methods 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000027950 fever generation Effects 0.000 description 1
- 229960003760 florfenicol Drugs 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000005722 itchiness Effects 0.000 description 1
- 125000000686 lactone group Chemical group 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229920001684 low density polyethylene Polymers 0.000 description 1
- 239000004702 low-density polyethylene Substances 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940041009 monobactams Drugs 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 235000020638 mussel Nutrition 0.000 description 1
- 229960000625 oxytetracycline Drugs 0.000 description 1
- 235000019366 oxytetracycline Nutrition 0.000 description 1
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 150000002959 penams Chemical class 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 239000004540 pour-on Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000003019 stabilising effect Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000009044 synergistic interaction Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- 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
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the invention relates to a composition for the treatment of infection, and most preferably, although not specifically for the treatment of mastitis.
- the present invention will be discussed in relation to a means by which infection within an animal can be treated.
- antibiotics are introduced to animals to combat bacterial infections. This may be via a number of administration routes, including oral and topical. A preferred application is through injection near the infected site (such as the udder).
- Injectable antibiotics have the advantage of treating all four quarters of the udder (vs intramammary which treat only one quarter) provided that high enough concentrations of active are achieved to cure the causative bacteria.
- Minimum Inhibitory Concentrations (MIC) of antibiotic required to inhibit specific bacteria signify the target concentration for mastitis treatment products. Products which fail to achieve the desired MIC are likely to fail to cure mastitis infection.
- Staphylococcus aureus can results in hard-to-cure mastitis and for which antibiotics such as Tylosin containing products are routinely prescribed.
- antibiotics such as Tylosin containing products are routinely prescribed.
- little work has been done internationally to establish the MIC for Tylosin vs S. aureus.
- Most MICs are established using Erythromycin, which is less commonly used for treatment of mastitis.
- the MIC for erythromycin vs S. aureus has been reported to be 0.5pg/ml, whereas the MIC for Tylosin vs S. aureus is 2 pg/ml. Essentially, this means the
- concentration of Tylosin required to effectively treat S. aureus is approximately 4- fold that which is required of erythromycin.
- compositions wherein excipients or additional actives are included to help the antibiotic act more effectively at treating the bacterial infection.
- US 2005/0277634 discloses a combination of NSAID (meloxicam) and an antibiotic (penethamate hydroiodide) in a suspension formulation for injection to treat mastitis. They discuss a synergistic reaction between the NSAID and antibiotic, to the effect that lower levels of antibiotic are needed to achieve a level above the MIC. Preferably, the higher the concentration of NSAID in the composition, the better the antibiotic appears to function.
- a significant problem associated with many injectable compositions can be the development of a site reaction and/or pain caused to the animal upon either intramuscular or subcutaneous delivery.
- This site reaction and pain on injection can often be due to the active agent, such as the antibiotic Tylosin.
- the active agent such as the antibiotic Tylosin.
- other excipients in the compositions typically solvents which act as carriers or solubilisers for the active agent(s).
- This problem is well documented in the review article Strickley et al., Pharmaceutical Research, Vol., 21 No.2 February 2004 titled "Solubilizing Excipients in Oral and Injectable Formulations" .
- veterinary chemists often aim to develop compositions as solutions with as low a concentration and/or volume of solvent(s) in an injectable
- composition as possible. As a consequence, this can lower the ability to achieve higher concentrations of the active agent(s), lower the stability of the composition as a whole, and ultimately lower the animal's likely success from treatment.
- veterinary chemists have preferred to use aqueous-based compositions to avoid site reactions and pain upon injection.
- aqueous based compositions can again lead to instability of the active agent(s), resulting in a shorter shelf-life of the composition (and ultimately bioavailability). It can also limit the ability to retain higher concentrations of active agent(s). It can then be necessary to then revert back to suspensions as discussed in US 2005/0277634.
- WO 02/41899 discloses pour-on or injectable compositions including an antibiotic and an analgesic both dissolved in solvent.
- the exemplified types antibiotics fluorenicol, gentamicin and oxytetracycline
- beta lactam and macrolide antibiotics are distinguishable from those which are the focus of the compositions of the present invention, namely beta lactam and macrolide antibiotics.
- beta lactam and macrolide antibiotics are particularly unstable and are likely to react with NSAIDs such as flunixin.
- NSAIDs such as flunixin.
- such antibiotics are very useful in treating microbial infections in such as that seen in mastitis.
- an injectable composition when used for the treatment of a microbial infection in a mammary gland of an animal, wherein the composition includes a. a non-steroidal anti-inflammatory drug (NSAID); b. an antibiotic selected from the group consisting of a beta lactam antibiotic and macrolide antibiotic; characterised in that: the composition includes a non-aqueous solvent, and the NSAID and antibiotic in the composition are dissolved in the non-aqueous solvent.
- NSAID non-steroidal anti-inflammatory drug
- a method of treating an animal for an internal microbial infection characterised by the step of administering a composition substantially as described above by injection.
- composition substantially as described above in the manufacture of a medicament for the treatment of a microbial infection.
- a method of preparing a composition substantially as described above A method of preparing a composition substantially as described above
- NSAIDs have been administered more-so to treat inflammation and/or pain.
- the inventors have identified an important synergistic effect by administering an NSAID and an antibiotic together in a single injectable composition. This synergistic effect may allow the antibiotic to treat the microbial infection more effectively than if antibiotic was administered alone.
- the inventors have found that the combination of the NSAID and antibiotic in a single formulation has a heightened synergistic effect which is not present if the animal is treated with NSAID and antibiotic in two separate formulations. This may be partially due to the ability to provide the two actives together in a stable composition.
- the synergistic interaction may result from the NSAID decreasing the inflammation in and around the site of the infection (at the udder in the case of mastitis) such that the NSAID allows effective distribution of the antibiotic within the otherwise inflamed site.
- synergistic effect may be partially attributed to the NSAID binding endo-toxins (endotoxaemia), which the inventors otherwise found hindered antibiotic effectiveness.
- G-negative bacteria which produce endo-toxins, are associated with mastitis.
- Such bacteria can cause systemic illness (fever and endotoxaemia).
- fever and endotoxaemia Although this is currently relatively uncommon in New Zealand (less that 1 % incidence), the increased use of feed-pads and herd homes may result in higher incidence rates of mastitis caused by G-negative pathogens.
- the present formulation is envisioned to become an important component of infection treatment regimes in the future, for example in mastitis.
- the synergistic effect may be further enhanced as the NSAID may act to reduce fever (pyrexia) to allow better effectiveness of the antibiotic as well as safety/comfort of the animal.
- the ability to provide two different actives in one combination formulation may help to overcome the need for delivery of multiple compositions, storage of compositions, costs, packaging and so forth.
- the inventors were able to identify a particular solvent type that aided the combination of the two actives, which previously were found to be very difficult to combine in a stable solution. In the past, suspensions were used in order to combine such actives together in a single composition.
- the inventors identified a further, unexpected, synergistic effect between the two actives as the concentration of the NSAID was increased, as discussed below. The aim of increasing the concentration of NSAID was to improve the synergistic effect initially identified by the inventors to help improve antibiotic effectiveness at the site of infection.
- Active agents have recommended dosages based on what has been established as effective. Thus when two agents are combined, the combination should provide the appropriate doses of each active. For example, for the recommended dosage of a particular antibiotic (e.g. Tylosin, 10 mg/kg) a concentration of is 20% Tylosin is often used in the composition. This high concentration of Tylosin can often be the limiting factor in such a composition as it can cause significant irritation on injection. In order to provide concomitant dose of an NSAID (e.g. Ketoprofen), a concentration of 6% w/v is preferred. Indeed, compatibility of dosage regimes between the multiple actives used can be an important aspect of the
- Ketoprofen the composition was not stable with an aqueous based solvent. With other NSAIDs tested, similarly poor stability results were seen in an aqueous based composition if NSAIDs were included at required concentrations to reflect recommended dosages. Without wanting to revert to suspensions, the inventors had to consider other avenues.
- non-aqueous solvent system To compensate for an increased concentration of NSAID, the inventors utilised a non-aqueous solvent system in attempt to provide a stable composition in solution at various conditions (e.g. temperatures above 4°C). However, it was expected, as generally understood in the art, that reverting to non-aqueous solvents would lead to increased site reaction and/or pain on delivery compared to aqueous-based compositions.
- an antibiotic and an NSAID can be included together in a stable composition in solution with an increased concentration of NSAID greater than normally achievable than when combined in an aqueous based system. Importantly, this was achievable without resulting in an increased site reaction or pain on delivery compared to industry standards (Tylan and Ketofen).
- the composition of the present invention is provided as an injectable liquid formulation.
- liquid formulation should be taken as meaning any therapeutic formulation that is of a "syringable" consistency. This is the mode of administration preferred by many farmers and veterinarians, particularly as localised application of a NSAID can be of greater effect when treating an infection site such as mammary glands (mastitis).
- the liquid formulation has a syringable viscosity at lower temperatures.
- the liquid formulation is a solution. This should be taken as meaning a composition wherein all the excipients and active agents are substantially solubilised in the solution, and not in suspension.
- a solution provides many advantages over suspensions. For example, there are no issues with caking, re-suspension, or difficulties with injection.
- the solution may have one or more phases.
- Non-steroidal anti-inflammatory drug is N-steroidal anti-inflammatory drug
- non-steroidal anti-inflammatory drug should be taken as meaning any drugs or active compound with antiinflammatory effects without using steroids.
- NSAID non-steroidal anti-inflammatory drug
- the NSAID is selected from the group consisting of Carprofen, Naproxen, Ibuprofen, Ketoprofen, Piroxicam, Diclofenac, Etodolac, Flunixin, Deracoxib, Meloxicam, Celecoxib, Rofecoxib, and combinations thereof.
- the NSAID is selected from the group consisting of Flunixin, Carprofen, Ketoprofen and combinations thereof.
- the NSAID is present in the liquid formulation at a concentration of 1- 15% w/v.
- concentration of NSAID it may be preferable to increase the concentration of NSAID to improve the synergistic effect between the two actives.
- the NSAID flunixin meglumine is present in the composition at a concentration of approximately 7.3% w/v. This may provide approximately 4.4 % Flunixin in the composition. This is as per dose rate in combination with Tylosin.
- each NSAID may also be dependent on it's anti-inflammatory efficacy and safety profiles, as well as the concentration of antibiotic used in the composition.
- the NSAID Meloxicam is present in the composition at a concentration of approximately 1% w/v.
- the NSAID Carprofen is present in the composition at a concentration of approximately 3% w/v.
- the NSAID Ketoprofen is present in the composition at a concentration of approximately 4% to 10 % w/v.
- the concentration of the antibiotic Tylosin is at 20% w/v in the composition
- the corresponding Ketoprofen concentration is preferably 6% w/v. If the Tylosin concentration is increased to 30% w/v, a preferred concentration of Ketoprofen is 9% w/v.
- the NSAID is selected from natural forms of anti-inflammatory agents.
- these may include green-lipped mussel extract, omega 3, and the like.
- antibiotic should be taken as meaning a substance or compound, either natural, synthetic or semi-synthetic, that kills bacteria (bactericidal) and/or inhibits bacterial growth (bacteriostatic).
- the antibiotic in the composition is selected from a group consisting of macrolide and beta-lactam antibiotics.
- macrolide antibiotic should be taken as meaning any antibiotic which activity stems from the presence of a macrolide ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached.
- the lactone rings are usually 14-, 15-, or 16-membered.
- Macrolide-class antibiotics are typically used in veterinary medicine and are considered to share a common mode of action. It is considered that macrolide antibiotics' mode of action involves interference with protein synthesis, for instance by blocking translation at the ribosome.
- the macrolide-class antibiotic is selected from Azithromycin,
- Clarithromycin Dirithromycin, Erythromycin, Roxithromycin, Telithromycin,
- Carbomycin A Josamycin, Kitasamycin, Midecamicine/midecamicine acetate, Oleandomycin, Spiramycin, Troleandomycin, and Tylosin/tylocine.
- the macrolide antibiotic is Tylosin.
- Tylosin is a macrolide-class antibiotic used in veterinary medicine to treat bacterial infections in a wide range of species and has a high margin of safety.
- a further advantage of Tylosin is that it is licensed for mastitis therapy in New Zealand.
- Tylosin has a wide spectrum of activity against gram positive bacteria including Staphylococci, Streptococci, Corynebacteria, and Erysipelothrix. It also has activity towards gram negative Campylobacter coli, and some spirochaetes. It is also active against Mycoplasma species.
- Injectable Tylosin formulations can cause pain, inflammation, and itchiness around the injection site. Therefore, it is important to be able to reduce the above side effects when Tylosin is injected.
- the provision of an antibiotic such as Tylosin together with a NSAID has an additional advantage in that the NSAID may help to avoid the side effects the Tylosin. This reduction in side effects may be aided by the synergistic effect between the NSAID and the antibiotic when administered in one formulation.
- beta lactam antibiotic should be taken as meaning any antibiotic including a beta lactam ring in its structure. For example, this may include penicillin derivatives (penams), cephalosporins (cephems), monobactams, and carbapenems.
- beta lactam antibiotics involves attacking bacterial cell walls.
- the beta-lactam antibiotics may be provided with beta-lactamase inhibitors such as clavulanic acid.
- the beta lactam antibiotic is penethamate.
- penethamate has a similar efficacy to Tylosin (a particularly preferred type of antibiotic used for the present invention).
- beta lactam and macrolide antibiotics are weak bases and are lipophilic. This may result in higher concentrations in bodily fluids such as milk than in plasma. As such, they are more likely than less lipophilic compounds to achieve concentrations greater than the minimum inhibitory concentration (MIC).
- MIC minimum inhibitory concentration
- the antibiotic is present in the liquid formulation at a
- concentration between 10-35% w/v, and most preferably approximately 20.0 - 30.0 % w/v.
- a higher antibiotic concentration will lead to a lesser volume of antibiotic needed to administer per dose, which may be more convenient for farmers and more comfortable for smaller animals.
- By increasing the NSAID levels in the composition it may also be possible to increase the antibiotic concentration in the composition without increased site reaction on delivery (similar to the effect seen when the inventors reverted to a non-aqueous based solvent, also expected to cause increased site reaction/pain).
- the inventors acknowledge that if the treatment is for Staph, aureus, the amount of antibiotic (e.g. Tylosin) may be increased up to 60% w/v to account for the minimum inhibitory concentration (MIC).
- antibiotic e.g. Tylosin
- the ratio of NSAID to antibiotic (w/v) in the liquid formulation is approximately 1 :3, respectively. This may be a particularly applicable ratio if the NSAID is flunixin. However if the NSAID is a different type of NSAID, such as meloxicam or carprofen, the ratio may vary.
- solvent should be taken as meaning any solvent or combination of different solvents which are present in the composition.
- the solvent has one or more of the following features: - non-aqueous;
- the composition is entirely non-aqueous.
- the inventors tested a range of different aqueous-based compositions which were found to be quite unstable under high temperature stress and often even at room temperature.
- Tylosin was found to be particularly unstable when combined with an NSAID in an aqueous based formulation.
- the composition remained stable, especially at lower temperatures (e.g. 2-15°C).
- the non-aqueous solvent has a dielectric point between 30 and 50.
- propylene glycol (32.1 ), NMP (32.2), DMSO (46.7) and DMA (38) were all found to improve stability of the active. Surprisingly such solvents were not seen to increase the site reaction/pain on delivery compared to aqueous based
- compositions (possibly due to secondary synergistic effect discussed above).
- non-aqueous solvent broadly classified as a dipolar aprotic solvent was found to be particularly advantageous.
- NMP was seen as a very useful solvent for improving stability yet not increasing site reaction, despite it being considered an irritating solvent and one which causes site reaction on injection.
- the non aqueous solvent is selected from N- Methyl-2-Pyrrolidone (NMP), glycerine formal, propylene glycol, and benzyl alcohol.
- Solvents such as NMP and propylene glycol which were found to be particularly effective in stabilising the composition and allowing higher concentrations of NSAID, are also known to be high irritants when injected. Therefore, it was particularly surprising to find these solvents did not lead to increased site reaction when the composition was injected.
- the liquid formulation includes at least two different non-aqueous based solvents.
- the liquid formulation includes a first and second non-aqueous based solvent, wherein the first solvent acts as a solubilising agent, and wherein the second solvent acts as a carrier solvent.
- the inventors have identified that a combination of NMP and propylene glycol provide particularly stable actives in the formulation.
- the inclusion of NMP, glycerine formal and/or benzyl alcohol may be used as solubilising agent for the actives, whereas a solvent such as propylene glycol may be used as a carrier in the composition to provide improved stability.
- a solvent such as propylene glycol
- solubilising agent such as NMP
- the amount of solubilising agent may vary depending on the type and solubility of the active agents in the composition.
- the amount of solubilising agent in the composition is less than 40% w/v.
- the amount of solubilising agent in the composition is
- NMP preferably is instead only used at minimal levels and merely as a solubilising agent(s).
- the main solvent is NMP
- the composition is made to volume with the NMP (in most cases equating to approximately 60% w/v or more in the final composition).
- the simple use of NMP as a main solvent (disclosed on page 4 of WO'899 as being up to 95% w/v of the final composition) reflects the antibiotics used, i.e. not beta lactam or macrolide type antibiotics.
- the amount of carrier solvent in the composition is at least 30% w/v. More preferably, the amount of carrier solvent in the formulation is at least 40% w/v.
- the ratio of the first solvent to the second solvent is between 1 :10 and 1 :1. More preferably, the ratio of the first solvent to the second solvent is approximately between 1 :2 and 1 :1.
- Carrier solvents such as propylene glycol are much harsher as a solvent and are understood to cause more site reaction on injection than NMP. Based on what was generally understood in the art, this is also possibly a further reason why disclosures such as WO'899 may not have directed the reader to using a carrier solvent such as propylene glycol, and instead relied primarily on large amounts of NMP.
- this carrier solvent in the present invention is what helps to provide good stability of the beta-lactam/macrolide antibiotic and NSAID in the composition.
- WO'899 does not teach towards use of a carrier solvent feature in any way, let alone towards the types of antibiotics used in the present invention.
- macrolide/beta lactam antibiotics are shown to have good stability in a range of conditions (seen in Example 6 of the Best Modes section).
- the non-aqueous based solvent accounts for over 10% w/v of the composition. More preferably, the non-aqueous based solvent accounts for between 30% w/v to 80% of the composition. As discussed previously, such high levels of non-aqueous solvent (and particularly a carrier solvent in comparison to the solubilising agent) were beneficial in providing more stable compositions and increased
- the liquid formulation includes at least one antioxidant.
- the antioxidant is selected from sodium formaldehyde sulphoxylate or butylated hydroxyl toluene (BHT).
- BHT butylated hydroxyl toluene
- the antioxidant is present in the liquid formulation at a concentration between 0.01 - 0.3 % w/v, and most preferably approximately 0.05% w/v.
- administration should be taken as meaning the delivery of actives in the composition to the site of infection, either as a result of local or systemic application (i.e. substantially throughout the blood stream and body of the animal).
- the composition is for treating an internal infection.
- an internal infection should be taken as meaning a site inside the body, which includes bodily cavities which are accessible from outside the body. For instance, this includes cavities such as the mouth, teat canal, udder, anus, vagina and so forth.
- the composition is administered systemically. Examples of systemic administration may include delivery via injection, bolus, or drench, wherein the actives may then be distributed through the animal's bloodstream to the site of infection and/or inflammation. Most preferably, the composition is administered via injection. It should be noted that the injection may occur locally near or at the site of infection whilst still resulting in good systemic delivery of the active.
- the composition may be injected subcutaneously or intramuscularly.
- the composition is used to treat clinical mastitis.
- the composition may be used for the prevention of early stage mastitis.
- the use of NSAID in a composition to treat mastitis is a new concept, with considerable advantages as discussed throughout this specification.
- composition may be used to treat substantially any type of internal microbial infection and/or associated inflammation/pain.
- the composition is used to treat non-human animals such as cows, sheep, goats or other animals commonly used in the dairy industry.
- the composition is administered with a dosage of 5-20 mg/kg/day (by weight drug/animal) antibiotic and 0.2 mg - 4 mg/kg/day NSAID.
- this dosage appears to provide the MIC needed for Tylosin (2 pg/ml), such that a therapeutic level of antibiotic is provided.
- the antibiotic may be more effective than normal such that lower levels of antibiotic are required whilst still effectively treating the bacterial infection.
- the amount of NSAID will vary depending on the type. For instance, the preferred approximate dosage of each NSAID may be dependent on it's anti-inflammatory efficacy and safety profiles.
- the dosage of Flunixin is between 1-3 mg/kg/day. Most preferably, the dosage of Flunixin is approximately 2.2 mg/kg/day.
- the dosage of Meloxicam is between 0.1-1 mg/kg/day. Most preferably, the dosage of Meloxicam is approximately 0.5 mg/kg/day. Preferably, the dosage of Ketoprofen is between 2-4 mg/kg/day. Most preferably, the dosage of Ketoprofen is approximately 3 mg/kg/day.
- the dosage of Carprofen is between 0.5-2.5 mg/kg/day. Most preferably, the dosage of Carprofen is approximately 1.4 mg/kg/day.
- the treatment method may utilise a flexible dosage approach to allow adjustments in treating the disease based on its type and severity.
- a flexipack may be particularly useful for applying this flexible dosage approach.
- a flexipack is typically a container made from a mixture of high and low density polyethylene. Such packaging is readily available from many manufacturers.
- a major advantage of using nonaqueous solvents is that the concentration of actives in the composition can be increased. This has numerous benefits, including being able to administer a greater quantity of active to the animal in a lower volume. This may help to decrease administration time, and discomfort to the animal during injection.
- a lower volume dosage is beneficial for storage as it takes up less space.
- the NSAID in the composition is increased to a concentration (% w/v) which would not be storage stable at room temperature in a corresponding aqueous based composition.
- the NSAID is Ketoprofen and wherein the concentration of Ketoprofen is above 4% w/v.
- a first and second non-aqueous solvent is added to a mixing container prior to the addition of either the NSAID or antibiotic.
- first and second non-aqueous solvents chosen may depend on the type, number or concentration of NSAID and antibiotic used in the formulations. Examples of first and second non aqueous solvents are provided in the Best Modes section. However, these examples are not intended to be limiting.
- additional non aqueous solvents may be added.
- the non-aqueous solvent(s) are heated to approximately 55-80°C prior to the addition of either the NSAID or antibiotic.
- the temperature used may depend on the specific actives used in the composition.
- the antibiotic is added to the non aqueous solvent(s) and dissolved prior to the addition of the NSAID.
- the NSAID may then be added and dissolved into the mixture of dissolved antibiotic and non aqueous solvent(s). It was found by the inventors that this step wise addition of solvents, antibiotic and finally NSAID provided improved solubility and stability of the composition.
- the temperature is maintained at 55-80°C throughout the step-wise addition of the NSAID and antibiotic to the formulation.
- the composition containing the NSAID and antibiotic is then cooled to
- composition may then be stored at approximately 4°C prior to administration.
- a non aqueous solvent helps to overcome issues of incompatibility between actives, and in particular instability of many antibiotics.
- Use of a non aqueous solvent allows the composition to be provided as a stable composition in solution (not a suspension) over a range of storage conditions.
- a solution avoids caking, the need for re-suspension of the composition prior to delivery, and problems with injection (clogging of the needle, and potential pain to the animal from the particulate matter).
- non aqueous solvents allow the concentration of the NSAID to be increased beyond levels obtainable in an aqueous based composition. Despite the expected increase in site reaction and pain on delivery due to the known traits of non-aqueous solvents, an increase in these side effects were not seen.
- the increase in the NSAID obtained may also help to lower the site reaction caused, not only by the solvents, but potentially also the antibiotic (tylosin is a known irritant). Potentially, the concentration of tylosin in the composition may be increased due to the lower site reaction on injection.
- composition to a desired pH, removing additional steps in the
- NSAIDs may bind with the endotoxins (G-negative bacteria) improving treatment outcomes, and as such will become an important component of mastitis treatment regimens the future.
- Formulation likely to be particularly effective in treating Gram-negative mastitis which is expected to rise in prevalence in New Zealand over the coming years.
- Table 1 illustrates a number of initial formulations trialed by the inventors accordance with the present invention.
- Flunixin injection (Brand Name: Fluxamine injection) which is registered with ACVM.
- F3 Product color turned to dark brown within 48hrs at room temperature.
- F6 Antioxidant was changed to BHT instead of sodium formaldehyde sulfoxylate.
- F7 Glycerine formal stabilised was incorporated to stabilize the formulation.
- Formulation F5 appeared the most stable of the Tylosin/Flunixin formulations.
- One method of preparing the F5 formulation is provided below.
- the inventors then trialed a combination containing Tylosin/Ketoprofen.
- the inventors aimed to provide a composition containing higher levels of NSAID Ketoprofen than seen in Example 3, together with Tylosin.
- the rationale was that an increased amount of NSAID would synergistically aid the antibiotic's effectiveness at the site of infection, whilst also providing increased pain relief to the animal.
- NMP N-Methyl-2-Pyrrolidone
- NMP N-Methyl- 2-Pyrrolidone
- BHT Butylated Hydroxy toluene
- Ketofen Muscular New Zealand, Auckland, New Zealand
- Tylan has 20% w/v Tylosin; with a prescribed dosage of 10 mg/kg body weight.
- Ketofen has 10% w/v ketoprofen with a prescribed dosage of 3 mg/kg. Both Tylan and Ketofen are aqueous based compositions.
- Solid line represents Tylosin serum levels from using the test composition from Example 4. Dotted line represents Tylosin serum levels from using Tylan.
- Solid line represents Ketoprofen serum levels from using the test composition from Example 4.
- Dotted line represents Ketoprofen serum levels from using Ketofen.
- the study results showed similar levels of bioequivalence between two compositions when dosages were kept constant. This illustrates that the combination composition has good bioavailability compared to industry standards which are administered separately. This in itself is a major advantage.
- Ketoprofen beyond 3 mg/kg could be achieved whilst avoiding increased (or even decreasing) site reaction/pain compared to currently available compositions.
- Increased dosage through increased concentration of NSAID may be achieved because a non-aqueous solvent is used to stabilise the active in the composition.
- the batches were packed in 100 ml glass amber vials and stored at the designated storage conditions of 25°C/60& RH, 30°C/65%RH and 40°C/75%RH.
- compositions were stable for at least six months at 25°C/60%RH and 30°C/65%RH.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Pain & Pain Management (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Rheumatology (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BR112013018557-0A BR112013018557B1 (pt) | 2011-01-20 | 2012-01-20 | Composição injetável, seu uso e seu método de preparação |
MX2013008407A MX353876B (es) | 2011-01-20 | 2012-01-20 | Metodo para el tratamiento de una infeccion. |
AU2012207698A AU2012207698A1 (en) | 2011-01-20 | 2012-01-20 | Injectable compositions for mastitis comprising an NSAID and an antibiotic in a non-aqueous solvent |
KR1020137021988A KR101905173B1 (ko) | 2011-01-20 | 2012-01-20 | 비-수성 용매 중 nsaid 및 항생제를 포함하는 유방염 치료를 위한 주사가능한 조성물 |
CN201280005989.4A CN103327984B (zh) | 2011-01-20 | 2012-01-20 | 包含在非水性溶剂中nsaid和抗生素的用于治疗乳腺炎的可注射组合物 |
IL227540A IL227540A (en) | 2011-01-20 | 2013-07-18 | Injectable preparations containing nsaid and antibiotics in an aqueous solvent and their uses |
AU2015268626A AU2015268626C1 (en) | 2011-01-20 | 2015-12-10 | Injectable compositions for mastitis comprising an NSAID and an antibiotic in a non-aqueous solvent |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ588686 | 2011-01-20 | ||
NZ588686A NZ588686A (en) | 2011-01-20 | 2011-01-20 | Injectable composition comprising an NSAID and an antibiotic in a non-aqueous solvent for treating a microbial infection in a mammary gland |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2012099479A1 true WO2012099479A1 (fr) | 2012-07-26 |
Family
ID=46515931
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/NZ2012/000003 WO2012099479A1 (fr) | 2011-01-20 | 2012-01-20 | Compositions injectables utilisées pour traiter une mammite comprenant un médicament anti-inflammatoire non stéroïde (nsaid) et un antibiotique dans un solvant non aqueux |
Country Status (15)
Country | Link |
---|---|
KR (1) | KR101905173B1 (fr) |
CN (1) | CN103327984B (fr) |
AU (1) | AU2012207698A1 (fr) |
BR (1) | BR112013018557B1 (fr) |
CL (1) | CL2013002086A1 (fr) |
CO (1) | CO6801732A2 (fr) |
CR (1) | CR20130401A (fr) |
GT (1) | GT201300182A (fr) |
IL (1) | IL227540A (fr) |
MX (1) | MX353876B (fr) |
NI (1) | NI201300063A (fr) |
NZ (1) | NZ588686A (fr) |
PE (1) | PE20140035A1 (fr) |
WO (1) | WO2012099479A1 (fr) |
ZA (1) | ZA201305780B (fr) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2995297A1 (fr) * | 2014-09-09 | 2016-03-16 | Ceva Sante Animale | Compositions parentérales et leurs utilisations |
WO2017060550A1 (fr) * | 2015-10-05 | 2017-04-13 | Quimica Luar Srl | Composition pharmaceutique bactéricide et virucide |
CN111035614A (zh) * | 2019-12-20 | 2020-04-21 | 北京喜禽药业有限公司 | 一种高含量土霉素注射液及其制备方法 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105663037A (zh) * | 2016-01-27 | 2016-06-15 | 成都乾坤动物药业有限公司 | 一种阿莫西林溶液剂及其制备方法和用途 |
CN112472667B (zh) * | 2019-08-23 | 2022-11-15 | 北京欧博方医药科技有限公司 | 一种维他昔布长效注射液及其制备方法和应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002041899A1 (fr) * | 2000-11-27 | 2002-05-30 | Phoenix Scientific, Inc. | Preparation antibiotique/analgesique et procede d'elaboration de cette preparation |
US20050148519A1 (en) * | 2003-10-29 | 2005-07-07 | Murthy Yerramilli V.S. | Salts of pharmacologically active compounds |
US20050277634A1 (en) * | 2004-05-19 | 2005-12-15 | Boehringer Ingelheim Vetmedica Gmbh | Liquid composition for veterinary medicine and process for the preparation and use thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1297319C (zh) * | 2003-09-22 | 2007-01-31 | 王玉万 | 以硅油为介质制备含抗微生物药物的制剂 |
-
2011
- 2011-01-20 NZ NZ588686A patent/NZ588686A/xx unknown
-
2012
- 2012-01-20 WO PCT/NZ2012/000003 patent/WO2012099479A1/fr active Application Filing
- 2012-01-20 MX MX2013008407A patent/MX353876B/es active IP Right Grant
- 2012-01-20 KR KR1020137021988A patent/KR101905173B1/ko active IP Right Grant
- 2012-01-20 PE PE2013001576A patent/PE20140035A1/es not_active Application Discontinuation
- 2012-01-20 AU AU2012207698A patent/AU2012207698A1/en not_active Abandoned
- 2012-01-20 CN CN201280005989.4A patent/CN103327984B/zh active Active
- 2012-01-20 BR BR112013018557-0A patent/BR112013018557B1/pt active IP Right Grant
-
2013
- 2013-07-17 NI NI201300063A patent/NI201300063A/es unknown
- 2013-07-17 GT GT201300182A patent/GT201300182A/es unknown
- 2013-07-18 IL IL227540A patent/IL227540A/en not_active IP Right Cessation
- 2013-07-19 CL CL2013002086A patent/CL2013002086A1/es unknown
- 2013-07-31 ZA ZA2013/05780A patent/ZA201305780B/en unknown
- 2013-08-05 CO CO13186092A patent/CO6801732A2/es unknown
- 2013-08-19 CR CR20130401A patent/CR20130401A/es unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002041899A1 (fr) * | 2000-11-27 | 2002-05-30 | Phoenix Scientific, Inc. | Preparation antibiotique/analgesique et procede d'elaboration de cette preparation |
US20050148519A1 (en) * | 2003-10-29 | 2005-07-07 | Murthy Yerramilli V.S. | Salts of pharmacologically active compounds |
US20050277634A1 (en) * | 2004-05-19 | 2005-12-15 | Boehringer Ingelheim Vetmedica Gmbh | Liquid composition for veterinary medicine and process for the preparation and use thereof |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2995297A1 (fr) * | 2014-09-09 | 2016-03-16 | Ceva Sante Animale | Compositions parentérales et leurs utilisations |
WO2016038059A1 (fr) * | 2014-09-09 | 2016-03-17 | Ceva Sante Animale | Compostions parentérales et leurs utilisations |
EP3513781A1 (fr) * | 2014-09-09 | 2019-07-24 | Ceva Sante Animale | Compositions parentérales et leurs utilisations |
AU2015314311B2 (en) * | 2014-09-09 | 2020-11-26 | Ceva Sante Animale | Parenteral compositions and uses thereof |
RU2744987C2 (ru) * | 2014-09-09 | 2021-03-17 | Сева Сантэ Анималь | Парентеральные композиции и их применение |
WO2017060550A1 (fr) * | 2015-10-05 | 2017-04-13 | Quimica Luar Srl | Composition pharmaceutique bactéricide et virucide |
US10973787B2 (en) | 2015-10-05 | 2021-04-13 | Quimica Luar Srl | Bactericidal and virucidal pharmaceutical composition |
US11925612B2 (en) | 2015-10-05 | 2024-03-12 | Quimica Luar Srl | Bactericidal and virucidal pharmaceutical composition |
CN111035614A (zh) * | 2019-12-20 | 2020-04-21 | 北京喜禽药业有限公司 | 一种高含量土霉素注射液及其制备方法 |
CN111035614B (zh) * | 2019-12-20 | 2024-02-02 | 北京喜禽药业有限公司 | 一种高含量土霉素注射液及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
KR101905173B1 (ko) | 2018-11-28 |
BR112013018557B1 (pt) | 2021-11-03 |
MX2013008407A (es) | 2013-09-26 |
KR20140012646A (ko) | 2014-02-03 |
CN103327984B (zh) | 2016-08-17 |
NZ588686A (en) | 2013-07-26 |
NI201300063A (es) | 2014-05-23 |
AU2012207698A1 (en) | 2013-04-18 |
ZA201305780B (en) | 2014-04-30 |
IL227540A0 (en) | 2013-09-30 |
BR112013018557A2 (pt) | 2016-11-22 |
CR20130401A (es) | 2014-02-04 |
CL2013002086A1 (es) | 2014-07-25 |
IL227540A (en) | 2017-12-31 |
CO6801732A2 (es) | 2013-11-29 |
GT201300182A (es) | 2014-07-28 |
MX353876B (es) | 2018-02-01 |
PE20140035A1 (es) | 2014-02-16 |
CN103327984A (zh) | 2013-09-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2325189C2 (ru) | Способ и фармацевтическая композиция для доставки противовоспалительного средства | |
EP1744756B1 (fr) | Utilisation de formulations a base de meloxicame en medecine veterinaire | |
AU2007339312B2 (en) | Pharmaceutical compositions and method for treating inflammation in cattle and other animals | |
EP2293777B1 (fr) | Compositions transdermiques pharmaceutiques et methode pour le traitement de l'inflammation chez le betail | |
WO2012099479A1 (fr) | Compositions injectables utilisées pour traiter une mammite comprenant un médicament anti-inflammatoire non stéroïde (nsaid) et un antibiotique dans un solvant non aqueux | |
AU2015268626C1 (en) | Injectable compositions for mastitis comprising an NSAID and an antibiotic in a non-aqueous solvent | |
RU2432945C1 (ru) | Ветеринарная композиция для профилактики и лечения различных форм эндометрита, содержащая пропранолол в сочетании с антибактериальным компонентом, и ветеринарное лекарственное средство для профилактики и лечения различных форм эндометрита | |
AU2015100768A4 (en) | Development of Doxycycline Injectable for Caged and Aviary Birds and there of | |
CA2626273C (fr) | Compositions de cefquinome et procedes d'utilisation de celles-ci | |
NZ769844A (en) | Method of treatment of infection | |
RU2698820C1 (ru) | Препарат для лечения мастита у коров в период лактации | |
CN110721152B (zh) | 一种治疗动物皮肤寄生虫、真菌感染的缓释组合物 | |
CN103181921A (zh) | 一种氨苄西林苄星氯唑西林乳房注入剂组合物及制备方法 | |
EA001530B1 (ru) | Способ лечения или предотвращения бактериальной респираторной или кишечной инфекции домашнего скота | |
RU2442573C1 (ru) | Способ лечения дизентерии свиней | |
US20240058366A1 (en) | Methods of treating mastitis with an orthosomycin antimicrobial compound | |
EP0238207A1 (fr) | Mélanges bactéricides | |
CN103655560A (zh) | 一种复方盐酸沃尼妙林口服溶液剂及其制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
DPE2 | Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12736881 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2012207698 Country of ref document: AU Date of ref document: 20120120 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12013501449 Country of ref document: PH |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2013002086 Country of ref document: CL Ref document number: 001576-2013 Country of ref document: PE Ref document number: MX/A/2013/008407 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1301004006 Country of ref document: TH |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13186092 Country of ref document: CO |
|
WWE | Wipo information: entry into national phase |
Ref document number: CR2013-000401 Country of ref document: CR |
|
ENP | Entry into the national phase |
Ref document number: 20137021988 Country of ref document: KR Kind code of ref document: A |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112013018557 Country of ref document: BR |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 12736881 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 112013018557 Country of ref document: BR Kind code of ref document: A2 Effective date: 20130719 |