CN104906039B - A kind of Tilmicosin suspension and preparation method thereof - Google Patents
A kind of Tilmicosin suspension and preparation method thereof Download PDFInfo
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- CN104906039B CN104906039B CN201510366424.4A CN201510366424A CN104906039B CN 104906039 B CN104906039 B CN 104906039B CN 201510366424 A CN201510366424 A CN 201510366424A CN 104906039 B CN104906039 B CN 104906039B
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- Prior art keywords
- tilmicosin
- injection
- fat emulsion
- suspension
- thickener
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- JTSDBFGMPLKDCD-XVFHVFLVSA-N tilmicosin Chemical compound 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]1CCN1C[C@H](C)C[C@H](C)C1)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N(C)C)[C@H]1O JTSDBFGMPLKDCD-XVFHVFLVSA-N 0.000 title claims abstract description 100
- 229960000223 tilmicosin Drugs 0.000 title claims abstract description 91
- 239000000725 suspension Substances 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 238000002347 injection Methods 0.000 claims abstract description 52
- 239000007924 injection Substances 0.000 claims abstract description 52
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 17
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 16
- 239000004094 surface-active agent Substances 0.000 claims abstract description 15
- 239000002562 thickening agent Substances 0.000 claims abstract description 14
- 230000001954 sterilising effect Effects 0.000 claims description 23
- 239000002960 lipid emulsion Substances 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 19
- 239000000084 colloidal system Substances 0.000 claims description 18
- 239000003549 soybean oil Substances 0.000 claims description 18
- 235000012424 soybean oil Nutrition 0.000 claims description 18
- 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 claims description 16
- 238000002156 mixing Methods 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- -1 ethoxycarbonyl hydroxyethyl methyl sulfate methyl ammonium Chemical compound 0.000 claims description 6
- 239000003921 oil Substances 0.000 claims description 6
- 235000019198 oils Nutrition 0.000 claims description 6
- NWGKJDSIEKMTRX-MDZDMXLPSA-N Sorbitan oleate Chemical group CCCCCCCC\C=C\CCCCCCCC(=O)OCC(O)C1OCC(O)C1O NWGKJDSIEKMTRX-MDZDMXLPSA-N 0.000 claims description 5
- 229910052782 aluminium Inorganic materials 0.000 claims description 5
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 5
- 239000004411 aluminium Substances 0.000 claims description 5
- 240000008415 Lactuca sativa Species 0.000 claims description 4
- BGNXCDMCOKJUMV-UHFFFAOYSA-N Tert-Butylhydroquinone Chemical compound CC(C)(C)C1=CC(O)=CC=C1O BGNXCDMCOKJUMV-UHFFFAOYSA-N 0.000 claims description 4
- 235000012045 salad Nutrition 0.000 claims description 4
- 239000008117 stearic acid Substances 0.000 claims description 4
- 239000004250 tert-Butylhydroquinone Substances 0.000 claims description 4
- 235000019281 tert-butylhydroquinone Nutrition 0.000 claims description 4
- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims description 3
- 239000000194 fatty acid Substances 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 3
- 229920000136 polysorbate Polymers 0.000 claims description 3
- NESIVXZOSKKUDP-ARVJLQODSA-N (4r,5s,6s,7r,9r,11e,13e,15r,16r)-6-[(2r,3r,4s,5s,6r)-4-(dimethylamino)-3,5-dihydroxy-6-methyloxan-2-yl]oxy-7-[2-[(3s,5r)-3,5-dimethylpiperidin-1-yl]ethyl]-16-ethyl-4-hydroxy-15-[[(2r,3r,4r,5r,6r)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxymethyl]-5,9,13 Chemical compound OP(O)(O)=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]1CCN1C[C@H](C)C[C@H](C)C1)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N(C)C)[C@H]1O NESIVXZOSKKUDP-ARVJLQODSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 239000004359 castor oil Substances 0.000 claims description 2
- 235000019438 castor oil Nutrition 0.000 claims description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 2
- 235000010388 propyl gallate Nutrition 0.000 claims description 2
- 239000008159 sesame oil Substances 0.000 claims description 2
- 235000011803 sesame oil Nutrition 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 229960000757 tilmicosin phosphate Drugs 0.000 claims description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims 2
- BKPHIEZQGNMZNZ-UHFFFAOYSA-N 2-hydroxyethyl methyl sulfate;methanamine Chemical compound NC.COS(=O)(=O)OCCO BKPHIEZQGNMZNZ-UHFFFAOYSA-N 0.000 claims 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 claims 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical group COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 claims 1
- 125000004494 ethyl ester group Chemical group 0.000 claims 1
- 239000000473 propyl gallate Substances 0.000 claims 1
- 229940075579 propyl gallate Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 38
- 229940079593 drug Drugs 0.000 abstract description 24
- 241001465754 Metazoa Species 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 7
- 238000001727 in vivo Methods 0.000 abstract description 5
- 230000000857 drug effect Effects 0.000 abstract description 4
- 244000144972 livestock Species 0.000 abstract description 4
- 244000144977 poultry Species 0.000 abstract description 4
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 241000282898 Sus scrofa Species 0.000 description 29
- 238000012360 testing method Methods 0.000 description 13
- 238000010438 heat treatment Methods 0.000 description 10
- 238000004659 sterilization and disinfection Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 208000024891 symptom Diseases 0.000 description 8
- 208000001572 Mycoplasma Pneumonia Diseases 0.000 description 7
- 201000008235 Mycoplasma pneumoniae pneumonia Diseases 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000000273 veterinary drug Substances 0.000 description 6
- 206010011224 Cough Diseases 0.000 description 5
- 230000001133 acceleration Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 238000013112 stability test Methods 0.000 description 5
- OVGORFFCBUIFIA-UHFFFAOYSA-N Fenipentol Chemical class CCCCC(O)C1=CC=CC=C1 OVGORFFCBUIFIA-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000005286 illumination Methods 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 238000010255 intramuscular injection Methods 0.000 description 4
- 239000007927 intramuscular injection Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 240000007594 Oryza sativa Species 0.000 description 3
- 235000007164 Oryza sativa Nutrition 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 235000013339 cereals Nutrition 0.000 description 3
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 3
- 238000007689 inspection Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 235000009566 rice Nutrition 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000204031 Mycoplasma Species 0.000 description 2
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 2
- KIPLYOUQVMMOHB-MXWBXKMOSA-L [Ca++].CN(C)[C@H]1[C@@H]2[C@@H](O)[C@H]3C(=C([O-])[C@]2(O)C(=O)C(C(N)=O)=C1O)C(=O)c1c(O)cccc1[C@@]3(C)O.CN(C)[C@H]1[C@@H]2[C@@H](O)[C@H]3C(=C([O-])[C@]2(O)C(=O)C(C(N)=O)=C1O)C(=O)c1c(O)cccc1[C@@]3(C)O Chemical compound [Ca++].CN(C)[C@H]1[C@@H]2[C@@H](O)[C@H]3C(=C([O-])[C@]2(O)C(=O)C(C(N)=O)=C1O)C(=O)c1c(O)cccc1[C@@]3(C)O.CN(C)[C@H]1[C@@H]2[C@@H](O)[C@H]3C(=C([O-])[C@]2(O)C(=O)C(C(N)=O)=C1O)C(=O)c1c(O)cccc1[C@@]3(C)O KIPLYOUQVMMOHB-MXWBXKMOSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000005713 exacerbation Effects 0.000 description 2
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical class CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 229940063650 terramycin Drugs 0.000 description 2
- 230000001225 therapeutic 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
- ZMOUALJOEYJPSZ-BDMZYGHZSA-N (4r,5s,6s,7r,9r,11e,13e,15s,16r)-6-[(2r,3r,4s,5s,6r)-4-(dimethylamino)-3,5-dihydroxy-6-methyloxan-2-yl]oxy-7-[2-[(3s,5r)-3,5-dimethylpiperidin-1-yl]ethyl]-16-ethyl-4-hydroxy-15-[(2s,3r,4r,5r,6r)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxy-5,9,13-trimeth Chemical compound 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]1CCN1C[C@H](C)C[C@H](C)C1)O[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N(C)C)[C@H]1O ZMOUALJOEYJPSZ-BDMZYGHZSA-N 0.000 description 1
- OWFJMIVZYSDULZ-PXOLEDIWSA-N (4s,4ar,5s,5ar,6s,12ar)-4-(dimethylamino)-1,5,6,10,11,12a-hexahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide 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)C3=C(O)C2=C1O OWFJMIVZYSDULZ-PXOLEDIWSA-N 0.000 description 1
- RSWGJHLUYNHPMX-UHFFFAOYSA-N 1,4a-dimethyl-7-propan-2-yl-2,3,4,4b,5,6,10,10a-octahydrophenanthrene-1-carboxylic acid Chemical compound C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 206010028470 Mycoplasma infections Diseases 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- AEOWNGURGDYPSO-UHFFFAOYSA-N S(=O)(=O)(OCCC)[O-].C[NH3+] Chemical compound S(=O)(=O)(OCCC)[O-].C[NH3+] AEOWNGURGDYPSO-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 229960003760 florfenicol Drugs 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229940074391 gallic acid Drugs 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 244000144993 groups of animals Species 0.000 description 1
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical class COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000021760 high fever Diseases 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002932 luster Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- CKQVRZJOMJRTOY-UHFFFAOYSA-N octadecanoic acid;propane-1,2,3-triol Chemical class OCC(O)CO.CCCCCCCCCCCCCCCCCC(O)=O CKQVRZJOMJRTOY-UHFFFAOYSA-N 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to livestock and poultry pharmaceutical arts, specifically provide a kind of Tilmicosin suspension and preparation method thereof；The Tilmicosin suspension contains following components with quality volume percentage：Tilmicosin 5%~30%, thickener 0.1%~5.0%, surfactant 0.1%~15.0%, antioxidant 0.01%~1%.Tilmicosin suspension of the present invention reduces the toxic side effect of drug after being injected in vivo, extend the Half-life in vivo of drug, improves the bioavilability of drug, reduces the dosage of drug；And the surface area with bigger, it absorbs in animal body fast；Expand Tilmicosin injection uses target animals range, improves drug effect, has saved cost.
Description
Technical field
The present invention relates to livestock and poultry pharmaceutical arts, specifically, being related to a kind of Tilmicosin suspension and its system
Preparation Method.
Background technology
Tilmicosin (Timicosin) is a kind of semi-synthetic special antibiotic of macrolides livestock and poultry, has very strong resist
Bacterium activity, has a broad antifungal spectrum, to all gram-positive bacterias and part Gram-negative bacteria, Mycoplasma, conveyor screw, mycoplasma etc.
There is inhibiting effect.The medicine is successively in the national quilt such as Australia, Brazil, France, Malaysia, Italy, Spain, U.S.
Ratify clinical application, for treating the infectious diseases of the animals such as goat, milk cow, pig, chicken.Tilmicosin class is ratified in China
Drug is used for the clinical treatment of livestock and poultry animal, mainly has tilmicosin solution and Tilmicosin injection by administration for oral administration at present
Liquid.Because Tilmicosin is there are Cardiotoxity, during drug administration by injection, Use out of range easily causes animal tachycardia and dead, especially
For pig, the death rate is very high for it.Above-mentioned in order to solve the problems, such as, it is an object of the present invention to provide a kind of of low cost, productions
Tilmicosin suspension simple for process.
Invention content
In order to realize the object of the invention, the present invention provides a kind of Tilmicosin suspension and preparation method thereof.
Present invention firstly provides a kind of Tilmicosin suspension, with quality volume percentage, containing with the following group
Point：Tilmicosin 5%~30%, thickener 0.1%~5.0%, surfactant 0.1%~15.0%, antioxidant
0.01%~1%.
Preferably, with quality volume percentage, the Tilmicosin suspension contains following components：It is examined for rice
Star 10%~20%, thickener 0.2%~1.0%, surfactant 0.2%~1.0%, antioxidant 0.05%~
0.50%.
It is highly preferred that contain following components：Tilmicosin 20%, thickener 1%, surfactant 1%, antioxidant
0.05%.Quality volume percent mass of the present invention is in terms of kg, and volume is in terms of L.
Further, the Tilmicosin is the mixture of one or more of Tilmicosin, Tilmicosin salt.It is described
Mixture of the Tilmicosin salt for one or more of tilmicosin phosphate, tartaric acid Tilmicosin etc..
Further, the thickener is double stearic acids and/or monostearate class；Such as bi-tristearin, list
The mixture of one or more of tristerin, single-stearic acid aluminium.Preferably, the thickener is single-stearic acid
Aluminium；Single-stearic acid aluminium is done not to react with Tilmicosin, the advantageous stability for increasing product.
Further, the surfactant is sapn (Span) class, tween (Tween) class, bis-fatty acid ethoxycarbonyl hydroxyl
The mixture of one or more of ethyl-methyl sulfate methyl ammonium, tri-fatty ethoxycarbonyl hydroxyethyl methyl sulfate methyl ammonium.
Preferably, the surfactant is sorbester p17 (Span-80)；Selection sorbester p17 (Span-80) can make as surface-active
Tilmicosin oil-soluble is more preferable, reduces sedimentation coefficient, increases the suspension ability of product, is conducive to product stabilization.
Further, the antioxidant is butylated hydroxy anisole (BHA), butyl hydroxy toluene (BHT), gallic acid
The mixture of one or more of propyl ester (PG), tert-butyl hydroquinone (TBHQ).It is preferred that the antioxidant is two fourth hydroxyls
Base toluene (BHT)；Selection butyl hydroxy toluene (BHT) is more conducive to the stability of invention formulation, and safety as antioxidant
Property and antioxidant are more preferable.
Tilmicosin suspension of the present invention also contains fat emulsion for injection, with the injection-used fat emulsion
Agent is gathered to total amount to 100%；Preferably, the fat emulsion for injection is injection salad oil, injection soybean oil, is injected
With the mixture of one or more of castor oil, injection sesame oil；More preferably injection soybean oil；Soybean oil source is wide
It is general, it is of low cost.
The present invention also provides the preparation methods of above-mentioned Tilmicosin suspension, and described method includes following steps：
1) fat emulsion for injection is sterilized；
The sterilizing can be high-temperature sterilization, such as 121 DEG C~150 DEG C, 30~60 minutes；High-temperature sterilization postcooling is to room
Temperature, it is spare；
2) part (such as formula ratio 10%~30%, the fat emulsion for injection after preferably 20%) sterilizing, and for rice are taken
Star mixing is examined, crosses colloid mill；Generally 10um is must not exceed to three times, being subject to Tilmicosin granularity through colloid mill one；
3) it is another to take part (such as formula ratio 30%~90%, the fat emulsion for injection after preferably 60%) sterilizing add in
Thickener, heating (being generally heated to 70 DEG C~80 DEG C) dissolving add surfactant, antioxidant, mixing (general cooling
To 40~50 DEG C)；Add in the obtained mixture of step 2), stir (general 20~40 minutes), it is rapid cross colloid mill (general one to
Twice), embedding；It is preferred that the embedding while stirring of the mixture through colloid mill；
4) it sterilizes；To obtain the final product.The sterilizing can be 100 DEG C of flowing steam sterilizations 30 minutes.
The beneficial effects of the present invention are：
Tilmicosin suspension provided by the present invention after being injected in vivo, forms drug storage warehouse, makes drug for a long time
Slow release enters the toxic side effect in vivo, reducing drug, extends the Half-life in vivo of drug, improves the biology profit of drug
Expenditure reduces the dosage of drug；Suspension agent and process for producing same of the present invention is easy, in addition to colloid mill, without using special production
Equipment；Suspension of the present invention is of low cost, and raw material sources are extensive；And suspension of the present invention is because be dispersed in liquid
In, there is the surface area of bigger, absorb in animal body fast.The Tilmicosin suspension major auxiliary burden injection fat
Fat emulsion, oil base antioxidant, derive from a wealth of sources, cheap.The thickener can increase the viscosity of preparation, ensure that preparation is long
Time keeps homogeneity and stability.The surfactant reduces the surface tension of oil, ensures that drug will not settle rapidly, increases
Add the stability of agent.The antioxidant is common antioxidant, is derived from a wealth of sources.Further, since active constituent Tilmicosin
Effect is continued and is fully played, and side effect reduces, and bioavilability has large increase.Therefore it reduces and is examined for rice
The dosage of star, expand Tilmicosin injection uses target animals range, improves drug effect, has saved cost.
Specific embodiment
The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention..
Embodiment 1
The present embodiment provides a kind of Tilmicosin suspension, contain 15kg Tilmicosins in every 100L, 2kg is mono- hard
Resin acid aluminium, 1kg sorbester p17s, 0.05kg butyl hydroxy toluenes (BHT)；100L is complemented to injection soybean oil.
Embodiment 2
The present embodiment provides a kind of Tilmicosin suspension, contain 20kg tilmicosin phosphates, 1kg in every 100L
Aluminum monostearate, 1kg sorbester p17s, 0.05kg butyl hydroxy toluenes (BHT)；100L is complemented to injection soybean oil.
Embodiment 3
The present embodiment provides a kind of Tilmicosin suspension, contain 20kg Tilmicosins in every 100L, 1kg is mono- hard
Glycerol, 1kg sorbester p17s, 0.05kg butyl hydroxy toluenes (BHT)；100L is complemented to injection soybean oil.
Embodiment 4
The present embodiment provides a kind of Tilmicosin suspension, contain 5kg tilmicosin phosphates in every 100L,
0.1kg bi-tristearins, 0.1kg polysorbas20s, 0.01kg tert-butyl hydroquinone；It is complemented to injection salad oil
100L。
Embodiment 5
The present embodiment provides a kind of Tilmicosin suspension, contain 30kg Tilmicosin salt in every 100L, 5kg is mono-
Aluminum foil stearate, 15kg bis-fatty acid ethoxycarbonyl hydroxyethyl methyl sulfate methyl ammoniums, 1kg propylgallates；With injection salad
Oil complements to 100L.
Embodiment 6
The present embodiment provides a kind of Tilmicosin suspension, contain 20kg Tilmicosins, the bis- fat of 1kg in every 100L
Fat acid acid glyceride, 1kg tri-fatty ethoxycarbonyl hydroxyethyl methyl sulfate methyl ammoniums, 0.05kg butyl hydroxy toluenes (BHT)；With
Injection soybean oil complements to 100L.
Embodiment 7
The present embodiment provides a kind of Tilmicosin suspension, contain 10kg tilmicosin phosphates in every 100L,
0.2kg glycerin monostearates, 0.2kg sorbester p17s, 0.02kg butylated hydroxy anisoles；It is complemented to injection soybean oil
100L。
Embodiment 8
The present embodiment provides a kind of preparation method of Tilmicosin suspension, the Tilmicosin injection is suspended
The formula of agent specifically comprises the following steps with embodiment 1, the preparation method：
1) it by injection soybean oil high-temperature sterilization, 150 DEG C, 60 minutes, is cooled to room temperature, it is spare；
2) the injection soybean oil after the sterilizing of formula ratio 20% is taken, with Tilmicosin mixing, through colloid mill three times, makes grain
Degree must not exceed 10um；
3) it is another to take the injection soybean oil after the sterilizing of formula ratio 60%, aluminum monostearate is added in, is heated to 70 DEG C of dissolvings,
Sorbester p17, butyl hydroxy toluene (BHT) are added, is cooled to 40 DEG C after mixing；While stirring, the mixing that step 2) obtains is added in
Object is stirred for 20 minutes, and rapid colloid mill of crossing is primary, the embedding while stirring of the mixture through colloid mill；
4) after inspection is qualified in, embedding, 100 DEG C of flowing steam sterilizations 30 minutes to get.
Embodiment 9
The present embodiment provides a kind of preparation method of Tilmicosin suspension, the Tilmicosin injection is suspended
The formula of agent specifically comprises the following steps with embodiment 2, the preparation method：
1) it by injection soybean oil high-temperature sterilization, 150 DEG C, 60 minutes, is cooled to room temperature, it is spare；
2) the injection soybean oil after the sterilizing of formula ratio 20% is taken, with Tilmicosin mixing, through colloid mill three times, makes grain
Degree must not exceed 10um；
3) it is another to take the injection soybean oil after the sterilizing of formula ratio 60%, aluminum monostearate is added in, is heated to 80 DEG C of dissolvings,
Sorbester p17, butyl hydroxy toluene (BHT) are added, is cooled to 50 DEG C after mixing；While stirring, the mixing that step 2) obtains is added in
Object is stirred for 20 minutes, and rapid colloid mill of crossing is primary, the embedding while stirring of the mixture through colloid mill；
4) after inspection is qualified in, embedding, 100 DEG C of flowing steam sterilizations 30 minutes to get.
Embodiment 10
The present embodiment provides a kind of preparation method of Tilmicosin suspension, the Tilmicosin injection is suspended
The formula of agent specifically comprises the following steps with embodiment 3, the preparation method：
1) it by injection soybean oil high-temperature sterilization, 150 DEG C, 60 minutes, is cooled to room temperature, it is spare；
2) the injection soybean oil after the sterilizing of formula ratio 20% is taken, with Tilmicosin mixing, through colloid mill three times, makes grain
Degree must not exceed 10um；
3) it is another to take the injection soybean oil after the sterilizing of formula ratio 60%, glycerin monostearate is added in, is heated to 80 DEG C
Dissolving, adds Tween 80, butyl hydroxy toluene (BHT), is cooled to 40 DEG C after mixing；While stirring, add in step 2) and obtain
Mixture, stir 20 minutes, it is rapid cross colloid mill it is primary, the embedding while stirring of the mixture through colloid mill；
4) after inspection is qualified in, embedding, 100 DEG C of flowing steam sterilizations 30 minutes to get.
1 Tilmicosin suspension of experimental example treats the Clinical efficacy of mycoplasma pneumonia of swine
1st, test objective
In order to verify the drug effect of Tilmicosin suspension provided by the invention, this experiment embodiment of the present invention 2
Obtained Tilmicosin suspension is with comparison medicament respectively to mycoplasma pneumonia of swine therapeutic test.Test data is distinguished according to testing program
Acquisition.
2nd, test material
2.1 use drug
2.1.1 trial drug：Tilmicosin suspension made from embodiment 2.
2.1.2 comparison medicament 1：20% florfenicol injection (product batch number 2014012501) of certain company production.
2.1.3 comparison medicament 2：20% Ursocycline injection (product batch number 14080901) of certain offshore company production.
2.2 experimental animals and grouping
2.2.1 the commodity pig farm of Hunan Province Shaoyang County two occurs breathing in March, 2014, cough symptom, the price of deed
It is substantially reduced, the speed of growth declines serious.
Field diagnostic result is as follows：Coughing and panting, occur in the Landrace of A pig farms totally 165 95 ages in days or so,
Serious or even dog sits gesture breathing.B pig farms share the soil hybridization market pig of 502 90 ages in days or so, wherein there is 160 to show
It now coughs and pants, exacerbation of symptoms when during change in weather and close to daybreak.According to above-mentioned clinical symptoms, can determine whether as typical pig branch original
Body-sensing contaminates.
The sick pig on above-mentioned two pig farm is grouped at random.Wherein 15 are selected (not have to drug as blank control group in A pig farms
Group), remaining 150 pig is randomly divided into 3 groups (they being respectively 2 groups of trial drug group, 1 group of comparison medicament and comparison medicament), every group 50
Head.B pig farms select wherein 10 as blank control group, and it (is respectively trial drug group, control that remaining 150 pig, which is randomly divided into 3 groups,
2 groups of 1 group of medicament and comparison medicament), every group 50.
3rd, test method
3.1 trial drug group animal markings are I group, the Tilmicosin suspension obtained by embodiment 2, by every head
0.1ml trial drugs are penetrated in per kilogram body intramuscular injection.
2 groups of animals of 3.2 1 group of comparison medicaments and comparison medicament are respectively labeled as II group, III group, by every per kilogram body intramuscular injection
Penetrate 0.1ml comparison medicaments.
3.3 blank control groups are labeled as IV group, are only given chow diet, do not add any drug.
The above-mentioned equal continuous use of experimental animal 7 days, is observed 5 days again after medication, observes clinical symptoms and death condition daily,
Dissect is carried out to animals died of illness.Calculate the effective percentage, cure rate, Relapse rate situation of each test group.
3.4 criterion
3.4.1 effectively：Clinical symptom relief (cough and asthma mitigate, spirit improvement, and growth improves etc.).
3.4.2 it cures：(cough and asthma stop, and spirit improvement, growth recovery are just for clinical symptoms disappearance in 7 days after drug withdrawal
Often etc.).
3.4.3 Relapse rate：Clinical symptoms exacerbation or dead in 5 days after drug withdrawal.
It is 3.4.4 invalid：(including in after drug withdrawal 5 days), clinical symptoms are unchanged during experiment or aggravate or the dead or state of an illness
Recurrence.
4th, result of the test
A pig farms are shown in Table 1 to mycoplasma pneumonia of swine treatment results；B pig farms are shown in Table 2 to mycoplasma pneumonia of swine treatment results.
The treatment results of table 1A pig farms commodity mycoplasma pneumonia of swine compare
The treatment results of table 2B pig farms commodity mycoplasma pneumonia of swine compare
5th, test result analysis and conclusion
5.1 can be seen that total therapeutic effect of Tilmicosin suspension of the present invention from above-mentioned result of the test
It is much better than comparison medicament 1 and comparison medicament 2.
5.2 Tilmicosin suspension treatment commodity mycoplasma pneumonia of swine effects of the present invention are better than control group drug, difference
Significantly.The cure rate of Tilmicosin suspension also up to 96%, illustrates that this cause of disease is more sensitive to Tilmicosin.But phase
Than control drug, the present invention is either efficient or cure rate is better than control drug, illustrates that the present invention can improve the medicine
Drug effect.Terramycin treatment group does not obtain preferable effect, it may be possible to which terramycin prevention and health care is usually used on pig farm, thus pathogen goes out
Existing drug resistance causes.
5.3 Tilmicosin suspensions of the present invention reach the intramuscular injection amount of pig 30mg/kg, but do not go out during testing
The death of existing pig, illustrates that Tilmicosin suspension of the present invention is good safely to the intramuscular injection of pig.
Therefore Tilmicosin suspension for pig farm control mycoplasma infection be a kind of ideal system, i.e. safety again
Effectively.
2 Tilmicosin suspension stability test of experimental example
This experiment is by taking three batches of finished products made from embodiment 2 as an example, according to the Ministry of Agriculture《Veterinary drug stability test technical specification
(tentative)》Stability study has been carried out to it, it is therefore intended that examine Tilmicosin suspension provided by the invention to light,
Hot, wet stability.
1. materials and methods
1.1 main agents
Methanol (chromatographically pure) Beijing chemical reagents corporation
Ethyl alcohol (color is said pure) Beijing chemical reagents corporation
Acetonitrile (chromatographically pure) Beijing chemical reagents corporation
Glacial acetic acid (chromatographically pure) Beijing chemical reagents corporation
Hydrochloric acid (chemical analysis is pure) Beijing chemical reagents corporation
Tilmicosin reference substance (content 50.98%) China Veterinary Drugs Supervisory Inst.
The Tilmicosin suspension that embodiment 2 obtains.
1.2 key instrument
High performance liquid chromatograph (HPLC) LC-10A Japan Shimadzu
Qualitative filter paper middling speed Q/ZHJ3017-91 Hangzhou Xin Hua paper mills
Two factory of CX-100 ultrasonic cleaners Beijing Medical Devices
Precision acidity meter (PHS-3C) Shanghai Lei Ci instrument plants
2XZ-1 type rotary-vane vaccum pumps Jinggong Vacuum Equipment Plant, Linhai City
The micro semimicro-analy-tical balances of BP310S, Sartorius companies of BP211D assay balances Germany
D1810C dual pure water distiller Shanghai glass apparatus companies automatically
Instrucment and meter plant of JD-3 type illumination meter Shanghai International Automobile City Tourist Festivals student's federation
Huangshi medical apparatus and instruments factory of water isolation type electro-heating standing-temperature cultivator GSP-781 types Hubei Province
The detection method of content of Tilmicosin in 1.3 Tilmicosin suspensions
With reference to Ministry of Agriculture's relevant criterion detection.
1.4 acceleration by light are tested
It is formulated by embodiment 2 and three batches of Tilmicosin suspensions is made, represented, will be made with No. 1, No. 2, No. 3 respectively
Each finished product is fitted into colourless closed plastic bottle, put under conditions of illumination is 4500 ± 500LX and place 10 days, respectively at 0,
5th, 10 days timing samplings, the indexs such as determination sample character, suspension ability, content.
1.5 heating and moistenings are tested
According to《Ministry of Agriculture's veterinary drug stability techniques specification (tentative)》, determine this preparation preferably temperature be 30 ± 2 DEG C, relatively
Humidity carries out heating and moistening experiment under conditions of being 60 ± 5%.Sodium nitrite saturated solution is used to be placed in drier for humidizer
The sample that each three batches of obtained three batches of Tilmicosin suspensions are formulated by embodiment 2 is packed into vial, put by bottom
It in the upper strata of drier, is put into together in water isolation type electro-heating standing-temperature cultivator, temperature regulating is to 30 ± 2 DEG C, and monthly sampling is primary, fixed
Phase is observed 6 months, the indexs such as determination sample character, suspension ability, content.
2nd, result and analysis
2.1 acceleration by light are tested
Acceleration by light experiment has been carried out to three batches of Tilmicosin suspension samples respectively, the results are shown in Table 3.As a result table
Bright, in 4500 ± 500LX strong illuminations 10 days, suspension ability, content, character had no significant change said preparation.
3 acceleration by light result of the test of table
2.2 heating and moistenings are tested
Heating and moistening experiment is carried out to three batches of Tilmicosin suspension samples respectively, at 1 month, 2 months, 3
The moon, 4 months, 5 months, 6 months its appearance lusters, suspension ability, Tilmicosin content have no significant change, the results showed that, this hair
Bright Tilmicosin suspension is good to heating and moistening stability.It the results are shown in Table 4.
4 six months heating accelerated test results of table
3rd, brief summary and discussion
The requirement of No. 13 files of this experimental evidence Ministry of Agriculture in 1999 " veterinary drug stability test technical specification (tentative) ",
Under conditions of intense light irradiation, the projects such as the Tilmicosin content of said preparation, appearance character, suspension ability are investigated.Experiment knot
Fruit shows to test 10 days through acceleration by light, and indices meet the requirements, and illustrates that this preparation stablizes illumination relatively.This experimental evidence
The requirement of No. 13 files of the Ministry of Agriculture in 1999 " veterinary drug stability test technical specification (tentative) ", in high temperature, the condition of high humility
Under, the projects such as the Tilmicosin content of said preparation, appearance character, the uniformity are investigated.Result of the test shows heating
6 the end of month of stability test are humidified, significant change does not occur for the appearance luster of preparation, remaining indices is normal, symbol
It closes《Middle Chinese republic veterinary drug allusion quotation》Requirement, therefore, high humidity, high fever environment be still stable.
In conclusion Tilmicosin suspension provided by the present invention to light, heat, it is wet be stable.
Although above the present invention is described in detail with a general description of the specific embodiments,
On the basis of the present invention, it can be made some modifications or improvements, this will be apparent to those skilled in the art.Cause
This, these modifications or improvements, belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (6)
1. a kind of Tilmicosin suspension, which is characterized in that composed of the following components with quality volume percentage：
Tilmicosin or Tilmicosin salt 5%~30%, thickener 0.1%~5.0%, surfactant 0.1%~15.0%, antioxygen
Agent 0.01%~1%, fat emulsion for injection；It is gathered with the fat emulsion for injection to total amount to 100%；
The thickener is single-stearic acid aluminium；
The surfactant is sapn, tween, bis-fatty acid ethoxycarbonyl hydroxyethyl methyl sulfate methyl ammonium, tri-fatty ethyl ester
The mixture of one or more of base hydroxyethyl methyl sulfate methyl ammonium；
The antioxidant is butylated hydroxy anisole, in butyl hydroxy toluene, propylgallate, tert-butyl hydroquinone
One or more of mixtures；
The fat emulsion for injection is injection salad oil, in injection soybean oil, injection castor oil, injection sesame oil
One or more of mixtures；
The preparation method of the Tilmicosin suspension, includes the following steps：
1) fat emulsion for injection is sterilized；
2) fat emulsion for injection after the sterilizing of formula ratio 10%~30% is taken, with Tilmicosin or Tilmicosin salt mixing, mistake
Colloid mill；Tilmicosin or Tilmicosin salt granularity is made to must not exceed 10um；
3) the another fat emulsion for injection taken after the sterilizing of formula ratio 30%~90%, adds in thickener, is heated to 70 DEG C~80 DEG C
Dissolving, adds surfactant, antioxidant, mixing is cooled to 40~50 DEG C；The mixture that step 2) obtains is added in, is stirred
It mixes 20~40 minutes, rapid colloid mill one of crossing is to twice, embedding；
4) it sterilizes；To obtain the final product.
2. Tilmicosin suspension according to claim 1, which is characterized in that with quality volume percentage,
It is composed of the following components：Tilmicosin or Tilmicosin salt 10%~20%, thickener 0.2%~1.0%, surfactant
0.2%~1.0%, antioxidant 0.05%~0.50%, fat emulsion for injection；It is gathered with the fat emulsion for injection to total
It measures to 100%.
3. Tilmicosin suspension according to claim 2, which is characterized in that with quality volume percentage,
It is composed of the following components：Tilmicosin or Tilmicosin salt 20%, thickener 1.0%, surfactant 1.0%, antioxidant
0.05%, fat emulsion for injection；It is gathered with the fat emulsion for injection to total amount to 100%.
4. according to claim 1-3 any one of them Tilmicosin suspensions, which is characterized in that the Tilmicosin
Salt is the mixture of one or both of tilmicosin phosphate, tartaric acid Tilmicosin.
5. according to claim 1-3 any one of them Tilmicosin suspensions, which is characterized in that the surface-active
Agent is sorbester p17.
6. the preparation method of any one of the claim 1-5 Tilmicosin suspensions, which is characterized in that including as follows
Step：
1) fat emulsion for injection is sterilized；
2) fat emulsion for injection after the sterilizing of formula ratio 10%~30% is taken, with Tilmicosin or Tilmicosin salt mixing, mistake
Colloid mill；Tilmicosin or Tilmicosin salt granularity is made to must not exceed 10um；
3) the another fat emulsion for injection taken after the sterilizing of formula ratio 30%~90%, adds in thickener, is heated to 70 DEG C~80 DEG C
Dissolving, adds surfactant, antioxidant, mixing is cooled to 40~50 DEG C；The mixture that step 2) obtains is added in, is stirred
It mixes 20~40 minutes, rapid colloid mill one of crossing is to twice, embedding；
4) it sterilizes；To obtain the final product.
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| US5574020A (en) * | 1989-09-28 | 1996-11-12 | Eli Lilly And Company | Tilmicosin formulation |
| CN1572301A (en) * | 2003-06-15 | 2005-02-02 | 王玉万 | Tylosin containing antibiotic injection for animals |
| CN102440998A (en) * | 2010-10-15 | 2012-05-09 | 天津瑞普生物技术股份有限公司 | Compound doxycycline hyclate suspension injection and preparation method thereof |
| CN103550152A (en) * | 2013-10-30 | 2014-02-05 | 游锡火 | Method for preparing veterinary long-acting injection containing tilmicosin |
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|---|---|---|---|---|
| WO2007016153A2 (en) * | 2005-07-28 | 2007-02-08 | Eli Lilly And Company | Tilmicosin formulation |
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| US5574020A (en) * | 1989-09-28 | 1996-11-12 | Eli Lilly And Company | Tilmicosin formulation |
| CN1572301A (en) * | 2003-06-15 | 2005-02-02 | 王玉万 | Tylosin containing antibiotic injection for animals |
| CN102440998A (en) * | 2010-10-15 | 2012-05-09 | 天津瑞普生物技术股份有限公司 | Compound doxycycline hyclate suspension injection and preparation method thereof |
| CN103550152A (en) * | 2013-10-30 | 2014-02-05 | 游锡火 | Method for preparing veterinary long-acting injection containing tilmicosin |
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