CN103705452B - Containing the antibacterials injection of poloxamer188 and oil medium - Google Patents
Containing the antibacterials injection of poloxamer188 and oil medium Download PDFInfo
- Publication number
- CN103705452B CN103705452B CN201410005508.0A CN201410005508A CN103705452B CN 103705452 B CN103705452 B CN 103705452B CN 201410005508 A CN201410005508 A CN 201410005508A CN 103705452 B CN103705452 B CN 103705452B
- Authority
- CN
- China
- Prior art keywords
- injection
- medicine carrying
- antibacterials
- carrying microgranule
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- 238000002347 injection Methods 0.000 title claims abstract description 69
- 239000007924 injection Substances 0.000 title claims abstract description 69
- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 35
- 229940088710 antibiotic agent Drugs 0.000 title claims abstract description 35
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 229940044519 poloxamer 188 Drugs 0.000 title claims abstract description 12
- 229920001993 poloxamer 188 Polymers 0.000 title claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 82
- 239000004531 microgranule Substances 0.000 claims abstract description 50
- -1 hydroxypropyl Chemical group 0.000 claims abstract description 7
- 238000000227 grinding Methods 0.000 claims abstract description 4
- 239000003921 oil Substances 0.000 claims description 29
- 235000019198 oils Nutrition 0.000 claims description 29
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 15
- KEQFDTJEEQKVLM-JUODUXDSSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-(furan-2-carbonylsulfanylmethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydron;chloride Chemical compound Cl.S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC(=O)C1=CC=CO1 KEQFDTJEEQKVLM-JUODUXDSSA-N 0.000 claims description 14
- 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 14
- 229960001356 ceftiofur hydrochloride Drugs 0.000 claims description 14
- SPFYMRJSYKOXGV-UHFFFAOYSA-N Baytril Chemical compound C1CN(CC)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 SPFYMRJSYKOXGV-UHFFFAOYSA-N 0.000 claims description 10
- 229960000740 enrofloxacin Drugs 0.000 claims description 10
- 238000009472 formulation Methods 0.000 claims description 10
- 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 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 229960003760 florfenicol Drugs 0.000 claims description 9
- 239000001530 fumaric acid Substances 0.000 claims description 9
- 229960004885 tiamulin Drugs 0.000 claims description 9
- UURAUHCOJAIIRQ-QGLSALSOSA-N tiamulin Chemical compound CCN(CC)CCSCC(=O)O[C@@H]1C[C@@](C)(C=C)[C@@H](O)[C@H](C)[C@@]23CC[C@@H](C)[C@]1(C)[C@@H]2C(=O)CC3 UURAUHCOJAIIRQ-QGLSALSOSA-N 0.000 claims description 9
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 9
- CUJMCPPBTUATEJ-UHFFFAOYSA-N 1-(3-methyl-4-oxido-1-oxoquinoxalin-1-ium-2-yl)ethanone Chemical compound C1=CC=C2[N+](=O)C(C(=O)C)=C(C)N([O-])C2=C1 CUJMCPPBTUATEJ-UHFFFAOYSA-N 0.000 claims description 8
- 229960003276 erythromycin Drugs 0.000 claims description 7
- POUMFISTNHIPTI-BOMBIWCESA-N hydron;(2s,4r)-n-[(1r,2r)-2-hydroxy-1-[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-methylsulfanyloxan-2-yl]propyl]-1-methyl-4-propylpyrrolidine-2-carboxamide;chloride Chemical compound Cl.CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 POUMFISTNHIPTI-BOMBIWCESA-N 0.000 claims description 7
- 229960001595 lincomycin hydrochloride Drugs 0.000 claims description 7
- MYDXUJMODAZBGN-UHFFFAOYSA-N 6-bromo-5-methyl-2-methylsulfanyl-1h-[1,2,4]triazolo[1,5-a]pyrimidin-7-one Chemical compound CC1=C(Br)C(=O)N2NC(SC)=NC2=N1 MYDXUJMODAZBGN-UHFFFAOYSA-N 0.000 claims description 6
- 241001619326 Cephalosporium Species 0.000 claims description 6
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims description 6
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 229960004745 danofloxacin mesylate Drugs 0.000 claims description 6
- 235000012424 soybean oil Nutrition 0.000 claims description 6
- 239000003549 soybean oil Substances 0.000 claims description 6
- 239000001117 sulphuric acid Substances 0.000 claims description 6
- 235000011149 sulphuric acid Nutrition 0.000 claims description 6
- DVWJFTGEISXVSH-CWVFEVJCSA-N (1R,3S,5S,7Z,11R,12S,13Z,15Z,17Z,19Z,21R,23S,24R,25S)-21-[(2R,3S,4S,5S,6R)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-12-ethyl-1,3,5,25-tetrahydroxy-11-methyl-9-oxo-10,27-dioxabicyclo[21.3.1]heptacosa-7,13,15,17,19-pentaene-24-carboxylic acid Chemical compound CC[C@H]1\C=C/C=C\C=C/C=C\[C@@H](C[C@@H]2O[C@@](O)(C[C@H](O)[C@H]2C(O)=O)C[C@@H](O)C[C@@H](O)C\C=C/C(=O)O[C@@H]1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](N)[C@@H]1O DVWJFTGEISXVSH-CWVFEVJCSA-N 0.000 claims description 5
- 239000003963 antioxidant agent Substances 0.000 claims description 5
- 230000003078 antioxidant effect Effects 0.000 claims description 5
- 229930183279 tetramycin Natural products 0.000 claims description 5
- 210000000582 semen Anatomy 0.000 claims description 4
- 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 claims description 3
- 229930182566 Gentamicin Natural products 0.000 claims description 3
- BPFYOAJNDMUVBL-UHFFFAOYSA-N LSM-5799 Chemical compound C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3N(C)COC1=C32 BPFYOAJNDMUVBL-UHFFFAOYSA-N 0.000 claims description 3
- 239000004182 Tylosin Substances 0.000 claims description 3
- 229930194936 Tylosin Natural products 0.000 claims description 3
- 229960002531 marbofloxacin Drugs 0.000 claims description 3
- YKQOSKADJPQZHB-RGYSVOEGSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(6r,9s,12r,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1r)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-hydr Chemical compound CCC(C)CCCC(=O)N[C@@H](CCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)C([C@@H](C)O)NC(=O)[C@@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O YKQOSKADJPQZHB-RGYSVOEGSA-N 0.000 claims description 3
- 235000010388 propyl gallate Nutrition 0.000 claims description 3
- 239000000473 propyl gallate Substances 0.000 claims description 3
- 229940075579 propyl gallate Drugs 0.000 claims description 3
- 229960004059 tylosin Drugs 0.000 claims description 3
- 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 3
- 235000019375 tylosin Nutrition 0.000 claims description 3
- QSHVAZMOLNGWSY-UHFFFAOYSA-N 3-butyl-4-methoxyphenol Chemical group CCCCC1=CC(O)=CC=C1OC QSHVAZMOLNGWSY-UHFFFAOYSA-N 0.000 claims description 2
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 2
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 claims description 2
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 claims description 2
- 235000010385 ascorbyl palmitate Nutrition 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 75
- 229940079593 drug Drugs 0.000 abstract description 15
- 238000000034 method Methods 0.000 abstract description 7
- 230000008569 process Effects 0.000 abstract description 5
- 230000029142 excretion Effects 0.000 abstract 1
- 230000002441 reversible effect Effects 0.000 abstract 1
- 229940090044 injection Drugs 0.000 description 53
- 239000002245 particle Substances 0.000 description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 239000000084 colloidal system Substances 0.000 description 18
- 239000004576 sand Substances 0.000 description 18
- 239000006104 solid solution Substances 0.000 description 14
- 238000010257 thawing Methods 0.000 description 11
- 238000001816 cooling Methods 0.000 description 9
- 210000002381 plasma Anatomy 0.000 description 9
- 238000007711 solidification Methods 0.000 description 8
- 230000008023 solidification Effects 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 230000006837 decompression Effects 0.000 description 6
- 238000011065 in-situ storage Methods 0.000 description 6
- 238000009835 boiling Methods 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 229960000223 tilmicosin Drugs 0.000 description 5
- 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 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000010255 intramuscular injection Methods 0.000 description 4
- 239000007927 intramuscular injection Substances 0.000 description 4
- 241000282898 Sus scrofa Species 0.000 description 3
- 210000001124 body fluid Anatomy 0.000 description 3
- 239000010839 body fluid Substances 0.000 description 3
- 229960005229 ceftiofur Drugs 0.000 description 3
- ZBHXIWJRIFEVQY-IHMPYVIRSA-N ceftiofur Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC(=O)C1=CC=CO1 ZBHXIWJRIFEVQY-IHMPYVIRSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000008961 swelling Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 description 3
- 239000008158 vegetable oil Substances 0.000 description 3
- 239000000273 veterinary drug Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 241000282894 Sus scrofa domesticus Species 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000003640 drug residue Substances 0.000 description 2
- 208000001848 dysentery Diseases 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 229940069952 erythromycin injection Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000010419 fine particle Substances 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 229960005287 lincomycin Drugs 0.000 description 2
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
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- 239000007787 solid Substances 0.000 description 2
- YWKJNRNSJKEFMK-PQFQYKRASA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-8-oxo-3-(5,6,7,8-tetrahydroquinolin-1-ium-1-ylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound N([C@@H]1C(N2C(=C(C[N+]=3C=4CCCCC=4C=CC=3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 YWKJNRNSJKEFMK-PQFQYKRASA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 208000012353 Contagious Pleuropneumonia Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 239000004100 Oxytetracycline Substances 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
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- 238000010171 animal model Methods 0.000 description 1
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- 229920005601 base polymer Polymers 0.000 description 1
- 239000000227 bioadhesive Substances 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 229950009592 cefquinome Drugs 0.000 description 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
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- 239000008187 granular material Substances 0.000 description 1
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- 238000001727 in vivo Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
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- 208000008977 mycoplasmal pneumonia of swine Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
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- 239000002674 ointment Substances 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
- 238000004806 packaging method and process Methods 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 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
- 210000001519 tissue Anatomy 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Antibacterials and poloxamer188 combine by the present invention, are prepared into medicine carrying microgranule; Further medicine carrying microgranule is scattered in oil medium, through grinding, is prepared into the oily long-acting injection containing antibacterials/poloxamer188 medicine carrying microgranule.In medicine carrying microgranule, also can add hydroxypropyl emthylcellulose or Hydroxypropylcelliloxe, they add the slow releasing function that membership significantly strengthens preparation.This process for preparation of injection is simple, uniform drug release, good biocompatibility, organize reversible damage, injection part used and excretion invariably to injection site.
Description
Technical field
The invention belongs to veterinary drug preparation technology of preparing, being specifically related to poloxamer188 and oil medium is carrier, and preparation is containing the long-acting veterinary injection of antibacterials.
Background technology
Poloxamer is polyoxyethylene polyoxypropylene ether analog copolymer, this base polymer has plurality of specifications, wherein the aqueous solution of poloxamer188 (hereinafter referred to as P407) has " raising by the characteristic of colloidal sol to gel conversion with temperature ", generally more than 28 DEG C, namely there is gelling in certain density P407 aqueous solution, characteristic accordingly, P407 is used to the preparation of slow releasing injection, and said preparation is referred to as in-situ gelling preparation.After being injected in vivo containing the in-situ gelling injection of P407, under the effect of body temperature, generally at about 1 minute, namely change gel (semisolid) into by colloidal sol, medicine is wrapped in gel, thus slow down rate of releasing drug, and duration of efficacy is extended.The disclosed in-situ gelling injection containing P407 of document and patent, the solvent of its preparation is water, and in preparation, the concentration of P407 will reach more than 20% and just has good slow releasing function; Add the blocker such as a certain amount of methylcellulose, sodium carboxymethyl cellulose, Hydroxypropylcelliloxe (H-HPC) or hydroxypropyl emthylcellulose (HPMC) in the formulation, slow releasing function can be strengthened, but formulation viscosity can be caused to raise, make injection more difficult.
P407 is also the good non-ionic surface active agent of a kind of water solublity, is more used to prepare Emulsion, ointment, aqueous suppository, drop pill etc.; P407 is also by the dispersible carrier as insoluble medicine (medicine that water solublity is very poor), and for the preparation of solid solution, mostly solid solution prepared by published P407, be the preparation for oral preparations.
The present invention is different from published technology, the present invention is the medicine carrying microgranule (as agglomerate) medicine and P407 (or with P407 and cellulose ethers) being formed solid solution or other form, and with oil medium, (isopropyl myristate, hereinafter referred to as IPM; Vegetable oil) substitute water and prepare oily injection containing P407 medicine carrying microgranule.This preparation injects under animal skins or intramuscular, medicine carrying microgranule is after " breakthrough " oil phase contact body fluid (water), by means of P407 " water suction (body fluid) " or water absorption and swelling (when HPMC or H-HPC exists), " adhesive aggregation " together, high concentration and full-bodied and there is the semi-solid agglomerate of " bioadhesive " (when existing at H-HPC or HPMC) is formed in injection site, medicine is wrapped in agglomerate, thus effectively extends the release time of medicine.And due to the peptizaiton of P407, make insoluble medicine release comparatively complete, thus improve the bioavailability of hydrophobic drug, decrease injection site drug residue.
The antibacterials that the present invention relates to comprise: fumaric acid tiamulin, enrofloxacin, Danofloxacin mesylate, Marbofloxacin, Mequindox, for meter Ke Xing, tylosin, tetramycin hydrochloride, colistine sulfate, Ceftiofur Hydrochloride, sulphuric acid cephalosporium quinol, gentamycin sulfate, lincomycin hydrochloride, florfenicol, erythromycin.
Experiment shows; these antibacterials can be combined into the medicine carrying microgranule (as agglomerate) of solid solution fine particle or other form with P407 or with P407/HPMC (or H-HPC) above; and be scattered in oil medium, prepare the slow releasing injection of expectation.
" character, pharmacology and the purposes " of above antibacterials etc. are all on the books and describe in " veterinary drug handbook " (Zhu Mozhong edits, Chemical Industry Press, July in 2002 the 1st edition).Containing the commercially available injection of these antibacterials, majority be with water be primary solvent or with organic solvent (as 1,2-propylene glycol, dimethyl acetylamide, N-Methyl pyrrolidone, formal glycerine etc.) be solution type preparation prepared by primary solvent, also there is the oily injection prepared for medium with the oily compounds of vegetable oil or synthetic; The disclosed injection containing above-mentioned antibacterials of document or patent has solution type preparation, suspension type preparation, Emulsion, has the long-acting injection containing different slow-released carrier, and also having with water is the in-situ gelling injection containing P407 of medium.But have no report containing the oily long-acting injection of antibacterials/P407 medicine carrying microgranule.In oil medium, adding suitable slow releasing carrier material, improve traditional oily injection, is the feasible way of the efficient long-acting veterinary injection of exploiting economy.
Summary of the invention
By medicine and P407, or medicine and P407 and HPMC (or H-HPC) are formed medicine carrying microgranule, be suspended in preparation with medicine carrying microgranule state, be prepared into oily long-acting injection, this is the prominent features of this preparation.
This preparation composition and preparation method are described below:
Preparation forms: this preparation forms primarily of antibacterials, P407 and oil medium.1 liter is added to containing antibacterials 25-200g, P40725-150g, oil medium in often liter of injection.
Described antibacterials comprise: fumaric acid tiamulin, enrofloxacin, Danofloxacin mesylate, Marbofloxacin, Mequindox, for meter Ke Xing, tylosin, tetramycin hydrochloride, colistine sulfate, Ceftiofur Hydrochloride, sulphuric acid cephalosporium quinol, gentamycin sulfate, lincomycin hydrochloride, florfenicol, erythromycin.These antibacterials are all commercial medicines, all can find in " Chinese veterinary pharmacopoeia " and veterinary drug handbook and pertinent literature.
Described oil medium is the one in IPM, injection soybean oil, Semen Maydis oil, Oleum Camelliae.
Also can add 20-60gHPMC or H-HPC in often liter of described injection, HPMC or H-HPC need be combined into solid solution with P407 or form medicine carrying microgranule with P407 together with antibacterials, could be used for the preparation of this preparation.H-HPC has good dissolubility in the low boiling point organic solvent such as methanol, ethanol, most antibacterials have good dissolubility equally in these low boiling point organic solvents, this is that H-HPC, P407 and antibacterials can form one, is prepared into the important foundation of medicine carrying microgranule.
H-HPC and HPMC be nontoxic, without pharmacological action, physiologically active shows extreme inertia.HPMC, H-HPC or P407 is insoluble in the oil mediums such as IPM, therefore, H-HPC or HPMC and P407 is formed microgranule, even if be scattered in oil medium with higher concentration, also formulation viscosity can not be made obviously to raise, but contain the medicine carrying microgranule of high concentration H-HPC or HPMC at injection part energy water absorption and swelling, form full-bodied agglomerate, full-bodied agglomerate has the effect of stronger retardance (slowing down) drug release, therefore, appropriate H-HPC and HPMC is added in medicine carrying microgranule, the slow release effect of expection can be reached, especially for the long-acting injection preparing containing water-soluble antibacterials, in medicine carrying microgranule, add a certain amount of H-HPC and HPMC is very necessary.
In often liter of injection, also can add 0.2-2g antioxidant, antioxidant comprises the mixture of one or more any ratios in tertiary butyl-4-hydroxy methoxybenzene (BHA), dibenzylatiooluene (BHT), propyl gallate (PG) or ascorbyl palmitate.
Preparation method: due to the different solubility of different antibacterials in low boiling point solvent, stability difference (mainly heat stability), therefore preparation method is also different, is summed up and mainly contains following three kinds.
(1) under heating or room temperature, antibacterials and P407 or antibacterials and P407 and HPMC or antibacterials and P407 and H-HPC mono-are reinstated low boiling point solvent dissolve, then distilling under reduced pressure or vacuum freeze-drying, removing low boiling point solvent, obtains antibacterials/P407 solid solution or antibacterials/P407/HPMC solid solution or antibacterials/P407/H-HPC solid solution; The solid solution of preparation was pulverized 40 mesh sieves, obtain medicine carrying microgranule, medicine carrying microgranule is scattered in part oil medium, be ground to particle diameter with colloid mill and be less than 100 μm, be ground to particle diameter with sand mill again and be less than 20 μm, add remaining media to final volume, homogenize further under 5000-10000rpm with high-shear homogenizing machine and obtain this preparation.
(2) medicine is scattered in oil medium, is ground to particle diameter with colloid mill and is less than 100 μm, then be ground to particle diameter with sand mill and be less than 1 μm, for subsequent use after centrifugalize; P407 is made it to melt in 60-70 DEG C, then the medicine particle diameter prepared above being less than 1 μm joins in the P407 of thawing, stirring and evenly mixing, through cooling curing, pulverize and sieve, obtain medicine carrying microgranule, medicine carrying microgranule is scattered in oil medium, is ground to particle diameter with colloid mill and sand mill further and is less than 20 μm, add remaining media, homogenize with high-shear homogenizing machine and obtain this preparation.
(3) medicine and P407 or medicine and solid solution (P407/HPMC or P407/H-HPC) are scattered in part oil medium, be ground to particle diameter with colloid mill and sand mill and be less than 20 μm, add remaining media, to homogenize to obtain this preparation with homogenizer.
Prepared by P407/H-HPC or P407/HPMC solid solution: in a heated condition, HPMC or H-HPC and P407 is dissolved in methanol or is dissolved in 80% alcoholic solution, mixing, under agitation removal of solvent under reduced pressure and get final product.
This formulation process need aseptically carry out, and during grinding, temperature of charge may not exceed 40 DEG C, and in preparation, the particle diameter of solid particle should be less than 20 μm, more suitable to be less than 10 μm.When preparing the suspensoid injectio of containing water-soluble medicine, drug particles is less, and slow release effect is better, this may larger with water-soluble pesticide composition granule time not easily wrapped by micelle, easily occur caused by drug microparticles " diafiltration ".
Feature of the present invention is summarized as follows:
It is the in-situ gelling preparation of medium that this medicament drug release process is different from water, is also different from traditional oil preparation, and main difference part there is medicine carrying microgranule " breakthrough " oil phase and bioresorbable and absorb water to form high viscosity agglomerate process.
Appropriate H-HPC or HPMC and P407 is formed solid solution pellet, be scattered in oil phase, solve the technical barrier that simple H-HPC (or HPMC) packaging medicine is difficult to grind to form fine particle (being less than 20 μm), remain H-HPC and HPMC to have water suction (body fluid) swelling simultaneously, forms the characteristic of high viscosity agglomerate.Pastille " agglomerate " adheres in injection site tissue, is conducive to medicine and better absorbs, and ensure that slow release effect to a certain degree, and it is high that this is that this agent has bioavailability, has again the basis of long-acting.
To the antibacterials of water be insoluble in, and form medicine carrying microgranule with the water-solubility carrier such as P407 and apply, its bioavailability can be improved, reduce injection site drug residue.
Substitute the slow releasing injection of water preparation containing P407 with oil medium, can reduce the consumption of P407, P407 consumption is when 5-10%, and preparation just has good slow releasing function.Take water as the in-situ gelling injection of solvent preparation containing P407, the consumption of P407 will reach 20 ~ 45%, and preparation just can demonstrate good slow releasing function.Current domestic P407 price more expensive (medical grade is at 160 ~ 200 yuan/kg), therefore, P407 in the formulation consumption is more, and preparation cost is higher, is unfavorable for applying in veterinary applications.
Detailed description of the invention
Embodiment 1, prepare 10% Ceftiofur Hydrochloride injection
Preparation forms: 90% Ceftiofur Hydrochloride 110g, P40760g, H-HPC30g, injection soybean oil add to 1 liter.
Preparation method: (1) by P407 in 60-70 DEG C of thawing, the methanol being equivalent to Ceftiofur Hydrochloride 2 times amount is added after adding H-HPC mixing, room temperature is down to after H-HPC dissolves, add Ceftiofur Hydrochloride, fully mix, decompression Ex-all methanol, cooling, pulverize after solidification, cross 40 mesh sieves, obtain the medicine carrying microgranule of hydrochloric ceftiofur.(2) medicine carrying microgranule is scattered in part soybean oil, cross colloid mill to be ground to particle diameter and to be less than 50 μm, grind with sand mill further, grind to particle diameter and be less than 10 μm, add remaining media, with high-shear homogenizing machine under about 5000rpm condition, after repeatedly homogenizing, the Ceftiofur Hydrochloride injection that obtained particle diameter is less than 10 μm.
Embodiment 2, prepare 8% Ceftiofur Hydrochloride injection
Preparation forms: 90% Ceftiofur Hydrochloride 90g, P40780g, IPM adds to 1 liter.
Preparation method: P407 in 60-70 DEG C of thawing, is added Ceftiofur Hydrochloride superfine powder, fully mixes by (1), cooling, pulverizes after solidification, crosses 40 mesh sieves, obtains the medicine carrying microgranule of hydrochloric ceftiofur.(2) medicine carrying microgranule is scattered in part IPM, cross colloid mill to be ground to particle diameter and to be less than 100 μm, grind with sand mill further, grind to particle diameter and be less than 20 μm, add remaining media, with high-shear homogenizing machine under about 5000rpm condition, after repeatedly homogenizing, the Ceftiofur Hydrochloride injection that obtained particle diameter is less than 20 μm.
Embodiment 3, blood drug level detect
Control formulation: Ceftiofur Hydrochloride superfine powder 9g, P4078g, sterilized water adds to 100ml, matching while using.
Select the health pig 6 of body weight about 30 kilograms, be divided into A, B two groups at random, often organize 3, respectively intramuscular injection control formulation and embodiment 2 preparation, dosage is 8mg/kgb.w., adopt cross matching, twice intertrial interval 20 days, takes a blood sample on time, centrifugal separation plasma, by the plasma sample mixed in equal amounts of same group of same time, obtain test specimens through processes such as extracting, purify, be concentrated, adopt high pressure lipuid chromatography (HPLC) (C
18post) measure ceftiofur concentration in blood plasma.Experimental result is in table 1 and table 2.
Table 1. first time testing inspection result
In ※ table, numerical value is the meansigma methods often organizing 3 porcine blood plasma drug level.
Table 2. second time testing inspection result
In ※ table, numerical value is the meansigma methods often organizing 3 porcine blood plasma drug level.
Embodiment 4, prepare 6% sulphuric acid cephalosporium quinol injection
Preparation forms: 90% sulphuric acid cephalosporium quinol 67g, P40780g, injection Semen Maydis oil adds to 1 liter.
Preparation method: P407 in 60-70 DEG C of thawing, is added sulphuric acid cephalosporium quinol superfine powder, fully mixes, pulverize after cooling curing by (1), crosses 40 mesh sieves, obtains the medicine carrying microgranule of sulfur acid Cefquinome.(2) medicine carrying microgranule is scattered in part Semen Maydis oil, cross colloid mill to be ground to particle diameter and to be less than 100 μm, grind with sand mill further, grind to particle diameter and be less than 20 μm, add remaining media, with high-shear homogenizing machine under about 5000rpm condition, after repeatedly homogenizing, the Ceftiofur Hydrochloride injection that obtained particle diameter is less than 20 μm.
Embodiment 5, prepare 15% tetramycin hydrochloride injection
Preparation forms: hydrochloric oxytetracycline 15g, P407/HPMC (2: 1) solid solution 9g, BHA0.01g, BHT0.01g, PG0.005g in every 100ml injection, EDTA-2 sodium 0.15g, IPM adds to final volume.
Preparation method: be scattered in part IPM by tetramycin hydrochloride and solid solution, is ground to particle diameter with colloid mill and sand mill and is less than 10 μm, add antioxidant and remaining media, homogenize and obtain this preparation with high-shear homogenizing machine.
This preparation is to pig intramuscular injection, and dosage is 20mg/kgb.w., 60 hours upon administration, and blood drug level still maintains Valid concentration (1-2 microgram/ml).
Embodiment 6, prepare 20% Danofloxacin mesylate injection
Preparation forms: Danofloxacin mesylate 200g, P407100g, Oleum Camelliae adds to 1 liter.
Preparation method: be scattered in by Danofloxacin mesylate in vegetable oil, is ground to particle diameter with colloid mill and is less than 100 μm, then is ground to particle diameter with sand mill and is less than 1 μm, for subsequent use through centrifugalize; P407 is made it to melt in 60-70 DEG C; The medicine above particle diameter being less than 1 μm joins in the P407 of thawing, and mixing solidification, pulverizes, in part Oleum Camelliae, be ground to particle diameter further and be less than 20 μm, add remaining media, homogenize and obtain this preparation with high-shear homogenizing machine with colloid mill and sand mill.
This preparation is to pig intramuscular injection, and dosage is 6.5mg/kgb.w., after administration 92 hours, and blood drug level still maintains Valid concentration (0.07-0.2 microgram/ml).
Embodiment 7, prepare 16% enrofloxacin injection
Preparation forms: enrofloxacin 160g, P40760g, HPMC35g, IPM adds to 1 liter.
Preparation method: be scattered in by enrofloxacin in oil medium, is ground to particle diameter with colloid mill and is less than 100 μm, then is ground to particle diameter with sand mill and is less than 1 μm, for subsequent use through centrifugalize; P407 and HPMC is mixed with proper amount of methanol, reflux is after HPMC dissolves completely, add the enrofloxacin being ground to particle diameter and being less than 1 μm, abundant mixing, decompression removing methanol, be ground to particle diameter with colloid mill and sand mill further after crushed and be less than 8 μm, add remaining media, homogenize with homogenizer and obtain this preparation.
Embodiment 8, blood drug level detect
Select the healthy sheep 10 of about 30kg body weight, random point two groups, often organize 5, (16% enrofloxacin superfine powder, 6%P407,3.5%HPMC, sterilized water adds to 100ml for ear dorsal sc injection embodiment 7 preparation and Comparative formulation.Matching while using), dosage is 15mg/kgb.w., takes a blood sample on time, centrifugal separation plasma, extracts same group with after the blood plasma mixed in equal amounts of time, adopts high pressure lipuid chromatography (HPLC) (C
18post) measure enrofloxacin concentration in blood plasma.Experimental result is as shown in the table:
In table, enrofloxacin concentration (μ g/ml) often organizes laboratory animal plasma drug level average.Numerical value finding from table, embodiment 7 preparation has obvious slow release effect, and at P407 content etc. simultaneously, its slow release effect is better than taking water as the preparation of medium.Further clinical trial, for preventing and treating sheep and goat streptococcicosis and contagious pleuropneumonia, be 15mg by per kilogram of body weight dosage, shot embodiment 7 preparation, duration of efficacy can reach more than 3 days.
Embodiment 9, prepare 12% fumaric acid tiamulin injection
Preparation forms: fumaric acid tiamulin 120g, P40770g, H-HPC40g, IPM adds to 1 liter.
Preparation method: (1) by P407 in 60-70 DEG C of thawing, the methanol being equivalent to fumaric acid tiamulin 3 times amount is added after adding H-HPC mixing, after H-HPC dissolves, add fumaric acid tiamulin, after all dissolving, decompression Ex-all methanol, cooling, pulverize after solidification, cross 40 mesh sieves, obtain fumaric acid tiamulin/P407/H-HPC medicine carrying microgranule.(2) medicine carrying microgranule is scattered in part IPM, cross colloid mill to be ground to particle diameter and to be less than 50 μm, grind with sand mill further, grind to particle diameter and be less than 10 μm, add remaining media, with high-shear homogenizing machine under about 5000rpm condition, after repeatedly homogenizing, the fumaric acid tiamulin injection that obtained particle diameter is less than 10 μm.
Preliminary clinical experimental shows, this preparation is for preventing and treating Mycoplasma ovipneumonia and mycoplasmal pneumonia of swine, Sanguis sus domestica dysentery, and by per kilogram of body weight 15-20mg administration, be administered once at interval of 3 days, administration 2-3 time, cure rate is more than 80%.
Embodiment 10, prepare 15% hydrochloric acid lincomycin injection
Preparation forms: lincomycin hydrochloride 150g, P407100g, IPM adds to 1 liter.
Preparation method: P407 in 60-70 DEG C of thawing, is added lincomycin hydrochloride and the methanol being equivalent to lincomycin hydrochloride 3 times amount, after all dissolving by (1), decompression Ex-all methanol, cooling, pulverizes after solidification, cross 40 mesh sieves, obtain hydrochloric acid lincomycin/P407 medicine carrying microgranule.(2) medicine carrying microgranule is scattered in part IPM, cross colloid mill to be ground to particle diameter and to be less than 50 μm, grind with sand mill further, grind to particle diameter and be less than 10 μm, add remaining media, with high-shear homogenizing machine under about 5000rpm condition, after repeatedly homogenizing, the lincomycin hydrochloride injection that obtained particle diameter is less than 10 μm.
Embodiment 11, prepare 8% Mequindox injection
Preparation forms: Mequindox 80g, P407100g, injection soybean oil adds to 1 liter.
Preparation method: P407 in 60-70 DEG C of thawing, is added the Mequindox superfine powder that particle diameter is less than 1 μm by (1), after mixing, cooling, pulverizes after cured, crosses 40 mesh sieves, obtains Mequindox/P407 medicine carrying microgranule.(2) medicine carrying microgranule is scattered in part soybean oil, cross colloid mill to be ground to particle diameter and to be less than 50 μm, grind with sand mill further, grind to particle diameter and be less than 10 μm, add remaining media, with high-shear homogenizing machine under about 5000rpm condition, after repeatedly homogenizing, the Mequindox injection that obtained particle diameter is less than 10 μm.
This preparation confirms through clinical experiment, and for preventing and treating Sanguis sus domestica dysentery, a secondary amounts, 7.5-10mg/kgb.w., intramuscular injection, cure rate can reach more than 90%.This preparation good biocompatibility, is particularly useful for the control of piglet diarrhea disease.
Embodiment 12, prepare 15% florfenicol injection
Preparation forms: florfenicol 150g, P40760g, IPM adds to 1 liter.
Preparation method: P407 in 60-70 DEG C of thawing, is added florfenicol and the acetone being equivalent to florfenicol 2.5-3 times amount, backflow by (1), after all dissolving, decompression Ex-all acetone, cooling, pulverize after solidification, cross 40 mesh sieves, obtain florfenicol/P407 medicine carrying microgranule.(2) medicine carrying microgranule is scattered in part IPM, cross colloid mill to be ground to particle diameter and to be less than 50 μm, grind with sand mill further, grind to particle diameter and be less than 3 μm, add remaining media, with high-shear homogenizing machine under about 5000rpm condition, after repeatedly homogenizing, the florfenicol injection that obtained particle diameter is less than 3 μm.
Embodiment 13, prepare 10% erythromycin injection
Preparation forms: erythromycin 100g, P40780g, IPM adds to 1 liter.
Preparation method: P407 in 60-70 DEG C of thawing, is added erythromycin and the methanol being equivalent to erythromycin 2 times amount, backflow by (1), after all dissolving, decompression Ex-all methanol, cools, pulverizes after solidification, cross 40 mesh sieves, obtain erythromycin/P407 medicine carrying microgranule.(2) medicine carrying microgranule is scattered in part IPM, cross colloid mill to be ground to particle diameter and to be less than 50 μm, grind with sand mill further, grind to particle diameter and be less than 3 μm, add remaining media, with high-shear homogenizing machine under about 5000rpm condition, after repeatedly homogenizing, the erythromycin injection that obtained particle diameter is less than 3 μm.
Embodiment 14, prepare 10% tilmicosin injection
Preparation forms: tilmicosin 100g, P40780g, IPM adds to 1 liter.
Preparation method: P407 in 60-70 DEG C of thawing, is added tilmicosin and is equivalent to the methanol for meter Ke Xing 2 times amount, after all dissolving by (1), distilling under reduced pressure Ex-all methanol, cooling, pulverizes after solidification, cross 40 mesh sieves, obtain tilmicosin/P407 medicine carrying microgranule.(2) medicine carrying microgranule is scattered in part IPM, cross colloid mill to be ground to particle diameter and to be less than 50 μm, grind with sand mill further, grind to particle diameter and be less than 3 μm, add remaining media, with high-shear homogenizing machine under about 5000rpm condition, after repeatedly homogenizing, the tilmicosin injection that obtained particle diameter is less than 3 μm.
Claims (5)
1., containing a veterinary injection for antibacterials, it is characterized in that often liter of injection comprises following component:
Antibacterials 25-200g
Poloxamer188 25-150g
Oil medium adds to 1 liter;
Described oil medium is the one in isopropyl myristate, injection soybean oil, Semen Maydis oil, Oleum Camelliae;
Described antibacterials comprise: enrofloxacin, Danofloxacin mesylate, Marbofloxacin, Mequindox, tylosin, fumaric acid tiamulin, for meter Ke Xing, tetramycin hydrochloride, colistine sulfate, Ceftiofur Hydrochloride, sulphuric acid cephalosporium quinol, gentamycin sulfate, lincomycin hydrochloride, florfenicol, erythromycin;
In the formulation, described antibacterials and poloxamer188 are prepared to medicine carrying microgranule, are scattered in oil medium with medicine carrying microgranule state, and medicine carrying microgranule weight percent content is in the formulation 5-35%.
2., by veterinary injection according to claim 1, it is characterized in that in often liter of injection, add 20-60g hydroxypropyl emthylcellulose or Hydroxypropylcelliloxe.
3. by veterinary injection according to claim 2, antibacterials and poloxamer188 and Hydroxypropylcelliloxe is it is characterized in that to be prepared into medicine carrying microgranule, then medicine carrying microgranule is scattered in oil medium, through grinding the oily injection be prepared into containing antibacterials/poloxamer188/Hydroxypropylcelliloxe medicine carrying microgranule.
4. by veterinary injection according to claim 2, antibacterials and poloxamer188 and hydroxypropyl emthylcellulose is it is characterized in that to be prepared into medicine carrying microgranule, then medicine carrying microgranule is scattered in oil medium, through grinding the oily injection be prepared into containing antibacterials/poloxamer188/hydroxypropyl emthylcellulose medicine carrying microgranule.
5. by the veterinary injection described in claim 1-4 any one, it is characterized in that also can adding 0.2-2g antioxidant in often liter of injection, antioxidant is the mixture of one or more any ratios in tertiary butyl-4-hydroxy methoxybenzene, dibenzylatiooluene, propyl gallate or ascorbyl palmitate.
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| 固体分散技术的研究进展及应用;胡兴平;《兽药研究与应用》;20081231(第12期);第36-37页 * |
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