CN1502335A - Application of Netilmicin sulfate in preparation of eye drops - Google Patents
Application of Netilmicin sulfate in preparation of eye drops Download PDFInfo
- Publication number
- CN1502335A CN1502335A CNA021386625A CN02138662A CN1502335A CN 1502335 A CN1502335 A CN 1502335A CN A021386625 A CNA021386625 A CN A021386625A CN 02138662 A CN02138662 A CN 02138662A CN 1502335 A CN1502335 A CN 1502335A
- Authority
- CN
- China
- Prior art keywords
- preparation
- sodium
- eye drop
- netilmicin sulfate
- netilmicin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000003889 eye drop Substances 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- CZPLANDPABRVHX-UHFFFAOYSA-N cascade blue Chemical compound C=1C2=CC=CC=C2C(NCC)=CC=1C(C=1C=CC(=CC=1)N(CC)CC)=C1C=CC(=[N+](CC)CC)C=C1 CZPLANDPABRVHX-UHFFFAOYSA-N 0.000 title claims description 50
- 229960004832 netilmicin sulfate Drugs 0.000 title claims description 50
- 229940012356 eye drops Drugs 0.000 title abstract 3
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 239000003381 stabilizer Substances 0.000 claims abstract description 7
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 38
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 27
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 235000010265 sodium sulphite Nutrition 0.000 claims description 19
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 16
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 15
- 239000001632 sodium acetate Substances 0.000 claims description 15
- 235000017281 sodium acetate Nutrition 0.000 claims description 15
- 239000003963 antioxidant agent Substances 0.000 claims description 14
- 230000003078 antioxidant effect Effects 0.000 claims description 14
- 235000006708 antioxidants Nutrition 0.000 claims description 14
- 229940087511 calcium disodium versenate Drugs 0.000 claims description 14
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 13
- 239000004327 boric acid Substances 0.000 claims description 13
- 235000010338 boric acid Nutrition 0.000 claims description 13
- 229960000808 netilmicin Drugs 0.000 claims description 13
- 239000011780 sodium chloride Substances 0.000 claims description 13
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 13
- 239000008215 water for injection Substances 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 229920003081 Povidone K 30 Polymers 0.000 claims description 12
- 239000012153 distilled water Substances 0.000 claims description 10
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 9
- 229960004217 benzyl alcohol Drugs 0.000 claims description 9
- 230000002421 anti-septic effect Effects 0.000 claims description 7
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 7
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 238000005457 optimization Methods 0.000 claims description 6
- 239000002671 adjuvant Substances 0.000 claims description 5
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 5
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 5
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 claims description 5
- 230000001954 sterilising effect Effects 0.000 claims description 5
- 238000004659 sterilization and disinfection Methods 0.000 claims description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 235000011054 acetic acid Nutrition 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 4
- 238000012856 packing Methods 0.000 claims description 4
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 3
- 235000019800 disodium phosphate Nutrition 0.000 claims description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 claims description 2
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 claims description 2
- SHWNNYZBHZIQQV-UHFFFAOYSA-J EDTA monocalcium diisodium salt Chemical compound [Na+].[Na+].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O SHWNNYZBHZIQQV-UHFFFAOYSA-J 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- 229960002233 benzalkonium bromide Drugs 0.000 claims description 2
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 2
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 2
- 229910021538 borax Inorganic materials 0.000 claims description 2
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 claims description 2
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 229960004926 chlorobutanol Drugs 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- PHMMATAWQLJFIQ-UHFFFAOYSA-N cyanomercury(1+);oxygen(2-) Chemical compound [O-2].[Hg+]C#N.[Hg+]C#N PHMMATAWQLJFIQ-UHFFFAOYSA-N 0.000 claims description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 2
- 235000018417 cysteine Nutrition 0.000 claims description 2
- FYGDTMLNYKFZSV-MRCIVHHJSA-N dextrin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1O[C@@H]1[C@@H](CO)OC(O[C@@H]2[C@H](O[C@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-MRCIVHHJSA-N 0.000 claims description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- WQABCVAJNWAXTE-UHFFFAOYSA-N dimercaprol Chemical compound OCC(S)CS WQABCVAJNWAXTE-UHFFFAOYSA-N 0.000 claims description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 2
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 claims description 2
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 2
- 229960002216 methylparaben Drugs 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 2
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 235000011008 sodium phosphates Nutrition 0.000 claims description 2
- 239000004328 sodium tetraborate Substances 0.000 claims description 2
- 235000010339 sodium tetraborate Nutrition 0.000 claims description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 2
- 235000010199 sorbic acid Nutrition 0.000 claims description 2
- 239000004334 sorbic acid Substances 0.000 claims description 2
- 229940075582 sorbic acid Drugs 0.000 claims description 2
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 claims description 2
- 229940033663 thimerosal Drugs 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- -1 netilmicin sulfates Chemical class 0.000 claims 4
- 230000000694 effects Effects 0.000 abstract description 9
- 206010023332 keratitis Diseases 0.000 abstract description 5
- 241000894006 Bacteria Species 0.000 abstract description 4
- 241000589516 Pseudomonas Species 0.000 abstract description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 abstract description 2
- 230000001105 regulatory effect Effects 0.000 abstract 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 abstract 1
- 230000003064 anti-oxidating effect Effects 0.000 abstract 1
- 239000013000 chemical inhibitor Substances 0.000 abstract 1
- 230000001524 infective effect Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 239000003755 preservative agent Substances 0.000 abstract 1
- 230000002335 preservative effect Effects 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 13
- ZBGPYVZLYBDXKO-HILBYHGXSA-N netilmycin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@]([C@H](NC)[C@@H](O)CO1)(C)O)NCC)[C@H]1OC(CN)=CC[C@H]1N ZBGPYVZLYBDXKO-HILBYHGXSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 6
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 5
- 229930182566 Gentamicin Natural products 0.000 description 5
- 238000001914 filtration Methods 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 3
- 229940126575 aminoglycoside Drugs 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 208000030533 eye disease Diseases 0.000 description 3
- 230000007794 irritation Effects 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- KLCDQSGLLRINHY-UHFFFAOYSA-N 1-phenyldiazenylnaphthalen-2-amine Chemical compound NC1=CC=C2C=CC=CC2=C1N=NC1=CC=CC=C1 KLCDQSGLLRINHY-UHFFFAOYSA-N 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 2
- 241000304886 Bacilli Species 0.000 description 2
- 208000028006 Corneal injury Diseases 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 241000192125 Firmicutes Species 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 241000209094 Oryza Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- 230000036783 anaphylactic response Effects 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- 230000000843 anti-fungal effect Effects 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 229960003405 ciprofloxacin Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 206010023683 lagophthalmos Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000012982 microporous membrane Substances 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000001860 Eye Infections Diseases 0.000 description 1
- 206010015943 Eye inflammation Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229960004821 amikacin Drugs 0.000 description 1
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 1
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 208000011323 eye infectious disease Diseases 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 230000003118 histopathologic effect Effects 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- KFQVIRAGPXFJKG-UHFFFAOYSA-N sodium;acetic acid;dihydrogen borate Chemical compound [Na+].CC(O)=O.OB(O)[O-] KFQVIRAGPXFJKG-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention belongs to a preparation process of eye drops with obvious curative effect for curing keratitis due to pseudomonas and infective ophthalmopathies due to gram-negative bacteria, pseudomonas aeruginosa and other bacteria. Said eye drops preparation is of netilamicin sulfate which is used as main raw material and adding chemical inhibitor, antioxidation synergist, preservative, pH regulating agent, isoosmotic regulating agent, stabilizing agent and solvent as auxiliary material.
Description
Technical field
The present invention relates to a kind of preparation technology who treats the ophthalmic diseases medicine, specifically mainly cooperate adjuvant to prepare a kind of eye drop with netilmicin sulfate.
Background technology
In the present clinical ophthalmic remedy, the chemistry of antibiotics medicine has overwhelming superiority.According to statistics, at the patient 80%～90% that the ophthalmology outpatient service is gone to a doctor, outer eye infections.Local application is the main path of ophthalmic remedy, because local application not only can make the diseased region liquor strength higher, keeps the long period, and can save medicine greatly, reduces systemic side effects.Eye drop is the most frequently used topical remedy's dosage form of ophthalmology.In the eye drop of treatment eye inflammation, using more clinically is aminoglycoside, Macrolide, quinolones etc., and aminoglycoside, because permeability is good, has a broad antifungal spectrum, side effect is little, uses in rising trend always in recent years.
The netilmicin sulfate dosage form is a netilmicin sulfate inj, because this new drug belongs to aminoglycoside antibiotics of new generation, has the wide spectrum effect, especially this medicine relatively has lower kidney, neurotoxicity with similar antibiotic, event is easier to be accepted by the clinician, and it has been done many comparative study with similar medicine.The clinical efficacy of visible netilmicin and bacteriology's curative effect obviously are better than gentamycin (p＜0.05) when the homemade netilmicin of clinical use, but there was no significant difference between both adverse reaction rates.External drug sensitive test result shows the medicaments insensitive rate of netilmicin far above gentamycin, has 77.3% gentamycin fastbacteria still responsive to netilmicin.There is 92.9% pair of netilmicin still responsive to the drug-fast escherichia coli of ciprofloxacin.Therefore, netilmicin can be widely used in the infection that clinical treatment gram negative bacilli and a part of gram positive bacteria are caused, and can be used for the treatment of gentamycin fastbacteria, the also treatment of the infection that can cause in anti-ciprofloxacin escherichia coli with the beta-lactam antibiotic use in conjunction.
Netilmicin sulfate has advantages such as good effect, side effect be low, but netilmicin sulfate is not applied to ophthalmology illness so far
Summary of the invention
The objective of the invention is and to be applied to prepare a kind of eye drop to netilmicin sulfate.
The application of netilmicin sulfate in the preparation eye drop preparation is characterized in that cooperating adjuvant to be prepared into a kind of netilmicin sulfate eye drop with netilmicin sulfate.
Adjuvant is antioxidant, antioxidant synergist, antiseptic, PH regulator, isoosmotic adjusting agent, stabilizing agent and solvent in the prepared netilmicin sulfate eye drop.
Antioxidant can be one or more in sodium sulfite, sodium pyrosulfite, sodium sulfite, sodium thiosulfate, ascorbic acid, thiourea, the cysteine in the prepared netilmicin sulfate eye drop, is preferably sodium sulfite; Antioxidant synergist is one or more in Calcium Disodium Versenate, disodium edetate, calcium disodium edetate, diethyl triamine five acetic acid, the dimercaptopropanol, BAL, is preferably Calcium Disodium Versenate; Antiseptic is one or more in benzyl alcohol, methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, benzalkonium bromide, benzalkonium chloride, chlorobutanol, phenethanol, thimerosal, mercuric oxycyanide, sorbic acid, hibitane, the benzoic acid, is preferably benzyl alcohol; The PH regulator is one or more in boric acid, sodium dihydrogen phosphate, Borax, sodium hydrogen phosphate, sodium acetate, acetic acid, anhydrous sodium phosphate, citric acid, the sodium citrate, is preferably boric acid, sodium dihydrogen phosphate; Isoosmotic adjusting agent is sodium acetate or sodium chloride, is preferably sodium acetate; Stabilizing agent is a beta-schardinger dextrin-; Viscosifier are one or more in methylcellulose, Carboxymethyl cellulose sodium, hydroxypropyl methylcellulose, cellulose, polyvinyl alcohol, the 30 POVIDONE K 30 BP/USP 30, are preferably 30 POVIDONE K 30 BP/USP 30; Solvent is water for injection or distilled water.
Every 1000ml netilmicin sulfate eye drop prescription amount ranges is: netilmicin sulfate 10 ~ 20g, sodium sulfite 2 ~ 6g, benzyl alcohol 8 ~ 12g, beta-schardinger dextrin-3 ~ 8g, 30 POVIDONE K 30 BP/USP 30 8-12g, Calcium Disodium Versenate 0.05 ~ 0.5g, sodium acetate 10 ~ 15g, boric acid 0.8 ~ 2g, all the other are water for injection or distilled water.
Every 1000ml netilmicin sulfate eye drop optimization formula amount ranges is: netilmicin sulfate 15～18g, sodium sulfite 3 ~ 5g, benzyl alcohol 9 ~ 11g, beta-schardinger dextrin-4 ~ 6g, 30 POVIDONE K 30 BP/USP 30 9-11g, Calcium Disodium Versenate 0.08 ~ 0.2g, sodium acetate 11 ~ 14g, boric acid 1 ~ 2g, all the other are water for injection or distilled water.
Every 1000ml netilmicin sulfate eye drop optimization formula amount ranges is: netilmicin sulfate 15 ~ 18g, sodium sulfite 0.5 ~ 1.5g, Calcium Disodium Versenate 0.08 ~ 0.2g, ethyl hydroxybenzoate 0.1 ~ 0.3g, phosphoric acid hydrogen two is received 0.15 ~ 0.3g, biphosphate is received 0.5 ~ 0.7g, sodium chloride 0.2 ~ 0.4g, and all the other are water for injection or distilled water.
Every 1000ml netilmicin sulfate eye drop optimization formula amount ranges is: netilmicin sulfate 15 ~ 18g, and sodium sulfite 3 ~ 5g, ethyl hydroxybenzoate 0.1 ~ 0.3g, sodium chloride 0.5 ~ 0.9g, all the other are water for injection or distilled water.
The preparation method of netilmicin sulfate eye drop is: gets antioxidant, antioxidant synergist, antiseptic, PH regulator, isoosmotic adjusting agent, stabilizing agent in solvent, adds water to full dose, filter, and sterilization, cooling adds netilmicin sulfate, shakes up, and filters packing.
Its pharmacodynamics test of eye drop of the present invention preparation shows that the keratitis that rabbit bacillus pyocyaneus and staphylococcus aureus are caused all has therapeutical effect, and the performance inflammation obviously alleviates, and cornea is cultivated and is negative, and its curative effect is suitable with the amikacin eye drop.
Irritation test shows that single-dose does not have the obvious irritation reaction to the lagophthalmos mucosa; Also do not see local anaphylaxis in the experimental observation.Netilmicin eye drop successive administration is 7 days in addition, and drug withdrawal was observed 7 days, does not find that the lagophthalmos mucosa has the obvious irritation reaction; Also do not see local anaphylaxis; Histopathologic examination's medication group is identical with the normal saline matched group, no abnormal discovery.
The present invention has ideal therapeutic effect to the keratitis due to the pseudomonas strain; To have prior using value if be further used for the oculopathy of the clinical treatment strain infection of anti-the gentamycin.Because netilmicin sulfate has a broad antifungal spectrum, can be used for treating the infectious eye disease due to gram negative bacilli and a part of gram positive bacteria, can make choice drug the ophthalmic of the suspicious charrin's disease that can not affirm pathogen for the moment or the bacillary oculopathy of other not clear pathogen.Netilmicin sulfate eye drop nonirritant, safety, stable are a kind of up-and-coming antibiotic eye drop.Be expected to replace existing other aminoglycoside saccharide antibiotic and be considered as choice drug by the doctor.
The specific embodiment:
Preparation technology of the present invention: get sodium acetate, boric acid, sodium sulfite, Calcium Disodium Versenate, beta-schardinger dextrin-, benzyl alcohol, 30 POVIDONE K 30 BP/USP 30 and be dissolved in the water for injection, add water to full dose, add 0.01% 767 type needle-use activated carbons, stir after 30 minutes, take off charcoal through 0.45 μ m filtering with microporous membrane; 100 ℃ of 30 minutes circulation steam sterilizations are put cold back standby.Under the sterile working, add netilmicin sulfate, shake up, intermediate is up to the standards after packing behind the 0.22 μ m microporous filter membrane end-filtration, promptly.
The concrete operations step:
(1) the plastics eye drop bottle is cleaned, 100 ℃ of 20 minutes circulation steam sterilizations, standby;
(2) sodium acetate, boric acid, sodium sulfite, Calcium Disodium Versenate, beta-schardinger dextrin-, benzyl alcohol, 30 POVIDONE K 30 BP/USP 30 are dissolved in water for injection and add to full dose;
1. add 0.01% 767 type needle-use activated carbons, stir after 30 minutes, take off charcoal through 0.45 μ m filtering with microporous membrane, 100 ℃ of 30 minutes circulation steam sterilizations, standby;
2. under the sterile working, netilmicin sulfate is dissolved in above solution, stirs;
3. the intermediate passed examination is after packing behind the 0.22 μ m microporous filter membrane end-filtration;
4. product inspection.
Experimental formula of the present invention is table as a result:
Formula number 1234
Netilmicin sulfate (g) 16.9 16.9 16.9 16.9
Sodium sulfite (g) 1.0 444
Calcium Disodium Versenate (g) 0.1/0.1/
Ethyl hydroxybenzoate (g) 0.2 // 0.2
Benzyl alcohol (ml)/10 10/
30 POVIDONE K 30 BP/USP 30 (g)/10 10/
Beta-schardinger dextrin-(g)/15 5/
Sodium hydrogen phosphate (g) 0.24 ///
Sodium dihydrogen phosphate (g) 0.66 ///
Sodium acetate (g)/13 13/
Boric acid (g)/1.4 1.4/
Sodium chloride (g) 0.32 // 0.84
The face light yellow complexion is shallower than yellow No. 2 and is shallower than yellow No. 2 little Huangs
Accelerated test 1 clarity is up to specification to have the Xiao Bai piece up to specification
Related substance was up to specification in individual month
Content no change no change no change no change
Prescription 3 is through accelerated test after one month, and every index does not all have obvious change, so prescription 3 is an optimum formula of the present invention.Each component effect in the prescription
Netilmicin sulfate: principal agent
Sodium sulfite: antioxidant
Calcium Disodium Versenate: antioxidant synergist
Benzyl alcohol: antiseptic
Sodium acetate, boric acid: regulate pH, adjusting etc. and ooze
Beta-schardinger dextrin-: enhanced stability
30 POVIDONE K 30 BP/USP 30: viscosifier
Water for injection: solvent
Netilmicin sulfate in aqueous solution after tested pH be 3.5～5.5, consider clinical use and experimental studies results, this product is transferred pH with sodium acetate-borate buffer solution in process of production, the pH of finished product is between 4.0～7.0 after testing.
The filter that uses in the production process etc. all adopts suitable method to sterilize.
The sodium chloride of sodium sulfite 1% solution etc. oozes equivalent E=0.61, and the sodium chloride of sodium acetate 1% solution etc. oozes equivalent E=0.46, and the sodium chloride of boric acid 1% solution etc. oozes equivalent E=0.50, and the sodium chloride of benzyl alcohol 1% solution etc. oozes equivalent E=0.17
The sodium chloride equivalent of this product is 0.61 * 0.4+0.46 * 1.3+0.5 * 0.14=0.912
The osmotic pressure of this product is equivalent to 0.912% sodium chloride solution, and promptly this product is an isosmotic solution.
The netilmicin sulfate eye drop is to the inflammatory reaction scoring of the golden Portugal of rabbit (n=5) bacterium property keratitis
After the drug withdrawal of medication phase
Group
1d 2d 3d 1d 3d 5d 7d
The heavy dose of group 5.5 4.5 30000 of netilmicin
Netilmicin small dose group 5.5 5.5 4.0 2100
Positive controls 4.0 3.5 3.0 2.0 1.5 11
Corneal injury+infected group 25 25 25 23 22 20 20
Corneal injury is infected group 4.0 4.0 2.5 1.0 1.0 1.0 1.0 not
The netilmicin sulfate eye drop is to the therapeutical effect of rabbit gold Portugal bacterium property keratitis
After the drug withdrawal of medication phase
The group preface
1d 2d 3d 1d 3d 5d 7d
Alias
L R L R L R L R L R L R L R
How 11111 0.5 100000000
For 2 0.5 0.5 0.5 0.5 0000000000
Rice 3 0.5 0.5 000000000000
Star 4 0.5 0 0.5 0 0.5 000000000
Greatly
Agent
5 0.5 0.5 0.5 0.5 0.5 0.5 0 0 0 0 0 0 0 0
Amount
Group
How 1 0.5 0.5 0.5 0.5 0 0.5 00000000
For 2 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0000
Rice 3 0.5 0.5 0.5 0.5 0000000000
Star
4 0.5 1 0.5 1 0.5 1 0.5 0.5 0 0 0 0 0 0
Little
Agent
5 0.5 0.5 0.5 0.5 0.5 0.5 0 0 0 0 0 0 0 0
Amount
Group
Sun 10 0.5 000000000000
Property 2111111 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
To 3 0.5 0 0.5 00 0. 00000000
According to
4 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Medicine
5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0 0 0 0 0
Group
Angle 133333333333333
Film 222222222222222
Decrease 323232323222222
Hinder 433333322222222
+
Sense
5 2 2 2 2 2 2 2 2 2 2 1 1 1 1
Dye
Group
Angle 1 0.5 0.5 0.5 0.5 0.5 0.5 00000000
Film 200000000000000
Decrease 3 0.5 0.5 0.5 0.5 0.5 0.5 00000000
Hinder
4 1 0.5 1 0.5 0 0 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
No
No
Sense
5 0.5 0 0.5 0 0.5 0 0 0 0 0 0 0 0 0
Dye
Group
Annotate: L is a left eye, and R is a right eye
Claims (8)
1, the application of netilmicin sulfate in the preparation eye drop preparation is characterized in that cooperating adjuvant to be prepared into a kind of netilmicin sulfate eye drop with netilmicin sulfate.
2, the application of netilmicin sulfate according to claim 1 in the preparation eye drop preparation is characterized in that adjuvant is antioxidant, antioxidant synergist, antiseptic, PH regulator, isoosmotic adjusting agent, stabilizing agent and solvent in the prepared netilmicin sulfate eye drop.
3, the application of netilmicin sulfate according to claim 2 in the preparation eye drop preparation, it is characterized in that antioxidant in the prepared netilmicin sulfate eye drop can be one or more in sodium sulfite, sodium pyrosulfite, sodium sulfite, sodium thiosulfate, ascorbic acid, thiourea, the cysteine, is preferably sodium sulfite; Antioxidant synergist is one or more in Calcium Disodium Versenate, disodium edetate, calcium disodium edetate, diethyl triamine five acetic acid, the dimercaptopropanol, BAL, is preferably Calcium Disodium Versenate; Antiseptic is one or more in benzyl alcohol, methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, benzalkonium bromide, benzalkonium chloride, chlorobutanol, phenethanol, thimerosal, mercuric oxycyanide, sorbic acid, hibitane, the benzoic acid, is preferably benzyl alcohol; The PH regulator is one or more in boric acid, sodium dihydrogen phosphate, Borax, sodium hydrogen phosphate, sodium acetate, acetic acid, anhydrous sodium phosphate, citric acid, the sodium citrate, is preferably boric acid, sodium dihydrogen phosphate; Isoosmotic adjusting agent is sodium acetate or sodium chloride, is preferably sodium acetate; Stabilizing agent is a beta-schardinger dextrin-; Viscosifier are one or more in methylcellulose, Carboxymethyl cellulose sodium, hydroxypropyl methylcellulose, cellulose, polyvinyl alcohol, the 30 POVIDONE K 30 BP/USP 30, are preferably 30 POVIDONE K 30 BP/USP 30; Solvent is water for injection or distilled water.
4, according to claim 1, the application of 2 or 3 described netilmicin sulfates in the preparation eye drop preparation, it is characterized in that every 1000ml netilmicin sulfate eye drop prescription amount ranges is: netilmicin sulfate 10 ~ 20g, sodium sulfite 2 ~ 6g, benzyl alcohol 8 ~ 12g, beta-schardinger dextrin-3 ~ 8g, 30 POVIDONE K 30 BP/USP 30 8-12g, Calcium Disodium Versenate 0.05 ~ 0.5g, sodium acetate 10 ~ 15g, boric acid 0.8 ~ 2g, all the other are water for injection or distilled water.
5, according to claim 1, the application of 2 or 3 described netilmicin sulfates in the preparation eye drop preparation, it is characterized in that every 1000ml netilmicin sulfate eye drop optimization formula amount ranges is: netilmicin sulfate 15～18g, sodium sulfite 3 ~ 5g, benzyl alcohol 9 ~ 11g, beta-schardinger dextrin-4 ~ 6g, 30 POVIDONE K 30 BP/USP 30 9-11g, Calcium Disodium Versenate 0.08 ~ 0.2g, sodium acetate 11 ~ 14g, boric acid 1 ~ 2g, all the other are water for injection or distilled water.
6, according to claim 1, the application of 2 or 3 described netilmicin sulfates in the preparation eye drop preparation, it is characterized in that every 1000ml netilmicin sulfate eye drop optimization formula amount ranges is: netilmicin sulfate 15 ~ 18g, sodium sulfite 0.5 ~ 1.5g, Calcium Disodium Versenate 0.08 ~ 0.2g, ethyl hydroxybenzoate 0.1 ~ 0.3g, phosphoric acid hydrogen two receive 0.15 ~ 0.3g, and biphosphate is received 0.5 ~ 0.7g, sodium chloride 0.2 ~ 0.4g, all the other are water for injection or distilled water.
7, according to claim 1, the application of 2 or 3 described netilmicin sulfates in the preparation eye drop preparation, it is characterized in that every 1000ml netilmicin sulfate eye drop optimization formula amount ranges is: netilmicin sulfate 15 ~ 18g, sodium sulfite 3 ~ 5g, ethyl hydroxybenzoate 0.1 ~ 0.3g, sodium chloride 0.5 ~ 0.9g, all the other are water for injection or distilled water.
8, the application of netilmicin sulfate according to claim 1 in the preparation eye drop preparation, the preparation method that it is characterized in that the netilmicin sulfate eye drop is: get antioxidant, antioxidant synergist, antiseptic, PH regulator, isoosmotic adjusting agent, stabilizing agent in solvent, add water to full dose, filter, sterilization, cooling adds netilmicin sulfate, shake up, filter packing.
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|---|---|---|---|
| CN 02138662 CN1264517C (en) | 2002-11-21 | 2002-11-21 | Application of Netilmicin sulfate in preparation of eye drops |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02138662 CN1264517C (en) | 2002-11-21 | 2002-11-21 | Application of Netilmicin sulfate in preparation of eye drops |
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| CN1502335A true CN1502335A (en) | 2004-06-09 |
| CN1264517C CN1264517C (en) | 2006-07-19 |
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| CN 02138662 Expired - Fee Related CN1264517C (en) | 2002-11-21 | 2002-11-21 | Application of Netilmicin sulfate in preparation of eye drops |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101805382A (en) * | 2010-04-14 | 2010-08-18 | 无锡山禾集团福祈制药有限公司 | Separation and purification method of high-purity netilmicin |
| CN102525963A (en) * | 2012-02-08 | 2012-07-04 | 武汉普生制药有限公司 | Netilmicin sulfate lyophiled powder injection and preparation method thereof |
| CN105193722A (en) * | 2015-10-28 | 2015-12-30 | 辅必成（上海）医药科技有限公司 | Dimercaprol fat emulsion injection |
| CN105663520A (en) * | 2016-02-29 | 2016-06-15 | 李宏 | Wuhu oral liquid and preparing method thereof |
| CN112545985A (en) * | 2020-12-30 | 2021-03-26 | 卓和药业集团有限公司 | Eye drops containing netilmicin sulfate and preparation method thereof |
| CN114275906A (en) * | 2021-12-10 | 2022-04-05 | 安徽安泰农业开发有限责任公司 | Composite microbial inoculum for treating sewage of pig farm and preparation method thereof |
-
2002
- 2002-11-21 CN CN 02138662 patent/CN1264517C/en not_active Expired - Fee Related
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101805382A (en) * | 2010-04-14 | 2010-08-18 | 无锡山禾集团福祈制药有限公司 | Separation and purification method of high-purity netilmicin |
| CN101805382B (en) * | 2010-04-14 | 2012-08-08 | 无锡福祈制药有限公司 | Separation and purification method of high-purity netilmicin |
| CN102525963A (en) * | 2012-02-08 | 2012-07-04 | 武汉普生制药有限公司 | Netilmicin sulfate lyophiled powder injection and preparation method thereof |
| CN102525963B (en) * | 2012-02-08 | 2013-05-08 | 武汉普生制药有限公司 | Netilmicin sulfate lyophiled powder injection and preparation method thereof |
| CN105193722A (en) * | 2015-10-28 | 2015-12-30 | 辅必成（上海）医药科技有限公司 | Dimercaprol fat emulsion injection |
| CN105193722B (en) * | 2015-10-28 | 2021-12-14 | 辅必成（上海）医药科技有限公司 | Dimercaprol fat emulsion injection |
| CN105663520A (en) * | 2016-02-29 | 2016-06-15 | 李宏 | Wuhu oral liquid and preparing method thereof |
| CN105663520B (en) * | 2016-02-29 | 2019-10-29 | 李宏 | Five brave oral solutions and preparation method thereof |
| CN112545985A (en) * | 2020-12-30 | 2021-03-26 | 卓和药业集团有限公司 | Eye drops containing netilmicin sulfate and preparation method thereof |
| CN114275906A (en) * | 2021-12-10 | 2022-04-05 | 安徽安泰农业开发有限责任公司 | Composite microbial inoculum for treating sewage of pig farm and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1264517C (en) | 2006-07-19 |
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