WO2015088305A1 - Complejo recristalizado de clorhidrato de enrofloxacina dihidratado, y metodo para obtener el mismo - Google Patents
Complejo recristalizado de clorhidrato de enrofloxacina dihidratado, y metodo para obtener el mismo Download PDFInfo
- Publication number
- WO2015088305A1 WO2015088305A1 PCT/MX2014/000192 MX2014000192W WO2015088305A1 WO 2015088305 A1 WO2015088305 A1 WO 2015088305A1 MX 2014000192 W MX2014000192 W MX 2014000192W WO 2015088305 A1 WO2015088305 A1 WO 2015088305A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- enrofloxacin
- complex
- further characterized
- enr
- formula
- Prior art date
Links
- PZJWYUDBXNNVLZ-UHFFFAOYSA-N 1-cyclopropyl-7-(4-ethylpiperazin-1-yl)-6-fluoro-4-oxoquinoline-3-carboxylic acid;hydrochloride Chemical class Cl.C1CN(CC)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 PZJWYUDBXNNVLZ-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 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 abstract description 133
- 229960000740 enrofloxacin Drugs 0.000 claims abstract description 131
- 239000002253 acid Substances 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- 239000003814 drug Substances 0.000 claims description 38
- 239000000203 mixture Substances 0.000 claims description 33
- 239000000047 product Substances 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 238000007920 subcutaneous administration Methods 0.000 claims description 19
- 229940079593 drug Drugs 0.000 claims description 17
- -1 enrofloxacin hexahydrate Chemical class 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 238000007918 intramuscular administration Methods 0.000 claims description 12
- 239000000843 powder Substances 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 239000013078 crystal Substances 0.000 claims description 9
- 235000019441 ethanol Nutrition 0.000 claims description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical group [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 8
- 238000010907 mechanical stirring Methods 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 6
- 229920002125 Sokalan® Polymers 0.000 claims description 6
- 229960001631 carbomer Drugs 0.000 claims description 6
- 238000002329 infrared spectrum Methods 0.000 claims description 6
- 239000012528 membrane Substances 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000011148 porous material Substances 0.000 claims description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 238000002844 melting Methods 0.000 claims description 5
- 230000008018 melting Effects 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims description 4
- PMNLUUOXGOOLSP-UHFFFAOYSA-N 2-mercaptopropanoic acid Chemical compound CC(S)C(O)=O PMNLUUOXGOOLSP-UHFFFAOYSA-N 0.000 claims description 4
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 4
- 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
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 4
- 239000003963 antioxidant agent Substances 0.000 claims description 4
- 235000006708 antioxidants 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
- 239000008139 complexing agent Substances 0.000 claims description 4
- 239000003651 drinking water Substances 0.000 claims description 4
- 235000020188 drinking water Nutrition 0.000 claims description 4
- 239000003966 growth inhibitor Substances 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 229910021645 metal ion Inorganic materials 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 239000003755 preservative agent Substances 0.000 claims description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 4
- 239000003826 tablet Substances 0.000 claims description 4
- 239000002562 thickening agent Substances 0.000 claims description 4
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 3
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 3
- 239000002674 ointment Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 230000007704 transition Effects 0.000 claims description 3
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 claims description 2
- ODJQKYXPKWQWNK-UHFFFAOYSA-N 3,3'-Thiobispropanoic acid Chemical compound OC(=O)CCSCCC(O)=O ODJQKYXPKWQWNK-UHFFFAOYSA-N 0.000 claims description 2
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical class 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
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical class OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 239000003490 Thiodipropionic acid Substances 0.000 claims description 2
- 150000001242 acetic acid derivatives Chemical class 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
- 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
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 235000019437 butane-1,3-diol Nutrition 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229960004926 chlorobutanol Drugs 0.000 claims description 2
- 150000001860 citric acid derivatives Chemical class 0.000 claims description 2
- 239000003086 colorant Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000007919 dispersible tablet Substances 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 2
- 238000007912 intraperitoneal administration Methods 0.000 claims description 2
- 239000006194 liquid suspension Substances 0.000 claims description 2
- 239000006210 lotion Substances 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- 239000007912 modified release tablet Substances 0.000 claims description 2
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 150000002989 phenols Chemical class 0.000 claims description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 2
- 235000021317 phosphate Nutrition 0.000 claims description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 2
- 239000000473 propyl gallate Substances 0.000 claims description 2
- 235000010388 propyl gallate Nutrition 0.000 claims description 2
- 229940075579 propyl gallate Drugs 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 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
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 2
- 235000010265 sodium sulphite Nutrition 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 235000019303 thiodipropionic acid Nutrition 0.000 claims description 2
- 239000004034 viscosity adjusting agent Substances 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 2
- 229940124532 absorption promoter Drugs 0.000 claims 1
- 239000007884 disintegrant Substances 0.000 claims 1
- 229940001482 sodium sulfite Drugs 0.000 claims 1
- 210000002966 serum Anatomy 0.000 abstract description 31
- 230000015572 biosynthetic process Effects 0.000 abstract description 14
- 239000011777 magnesium Substances 0.000 abstract description 7
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 abstract description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 abstract description 5
- 229910052749 magnesium Inorganic materials 0.000 abstract description 5
- 238000001953 recrystallisation Methods 0.000 abstract description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 abstract 1
- 230000001580 bacterial effect Effects 0.000 description 31
- 241001465754 Metazoa Species 0.000 description 30
- 230000000694 effects Effects 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 230000035945 sensitivity Effects 0.000 description 20
- 239000000463 material Substances 0.000 description 19
- 239000008367 deionised water Substances 0.000 description 18
- 229910021641 deionized water Inorganic materials 0.000 description 18
- 238000010790 dilution Methods 0.000 description 18
- 239000012895 dilution Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 230000000844 anti-bacterial effect Effects 0.000 description 15
- 239000002585 base Substances 0.000 description 14
- 125000005843 halogen group Chemical group 0.000 description 14
- 230000005764 inhibitory process Effects 0.000 description 14
- 244000052769 pathogen Species 0.000 description 14
- 239000000523 sample Substances 0.000 description 14
- 238000004458 analytical method Methods 0.000 description 13
- 238000005070 sampling Methods 0.000 description 12
- 241000282887 Suidae Species 0.000 description 11
- 239000001963 growth medium Substances 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- 229920001817 Agar Polymers 0.000 description 10
- 241000283086 Equidae Species 0.000 description 10
- 239000008272 agar Substances 0.000 description 10
- 244000005700 microbiome Species 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- 239000003242 anti bacterial agent Substances 0.000 description 9
- NSNHWTBQMQIDCF-UHFFFAOYSA-N dihydrate;hydrochloride Chemical compound O.O.Cl NSNHWTBQMQIDCF-UHFFFAOYSA-N 0.000 description 9
- 241000283690 Bos taurus Species 0.000 description 8
- 241000282472 Canis lupus familiaris Species 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 8
- 241000271566 Aves Species 0.000 description 7
- 230000001419 dependent effect Effects 0.000 description 7
- 238000012545 processing Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 241000588724 Escherichia coli Species 0.000 description 6
- 229940088710 antibiotic agent Drugs 0.000 description 6
- 238000009792 diffusion process Methods 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- 239000011521 glass Substances 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- 150000007660 quinolones Chemical class 0.000 description 6
- 238000002798 spectrophotometry method Methods 0.000 description 6
- 238000002834 transmittance Methods 0.000 description 6
- 241000283707 Capra Species 0.000 description 5
- 208000035473 Communicable disease Diseases 0.000 description 5
- 241000287828 Gallus gallus Species 0.000 description 5
- 239000006154 MacConkey agar Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 210000004379 membrane Anatomy 0.000 description 5
- 238000013048 microbiological method Methods 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- 208000035143 Bacterial infection Diseases 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000002207 metabolite Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 241000204031 Mycoplasma Species 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 229940124307 fluoroquinolone Drugs 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002483 medication Methods 0.000 description 3
- 230000035515 penetration Effects 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 238000011085 pressure filtration Methods 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- XBHBWNFJWIASRO-UHFFFAOYSA-N 6-fluoro-1-(4-fluorophenyl)-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1=CC=C(F)C=C1 XBHBWNFJWIASRO-UHFFFAOYSA-N 0.000 description 2
- RUXPNBWPIRDVTH-UHFFFAOYSA-N Amifloxacin Chemical compound C1=C2N(NC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 RUXPNBWPIRDVTH-UHFFFAOYSA-N 0.000 description 2
- QMLVECGLEOSESV-RYUDHWBXSA-N Danofloxacin Chemical compound C([C@@H]1C[C@H]2CN1C)N2C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=CC=1N2C1CC1 QMLVECGLEOSESV-RYUDHWBXSA-N 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- 108010013381 Porins Proteins 0.000 description 2
- 241000282849 Ruminantia Species 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 229950009484 amifloxacin Drugs 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 235000013330 chicken meat Nutrition 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
- 230000006378 damage Effects 0.000 description 2
- 229960004385 danofloxacin Drugs 0.000 description 2
- 230000007123 defense Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 150000004687 hexahydrates Chemical class 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 229960001180 norfloxacin Drugs 0.000 description 2
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 210000000253 proventriculus Anatomy 0.000 description 2
- 210000003752 saphenous vein Anatomy 0.000 description 2
- 229950007734 sarafloxacin Drugs 0.000 description 2
- 229960005404 sulfamethoxazole Drugs 0.000 description 2
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 2
- 238000001757 thermogravimetry curve Methods 0.000 description 2
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 2
- 229960001082 trimethoprim Drugs 0.000 description 2
- QKDHBVNJCZBTMR-LLVKDONJSA-N (R)-temafloxacin Chemical compound C1CN[C@H](C)CN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1F QKDHBVNJCZBTMR-LLVKDONJSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 1
- 0 CC1C(N2CC[*+]CC2)=CC=*2C1N(C1CC1)C=C*2 Chemical compound CC1C(N2CC[*+]CC2)=CC=*2C1N(C1CC1)C=C*2 0.000 description 1
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 102100021202 Desmocollin-1 Human genes 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 101000968043 Homo sapiens Desmocollin-1 Proteins 0.000 description 1
- 101000880960 Homo sapiens Desmocollin-3 Proteins 0.000 description 1
- 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 description 1
- 241000282339 Mustela Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 238000001237 Raman spectrum Methods 0.000 description 1
- NJCJBUHJQLFDSW-UHFFFAOYSA-N Rufloxacin Chemical compound C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 NJCJBUHJQLFDSW-UHFFFAOYSA-N 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 229960002134 butafosfan Drugs 0.000 description 1
- YHLWPOLSPCBOPC-UHFFFAOYSA-O butyl(2-phosphopropan-2-yl)azanium Chemical compound CCCCNC(C)(C)[P+](O)=O YHLWPOLSPCBOPC-UHFFFAOYSA-O 0.000 description 1
- 229910052793 cadmium Inorganic materials 0.000 description 1
- 238000007707 calorimetry Methods 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000002288 cocrystallisation Methods 0.000 description 1
- 208000030499 combat disease Diseases 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000005115 demineralization Methods 0.000 description 1
- 230000002328 demineralizing effect Effects 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- NOCJXYPHIIZEHN-UHFFFAOYSA-N difloxacin Chemical compound C1CN(C)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1 NOCJXYPHIIZEHN-UHFFFAOYSA-N 0.000 description 1
- 229950001733 difloxacin Drugs 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 229960003306 fleroxacin Drugs 0.000 description 1
- XBJBPGROQZJDOJ-UHFFFAOYSA-N fleroxacin Chemical compound C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(CCF)C2=C1F XBJBPGROQZJDOJ-UHFFFAOYSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 125000000524 functional group Chemical class 0.000 description 1
- 244000000058 gram-negative pathogen Species 0.000 description 1
- 244000000059 gram-positive pathogen Species 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000008233 hard water Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 244000000013 helminth Species 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229960002422 lomefloxacin Drugs 0.000 description 1
- ZEKZLJVOYLTDKK-UHFFFAOYSA-N lomefloxacin Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 ZEKZLJVOYLTDKK-UHFFFAOYSA-N 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229960002531 marbofloxacin Drugs 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- FHFYDNQZQSQIAI-UHFFFAOYSA-N pefloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 FHFYDNQZQSQIAI-UHFFFAOYSA-N 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 229960004062 rufloxacin Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229960004576 temafloxacin Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 1
- JATLJHBAMQKRDH-UHFFFAOYSA-N vebufloxacin Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)CCC3=C1N1CCN(C)CC1 JATLJHBAMQKRDH-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- 210000001325 yolk sac Anatomy 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the present invention is related to the principles and techniques developed in the Veterinary Pharmaceutical Industry for the development of new pharmaceutical compositions for manufacturing drugs that contribute to animal health, and more specifically, it is related to a recrystallized complex of enrofloxacin dihydrated hydrochloride useful in Treatment of bacterial infectious diseases, as well as with the method to obtain it.
- the animal organism contains all the necessary components to maintain life. It is warm, moist and rich in many different nutrients. Because of this, animal tissues are extremely attractive to microorganisms that seek to invade them and exploit those resources for their benefit.
- microorganisms including viruses, protozoa and helminth parasites. In their attempt to survive, many of these microorganisms see the organism of animals as a rich source of nutrients and a place to shelter. That is why these microorganisms will look for ways to invade animal tissues, which, generally, the immune system avoids or at least controls.
- pathogens are the complicated biological process that arises during the penetration of the infectious microorganism.
- the infection of the animal appears as the result of the penetration of pathogens from the environment, such as infected animals, pens, water and contaminated food, among others; being in this case before an exogenous infection.
- the pathogens are found in the same organism of the healthy animal (on the skin or mucous membranes, which have communication with the outside world) as commensals, without manifesting their pathogenic power, while the microorganism possesses strong enough defenses.
- Antibiotics are obtained in two ways: i) naturally; where all antibiotics were made before from living organisms (bacteria, fungi), in other words, the organisms are the ones that manufactured the antibiotics; and, ii) in an artificial way (chemical or synthetic): they are made by changing the molecules of the chemical chains that go next to the nucleus (ring) of the penicillins, where different effects on different microorganisms are obtained according to the molecules that are changed.
- Quinolones are known antibiotics since the 60's and since then a large number of quinolones have been investigated and synthesized, but always seeking to increase the spectrum of action and increase its activity and how to reduce unwanted effects.
- Fluorquinolones are a group of synthetic antibacterial agents used in both human and veterinary medicine to treat a variety of infectious diseases. Although many of them have been synthesized, the best known among those developed and used in veterinary medicine include amifloxacin, ciprofloxacin, danofloxacin, enrofloxacin, marbofioxacin, norfloxacin and sarafloxacin.
- enrofloxacin acts in a concentration-dependent manner, exerting a rapid bactericidal effect against aerobic Gram-negative and mycoplasma, including some that are resistant to other antibacterials and quinolones and fluoroquinolones of first and second generation.
- the efficacy against Gram negative pathogens was increased and the spectrum of activity was broadened by acting against Gram positive pathogens.
- the enrofloxacin is characterized by a very good antimicrobial activity, even against microorganisms little susceptible or resistant to the antimicrobials commonly used in animals. It has an excellent pharmacokinetic behavior, almost complete absorption and a tissue distribution that guarantees minimum inhibitory concentrations against the microorganisms that cause most diseases in animals. Its therapeutic index is high, and it can be administered without major problems in therapies combined with other medications.
- Enrichofloxacin is stable to temperature changes and hydrolytic influences. Slight sensitivity to prolonged and intense exposures of light, however its activity is not affected.
- Enrichofloxacin is a very lipophilic antibiotic and the addition of a carboxylic acid and a tertiary amine contributes to the amphoteric properties of the molecule, whose formula is as follows:
- the active substance is stable at temperature and hydrolysis.
- Enrichofloxacin can exist in four possible forms: as a cation (C), a neutral non-ionized species (N), a zwitterion (Z) and a basic ion (A), depending on the pH of the medium. At a low pH, both the 7-piperazinyl group and the 3-carboxyl group are protonated.
- the pH-solubility profile of enrofloxacin has a low solubility zone around the isoelectric point.
- the maximum solubility is reached at pH 5.02 (10.42 ⁇ 0.96 mg / ml.
- the amount of solubilized enrofloxacin can be increased using a more concentrated acetate buffer solution, in which it is possible to solubilize 100 mg / ml enrofloxacin.
- the active pharmaceutical ingredients or drugs in their pure forms, have a defined value of solubility in a biological system.
- the commercially available drugs suffer from formulation difficulties due to their low water solubility, which in turn results in low bioavailability. Improving the solubility and dissolution profiles of these lipophilic drug molecules without altering the molecular structure It is a particular challenge for the successful development of pharmaceutical products.
- the maximum solubility for enrofloxacin is achieved at a pH of 5.02 and the highest percentage of transfer from aqueous to organic phase is at a pH of 7. This means that when the pH of the medium is close to neutrality, entry is favored.
- enrofloxacin bacteria as zwitterion through porin channels hydrophilic, while the pH found in 's acid is in the ionized form and can not enter the bacteria by diffusion or by porin channels.
- enrofloxacin The crystalline structures of enrofloxacin have been reported in the literature as metal complexes and three organic salts, namely: 2-hydroxyethanoamine enrofloxacinate; enrofloxacin picrate; and, as citrate monohydrate (Golovnev, Vasiliev et al. 2012).
- Mexican Patent No. 200,399 describes new solutions for injection and infusion of composition: a) enrofloxacin, 0.1 to 20% by weight, based on the total weight of the solution, in the form of its salts with polyhydroxycarboxylic acids or amino acids or mixtures thereof; b) polyhydroxycarboxylic acids or amino acids or mixtures thereof, in excess 0.1 to 5 molar, referred to enrofloxacin; c) if necessary, 0.1 to 30% by weight, of formulation aids, based on the total weight of the solution; d) water, up to 100% by weight.
- Mexican Patent No. 260,386 describes a pharmaceutical composition characterized in that it is a physico-chemically stable association containing enrofloxacin in a concentration of about 3% to about 10% weight / volume of the composition and piroxicam in a concentration of about 0.1% at about 2% weight / volume of the composition in solution and acceptable pharmaceutical carriers, carriers or excipients, the method of manufacturing the physicochemically stable association and its use in the field of veterinary medicine.
- WO2010123337 refers to the field of veterinary medicine, in particular, antibacterial agents derived from fluoroquinolones, and, in particular, to a series of enrofloxacin salts such as ENR-Mg, ENR-Fe, ENR- Mn, ENR-Cu, Co-ENR, ENR-Ni, ENR-Ca, ENR-Zn, Cd and ENR-ENR- U02.
- enrofloxacin achieves much greater bioavailability than enrofloxacin base or hydrochloric acid salt, as well as a longer residence time in the organisms of birds, pigs, cows, goats, sheep, dogs, cats and horses.
- Such salts also lose virtually all the bitter taste associated with basic enrofloxacin or hydrochloride.
- the average retention time in all of the mentioned species is increased, thus extending the time in which the concentrations considered to be therapeutic can be achieved.
- Korean Patent No. KR20130062187 describes a complex antibacterial composition to ensure excellent antibacterial activity against gram-positive and gram-negative bacteria, and for the treatment of various infections.
- the antibacterial composition contains from 10 to 35% by weight of enrofloxacin, 5 to 25% by weight of trimethoprim and 40 to 80% by weight of sulfamethoxazole.
- the complex antibacterial composition contains enrofloxacin, trimethoprim, sulfamethoxazole and is mixed in a weight ratio of 02:01: 05.
- a medicament for the treatment of infectious diseases in an animal digestive system or an animal respiratory system containing the complex antibacterial composition as an active ingredient is described.
- Chinese Patent No. C 10321818 refers to a pharmaceutical composition for the treatment or prevention of bacterial diseases and mycoplasma of cattle and their use.
- the pharmaceutical composition comprises 5 to 15% by weight of enrofloxacin, an enrofloxacin hydrate or a derivative of enrofloxacin (such as enrofloxacin base) and 1 to 10% by weight of butafosfan.
- the pharmaceutical composition containing enrofloxacin can reduce the frequency of injection, bacterial diseases and mycoplasma of cattle can be treated or prevented, and the weight gain of piglets can be improved after being injected into the piglet.
- Chinese Patent No. CN102038643 describes a soluble enrofloxacin powder and a method of preparation and application thereof, and can solve the problem of the poor sterilization effect due to the lower water solubility of enrofloxacin in the state of the art.
- a technical scheme is that the soluble enrofloxacin powder is a mixture of enrofloxacin and an organic alkaline or alkaline organic solid in accordance with a weight ratio of (1-10):.
- the invention also describes a method of preparing and applying the soluble enrofloxacin powder.
- the invention solves the problem of the low solubility of enrofloxacin in water, and overcomes the disadvantage of the poor curative effect due to the low concentration of enrofloxacin caused by carrying the medicament in water.
- the present invention relates to a new enrofloxacin salt, wherein said new salt is a recrystallized complex of enrofloxacin hydrochloride dihydrate comprising a mixture of salts or complexes of enrofloxacin with metal ions, the process for its preparation and its use in medicine. veterinary, and more specifically, in pharmaceutical compositions that contain it and that are useful in the treatment of diseases of bacterial origin.
- said mixture of enrofloxacin salts comprises: enrofloxacin hydrochloride dihydrate, enrofloxacin hexahydrate and enrofloxacin hydrochloride.
- step e) Wash the paste obtained in step e) above first with 50 ml of ethyl alcohol and then with 50 ml of acetone, preferably doing it twice; Y,
- Acid recrystallization and formation of complexes with chlorine, magnesium and sulfate produce a complex of recrystallized enrofloxacin hydrochloride of high solubility, which orally provides maximum serum concentrations (Cmax) and areas under the concentration curve (AUC) vs. time greater than those achieved with enrofloxacin base.
- the acid recrystallization and formation of complexes with chlorine, magnesium and sulfate produce a complex of recrystallized enrofloxacin hydrochloride of high solubility, which provides maximum serum concentrations (Cmax) and areas under the curve (AUC) of concentration vs subcutaneous route. . time greater than those achieved with enrofloxacin base.
- a further object of the present invention is to provide a recrystallized complex of enrofloxacin hydrochloride dihydrate that is highly soluble in water.
- a further object of the present invention is to provide a pharmaceutical composition based on the recrystallized complex of enrofloxacin hydrochloride used in veterinary medicine.
- a further object of the present invention is to provide the use of the pharmaceutical composition based on the recrystallized complex of enrofloxacin hydrochloride to manufacture a medicament useful for treating and preventing infectious diseases of bacterial type.
- Figure 1 is a graph showing the x-ray diffraction difractogtama of a recrystallized complex of enrofloxacin hydrochloride dihydrate, obtained in accordance with a particularly preferred embodiment herein. invention.
- Figure 2 is a graph showing the infrared spectrum of the recrystallized complex of enrofloxacin dihydrate hydrochloride of the present invention.
- Figure 3 is a scanning differential calorimetry analysis thermogram of the recrystallized enrofloxacin hydrochloride dihydrate complex of the present invention.
- Figure 4 is a graph showing UV-Vis spectra of enrofloxacin base (black), enrofloxacin hydrate and the recrystallized complex of enrofloxacin hydrochloride dihydrate.
- Figure 5 shows the concentration activity curve of ENR-O and ENR-CC orally in chickens, dosed at a rate of 10 mg / kg.
- Figure 6 shows tissue concentrations of enrofloxacin in 1-day-old chicks, dosed orally at a rate of 10 mg / kg with ENR-0 and ENR-CC.
- Figure 7 shows tissue concentrations of enrofloxacin in 1-day-old chicks, dosed orally at a rate of 10 mg / kg with ENR-0 and ENR-CC.
- Figure 8 shows tissue concentrations of enrofloxacin in 1-day-old chicks, dosed orally at a rate of 10 mg / kg with ENR-0 and ENR-CC.
- Figure 9 shows tissue concentrations of enrofloxacin in 1-day-old chicks, dosed orally at a rate of 10 mg / kg with ENR-0 and ENR-CC.
- Figure 10 shows tissue concentrations of enrofloxacin in 1-day-old chicks, dosed orally at a rate of 10 mg / kg with ENR-0 and ENR-CC.
- Figure 11 shows the activity / concentration curve in dogs dosed at a rate of 5 mg / kg via PO and SC of the product ENR-CC and ENR-O.
- Figure 12 shows the activity / concentration curve of enrofloxacin and its metabolites administered in horses at doses of 5 mg / kg of ENR-CC and ENR-O.
- Figure 13 shows the activity / concentration curve of enrofloxacin and its metabolites in F1 cattle at a rate of 7.5 mg / kg of ENR-CC and ENR-O.
- Figure 14 shows the activity / concentration curve of enrofloxacin and its metabolites in F1 pigs at a rate of 7.5 mg / kg for the IM route and 10 mg / kg for the PO route, of ENR-CC and ENR-O.
- Figure 15 shows the activity / concentration curve of enrofloxacin and its metabolites in F1 goats at a rate of 7.5 mg / kg of ENR-CC and ENR-O.
- a new enrofloxacin salt has been found, which is described in accordance with a particularly preferred embodiment of the present invention, wherein said new salt is a recrystallized complex of enrofloxacin hydrochloride dihydrate comprising a mixture of salts or enrofloxacin complexes. with metal ions, the procedure for its preparation and its use in veterinary medicine, and more specifically, in pharmaceutical compositions containing it and which are useful in the treatment of diseases of bacterial origin.
- said mixture of enrofloxacin salts comprises: enrofloxacin hydrochloride dihydrate, enrofloxacin hexahydrate and enrofloxacin hydrochloride.
- the reciristalized complex of enrofloxacin hydrochloride dihydrate is obtained from anhydrous enrofloxacin and a metal salt.
- the formation of enrofloxacin hexahydrate with yields of 10 to 90%, the formation of enrofloxacin hydrochloride with yields of 10 to 90%, the formation of enrofloxacin complexes with general formula (C19H22FN 3 O 3 ) x Mg S0 4 , where x 1, 2, 3 or 4 with yields of 0 to 60%.
- the recrystallized complex of enrofioxacin hydrochloride dihydrate of the present invention shows better yields and a better pharmacokinetic profile than enrofioxacin base and enrofioxacin hexahydrate found in the state of the art.
- the recrystallized complex of enrofioxacin dihydrate hydrochloride of the formula (I) has a peak of maximum intensity at a 2 ⁇ angle of 25.67 in the XRPD, as shown in Figure 1 of the accompanying drawings.
- the recrystallized complex of enrofloxacin dihydrate hydrochloride of the formula (I) has characteristic bands at 2392 cm “1 and 1630 cm “ 1 in the infrared spectrum, as can be seen in Figure 2 of the accompanying drawings.
- the infrared spectra were obtained by means of refractance by ATR in a FTIR SPECTRUM 400 Brand Perkin Elmer.
- the recrystallized complex of enrofloxacin hydrochloride dihydrate of the formula (I) has an endothermic melting point with a maximum at 327.9 ° C and a crystalline transition phase at 136 ° C according to Figure 3 of the accompanying drawings, which it is consistent with the molecular structure of said compound enrofloxacin hydrochloride dihydrate and the structure elucidated by X-rays.
- the DSC and TGA thermograms were obtained by applying differential scanning calorimetry with a Mettler Toledo device, model DSC1, with STAR software version 11.0. The equipment is calibrated for temperature adjustment, heat flow and total calibration. The samples were weighed in 40 L aluminum panels with a lid. Heating is started from 25 to 350 ° C with a heating ramp of 10 ° C / min, under a nitrogen atmosphere. The elucidation of the structure was carried out by X-ray diffraction in a device.
- the recrystallized complex of enrofloxacin hydrochloride dihydrate of the formula (I) contains in greater proportion the molecule identified by monocrystalline X-ray crystallography in which the following structure is presented crystalline:
- the recrystallized complex of enrofloxacin hydrochloride dihydrate of the formula (I) has an increase in solubility of up to 20 times more compared to enrfloxacin base.
- the solubility was determined at 25 ° C, where the samples were measured in a spectrophotometer at a maximum wavelength of 277 nm.
- Figure 4 of the accompanying drawings shows the increase in the solubility of the compound of formula (I).
- step e) filter with negative pressure through a membrane with a pore of 0.45 ⁇ to concentrate the product; f) wash the paste obtained in step e) above first with 50 ml of ethyl alcohol and then with 50 ml of acetone, preferably doing it twice; Y,
- Acid recrystallization and formation of complexes with chlorine, magnesium and sulfate produce a recrystallized enrofloxacin hydrochloride complex of high solubility, which orally provides maximum serum concentrations (Cmax) and areas under the concentration curve (AUC) vs. time greater than those achieved with enrofloxacin base.
- a peculiar aspect of the present invention is to provide a pharmaceutical composition employed in veterinary medicine, wherein said pharmaceutical composition comprises: from 10% to 99.9% by weight of the total of said composition of the recrystallized complex of enrofloxacin hydrochloride dihydrate; and from 0.1 to 90% by weight of the total composition of usual auxiliary substances, which are non-toxic pharmaceutical substances known as excipients, such as disintegrating diluents , lubricants, glidants, colorants, binders, viscosity modifiers, thickeners, promoters of the absorption, crystal growth inhibitors, complexing agents, light stability agents, antioxidants and preservatives, among others.
- excipients such as disintegrating diluents , lubricants, glidants, colorants, binders, viscosity modifiers, thickeners, promoters of the absorption, crystal growth inhibitors, complexing agents, light stability agents, antioxidants and preservatives, among others.
- the thickeners are selected from the group comprising: carbomer 971, carbomer 974, carbomer copolymers type A and B, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and gelatin.
- the preservatives are selected from the group comprising: esters of p-hydroxybenzoic acid, phenols, chlorobutanol, benzyl alcohol, ethanol, butanol, 1, 3- butanediol, chlorhexidine salts, benzoic acid and salts.
- the antioxidants are selected from the group comprising: ascorbic acid, L-cysteine, thiodipropionic acid, thiolactic acid, monothioglycerol, propyl gallate, sodium metabisulfite or sodium sulphite.
- the complexing agents are selected from the group comprising: salts of ethylenediaminetetraacetic acid, phosphates, acetates and citrates.
- Crystalline growth inhibitors are selected from the group comprising: polyvinylpyrrolidone.
- said pharmaceutical composition is provided to manufacture a medicament useful for treating and preventing infectious diseases of bacterial type.
- said medicament can have the following dosage forms: immediate release tablets, dispersible tablets, orodispersible tablets, modified release tablets, capsules, liquid suspensions and powder for reconstituting powders g r canceled, ointments, gels, suppositories, elixirs lotions and solutions sterile and non sterile.
- the medication may have the following presentations:
- a liter of a 5M solution of magnesium sulfate was prepared to which 90g of enrofloxacin was added preparing a thick dispersion of enrofloxacin. The mixture was kept under constant mechanical stirring for 2 hours.
- the product was concentrated by negative pressure filtration through a 0.45 ⁇ pore membrane.
- the paste obtained was washed in the following order: first with 250 ml of ethyl alcohol and then with 500 ml of acetone. Finally, the paste was dried under vacuum to obtain the product, where the yield of the product was 60 to 100%.
- a liter of a 5M solution of magnesium chloride was prepared by adding 90g of enrofloxacin by preparing a thick dispersion of enrofloxacin. The mixture was mechanically stirred for 2 hours.
- the paste obtained was washed in the following order: first with 500 ml of ethyl alcohol and then with 250 ml of acetone.
- recrystallized complex of enrofloxacin hydrochloride dihydrate described in the particularly preferred embodiment of the present invention and represented by formula (I) can be used in pharmaceutical compositions useful for making an antibiotic medicament used in the treatment of infectious diseases of Bacterial type, as it has the following advantages:
- AUC area under the curve
- SC subcutaneous
- IM intramuscular
- ENR-CC was prepared according to the procedure described above.
- the culture medium was solidified, it was sown with the bacterial standard.
- 5 ml of distilled water was placed in a sterile screw cap tube and a young bacterial culture reseeded with Escherichia coli was added 24 hours before.
- Me Farland standards the necessary adjustments to the dilution were made until a 0.5 concentration of Me Farland was obtained.
- the 0.5 turbidity of McFarland was obtained by means of a spectrophotometry at a transmittance of 60 ⁇ 5%, which corresponds to a bacterial concentration of approximately 1x10 14
- 20 g of ENRO- standard were weighed CC (98% purity), they were placed in a flask and it was packed at 100 ml with deionized water (for its dissolution it was necessary to add 0.5ml of a 0.1 N solution of NaOH, before adding deionized water). 10 tubes of 5ml (1 to 10) and one of 15ml were marked with the number 0.
- each serum was taken with a pipette and they were placed in each of the assigned wells according to the time of the sampling and the number of individual to which each one belonged.
- Each plate was covered and allowed to stand for 24 hours at 37 ° C. After the waiting time, each plate in the UV light chamber was sterilized again for 30 minutes. Readings of millimeters of halo of inhibition per well per plate were performed with the help of a digital Vernier.
- Sensitivity The sensitivity of the analytical technique is 0.06 g / ml
- the sensitivity of Salmonella sp in birds is in a range of 0.128 - 1.0 g / ml (of the most sensitive to the resistant ones) the ENR-0 covers 20% of the range, in contrast the ENR-CC covers 90% of that range. If the value of AUC / CMI> 125 is considered, the ENR-0 does not cover the range of activity, in contrast the ENR-CC covers more than 50%, since this variable is applied for modified release products.
- the ENR-0 maintains serum concentrations for 8 hours, while the ENR-CC for at least 24 h.
- the ENR-CC was prepared according to the procedure described.
- Sensitivity The sensitivity of the analytical technique is 0.06 g / ml
- FIGS 6 to 10 of the accompanying drawings show the results obtained for the tissues with the ENR-CC orally and the comparison with ENR-O.
- ENR-CC concentrations of ENR-CC in lung and yolk sac are much higher in animals dosed with ENR-CC (therapeutic concentrations), in addition to achieving more time to stay in these tissues.
- the ENR-CC complex was prepared according to the procedure described.
- the serum is obtained, labeled and immediately frozen at -4 ° C.
- the 0.5 turbidity of McFarland was obtained by means of a spectrophotometry at a transmittance of 60 ⁇ 5%, which corresponds to a bacterial concentration of approximately 1x10 14
- 20 g of enrofloxacin standard were weighed ( 98% purity), they were placed in a flask and it was packed at 100 ml with deionized water (for its dissolution it was necessary to add 0.5ml of a 0.1 NaOH solution, prior to the addition of deionized water).
- 10 5ml tubes from 1 to 10) and one of 15 milliliters were marked with the number 0.
- each serum was taken with a pipette and they were placed in each of the assigned wells according to the time of the sampling and the number of individual to which each one belonged.
- Each plate was covered and allowed to stand for 24 hours at 37 ° C. After the waiting time, each plate in the UV light chamber was sterilized again for 30 minutes. Readings of millimeters of halo of inhibition per well per plate were performed with the help of a digital Vernier.
- Sensitivity The sensitivity of the analytical technique is 0.06 g / ml
- Serum enrofloxacin vs. serum profiles time in dogs after the application of the ENR-CC. and of the original enrofloxacin, administered via SC and orally at doses of 5 mg / kg.
- ENR-0 covers less than 50% by SC route, but orally less than 10% of the range for the various pathogens, in contrast the ENR-CC by both PO and SC cover 100% of said range. If the value of AUC / CMI> 125 is considered, the ENR-0 orally does not cover the range of activity, in contrast the ENR-CC for the two routes evaluated covers 100%, since this variable is applied to modified release.
- the ENR-0 maintains serum concentrations for 8 hours, while the ENR-CC for at least 36 h
- Enrichofloxacin is not an antibacterial commonly used in horses, there is substantial evidence to indicate it for 3-5 days in a row in adults of this species without manifesting side effects. It is contraindicated in foals due to the adverse effect related to their joints due to the demineralization of joint surfaces and deforming arthritis. Therefore, the pharmacokinetics of the ENR-CC in horses is presented here.
- the serum is obtained, labeled and immediately frozen -4 ° C.
- Sensitivity The sensitivity of the analytical technique is 0.06 g / ml
- Serum enrofloxacin vs. serum profiles Quarter Mile horse time after application of the ENR-CC. and of the original enrofloxacin, administered via SC and orally at doses of 10 and 5 mg / kg.
- ENR-0 covers less than 50%, in contrast the ENR-CC covers 100% of that range.
- the ENR-0 maintains serum concentrations for 8 hours, while the ENR-CC for at least 36 h.
- the serum is obtained, labeled and immediately frozen at -4 ° C.
- Sensitivity The sensitivity of the analytical technique is 0.06 pg / ml
- Serum enrofloxacin vs. serum profiles Quarter Mile horse time after application of the ENR-CC. and of the original enrofloxacin, administered via SC and orally at doses of 10 and 10 mg / kg.
- the sensitivity of specific pathogens for cattle is in the range of 0.06 pg / ml to 0.5 g / ml, the ENR -O covers less than 50%, in contrast the ENR-CC covers 100% of that range.
- the ENR-O maintains serum concentrations for 8 hours, while the ENR-CC for at least 24 h.
- ENR-CC 3) PO original product and 3) PO ENR-CC.
- the dose in the PO route was 10 mg / kg and for the IM 10 mg / kg
- the serum is obtained, labeled and immediately frozen at -4 ° C.
- Sensitivity The sensitivity of the analytical technique is 0.06 g / ml
- Serum enrofloxacin vs. serum profiles time in pigs after the application of the ENR-CC. and of ENR-O, administered via IM and orally at doses of 5 and 10 mg / kg, respectively.
- ENR- 0 IM covers less than 50%, in contrast the ENR-CC covers 100% of that range both via PO and IM.
- the ENR-0 maintains serum concentrations for 8 hours, while the ENR-CC for at least 24 h.
- the serum is obtained, labeled and immediately frozen at -4 ° C.
- Sensitivity The sensitivity of the analytical technique is 0.06 g / ml
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MXMX/A/2013/014605 | 2013-12-11 | ||
MX2013014605A MX356443B (es) | 2013-12-11 | 2013-12-11 | Complejo recristalizado de clorhidrato de enrofloxacina dihidratado, y metodo para obtener el mismo. |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2015088305A1 true WO2015088305A1 (es) | 2015-06-18 |
Family
ID=53371519
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/MX2014/000192 WO2015088305A1 (es) | 2013-12-11 | 2014-12-03 | Complejo recristalizado de clorhidrato de enrofloxacina dihidratado, y metodo para obtener el mismo |
Country Status (2)
Country | Link |
---|---|
MX (1) | MX356443B (es) |
WO (1) | WO2015088305A1 (es) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1641439A1 (de) * | 2003-06-26 | 2006-04-05 | Bayer HealthCare AG | Tabletten enthaltend enrofloxacin und geschmack- und/oder aromastoffe |
WO2010123337A1 (es) * | 2009-04-24 | 2010-10-28 | Weisepharm S.A De C.V | Complejo de enrofloxacina con máximo tiempo de residencia en plasma de mamíferos y aves |
CN103211818A (zh) * | 2012-01-18 | 2013-07-24 | 洛阳惠中兽药有限公司 | 一种治疗或预防家畜细菌性和支原体疾病的药物组合物及其用途 |
-
2013
- 2013-12-11 MX MX2013014605A patent/MX356443B/es active IP Right Grant
-
2014
- 2014-12-03 WO PCT/MX2014/000192 patent/WO2015088305A1/es active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1641439A1 (de) * | 2003-06-26 | 2006-04-05 | Bayer HealthCare AG | Tabletten enthaltend enrofloxacin und geschmack- und/oder aromastoffe |
WO2010123337A1 (es) * | 2009-04-24 | 2010-10-28 | Weisepharm S.A De C.V | Complejo de enrofloxacina con máximo tiempo de residencia en plasma de mamíferos y aves |
CN103211818A (zh) * | 2012-01-18 | 2013-07-24 | 洛阳惠中兽药有限公司 | 一种治疗或预防家畜细菌性和支原体疾病的药物组合物及其用途 |
Non-Patent Citations (3)
Title |
---|
DATABASE REGISTRY IN CHEMICAL accession no. 4-2013 * |
J MIRANDA-CALDERÓN ET AL.: "Enrofloxacin hydrochloride dihydrate", ACTA CRYSTALLOGRAPHICA 2014, vol. 70, no. SECCIó, pages 468 - 469 * |
M KARANAM ET AL.: "Structural landscape of pure enrofloxacin and its novel salts: enhanced solubility for better pharmaceutical applicability", CRYSTAL GROWTH & DESIGN, vol. 13, no. 4, February 2013 (2013-02-01), pages 1626 - 1637 * |
Also Published As
Publication number | Publication date |
---|---|
MX2013014605A (es) | 2015-06-11 |
MX356443B (es) | 2018-05-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2609085T3 (es) | Composiciones farmacéuticas estables de tetraciclinas en solución, procedimiento para su obtención y sus usos | |
US9610251B2 (en) | Pharmaceutical compositions for substituted quinazolinones | |
KR101751726B1 (ko) | 특이한 정벽을 가지는 결정형 및 이 결정형을 유효 성분으로서 함유하는 약학 조성물 | |
EP3365323B1 (en) | Salts of tetracyclines | |
JP2014193913A (ja) | 安定化されたカリスバメートの小児用懸濁液 | |
CN113476469B (zh) | 抗微生物化合物、组合物及其用途 | |
EA016576B1 (ru) | Применение сложных эфиров гидроксибензойной кислоты для получения лекарственного средства для предупреждения и лечения папилломавирусной инфекции человека | |
RU2413514C2 (ru) | Лечение мастита с помощью энрофлоксацина | |
US20210046071A1 (en) | Tetracyclic compounds and their salts, compositions, and methods for their use | |
US10464915B2 (en) | Dapagliflozin crystal form and preparation method and use thereof | |
JP2022542304A (ja) | ブルシンゲル製剤及びその製造方法 | |
ES2811325T3 (es) | Sal de sodio del inhibidor del transportador de ácido úrico y de su forma cristalina | |
TW202115091A (zh) | 喹啉類似物之結晶型及其鹽類、組合物、及彼等之使用方法 | |
WO2011136631A1 (es) | N6 -(ferrocenmetil)quinazolin-2,4,6-triamina (h2), sus derivados y profarmacos, como agentes antimicrobianos antiparasitarios, antiprotozoarios y antileishmanias | |
US20220000862A1 (en) | Combination therapy for the treatment of uveal melanoma | |
WO2015088305A1 (es) | Complejo recristalizado de clorhidrato de enrofloxacina dihidratado, y metodo para obtener el mismo | |
CN104983686A (zh) | 畜禽用美洛昔康可溶性粉剂及其制备方法 | |
CN102060722A (zh) | 一种含砷化合物及其制备方法和用途 | |
KR20230156705A (ko) | 질병을 치료하기 위한 방법 및 약학적 조성물 | |
US20210094961A1 (en) | Form of ponatinib | |
JP6950966B2 (ja) | スガマデクス又はその薬理学的に許容される塩含有液剤及びその製造方法 | |
WO2007016153A2 (en) | Tilmicosin formulation | |
KR101468659B1 (ko) | R-7-(3-아미노메틸-4-메톡시이미노-3-메틸-피롤리딘-1-일)-1-시클로프로필-6-플루오로-4-옥소-1,4-디히드로-[1,8]나프티리딘-3-카르복실산 l-아스파르트산염, 이의 제조방법 및 이를 포함하는 항균용 약학적 조성물 | |
EP2908859A1 (en) | Aripiprazole formulations | |
TW200427458A (en) | Crystalline N-formyl hydroxylamine compounds |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 14870373 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 14870373 Country of ref document: EP Kind code of ref document: A1 |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112016013625 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 112016013625 Country of ref document: BR Kind code of ref document: A2 Effective date: 20160613 |