WO2002039992A2 - Composes d'addition d'agents antibacteriens quinoloniques avec des polymeres de polysaccharides naturels - Google Patents
Composes d'addition d'agents antibacteriens quinoloniques avec des polymeres de polysaccharides naturels Download PDFInfo
- Publication number
- WO2002039992A2 WO2002039992A2 PCT/IB2001/002171 IB0102171W WO0239992A2 WO 2002039992 A2 WO2002039992 A2 WO 2002039992A2 IB 0102171 W IB0102171 W IB 0102171W WO 0239992 A2 WO0239992 A2 WO 0239992A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- adduct
- aqueous solution
- weight
- solution
- water
- Prior art date
Links
- 229920000642 polymer Polymers 0.000 title claims abstract description 20
- 150000004676 glycans Chemical class 0.000 title claims description 17
- 229920001282 polysaccharide Polymers 0.000 title claims description 17
- 239000005017 polysaccharide Substances 0.000 title claims description 17
- 239000003795 chemical substances by application Substances 0.000 title 1
- 239000007864 aqueous solution Substances 0.000 claims abstract description 23
- 239000004480 active ingredient Substances 0.000 claims abstract description 19
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 18
- 239000000843 powder Substances 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 32
- 239000000243 solution Substances 0.000 claims description 30
- 238000002360 preparation method Methods 0.000 claims description 16
- 229920002307 Dextran Polymers 0.000 claims description 11
- 239000012153 distilled water Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 229960001180 norfloxacin Drugs 0.000 claims description 11
- 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 claims description 11
- 238000004108 freeze drying Methods 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 9
- 229920001202 Inulin Polymers 0.000 claims description 7
- 229920002774 Maltodextrin Polymers 0.000 claims description 7
- JYJIGFIDKWBXDU-MNNPPOADSA-N inulin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(OC[C@]4(OC[C@]5(OC[C@]6(OC[C@]7(OC[C@]8(OC[C@]9(OC[C@]%10(OC[C@]%11(OC[C@]%12(OC[C@]%13(OC[C@]%14(OC[C@]%15(OC[C@]%16(OC[C@]%17(OC[C@]%18(OC[C@]%19(OC[C@]%20(OC[C@]%21(OC[C@]%22(OC[C@]%23(OC[C@]%24(OC[C@]%25(OC[C@]%26(OC[C@]%27(OC[C@]%28(OC[C@]%29(OC[C@]%30(OC[C@]%31(OC[C@]%32(OC[C@]%33(OC[C@]%34(OC[C@]%35(OC[C@]%36(O[C@@H]%37[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O%37)O)[C@H]([C@H](O)[C@@H](CO)O%36)O)[C@H]([C@H](O)[C@@H](CO)O%35)O)[C@H]([C@H](O)[C@@H](CO)O%34)O)[C@H]([C@H](O)[C@@H](CO)O%33)O)[C@H]([C@H](O)[C@@H](CO)O%32)O)[C@H]([C@H](O)[C@@H](CO)O%31)O)[C@H]([C@H](O)[C@@H](CO)O%30)O)[C@H]([C@H](O)[C@@H](CO)O%29)O)[C@H]([C@H](O)[C@@H](CO)O%28)O)[C@H]([C@H](O)[C@@H](CO)O%27)O)[C@H]([C@H](O)[C@@H](CO)O%26)O)[C@H]([C@H](O)[C@@H](CO)O%25)O)[C@H]([C@H](O)[C@@H](CO)O%24)O)[C@H]([C@H](O)[C@@H](CO)O%23)O)[C@H]([C@H](O)[C@@H](CO)O%22)O)[C@H]([C@H](O)[C@@H](CO)O%21)O)[C@H]([C@H](O)[C@@H](CO)O%20)O)[C@H]([C@H](O)[C@@H](CO)O%19)O)[C@H]([C@H](O)[C@@H](CO)O%18)O)[C@H]([C@H](O)[C@@H](CO)O%17)O)[C@H]([C@H](O)[C@@H](CO)O%16)O)[C@H]([C@H](O)[C@@H](CO)O%15)O)[C@H]([C@H](O)[C@@H](CO)O%14)O)[C@H]([C@H](O)[C@@H](CO)O%13)O)[C@H]([C@H](O)[C@@H](CO)O%12)O)[C@H]([C@H](O)[C@@H](CO)O%11)O)[C@H]([C@H](O)[C@@H](CO)O%10)O)[C@H]([C@H](O)[C@@H](CO)O9)O)[C@H]([C@H](O)[C@@H](CO)O8)O)[C@H]([C@H](O)[C@@H](CO)O7)O)[C@H]([C@H](O)[C@@H](CO)O6)O)[C@H]([C@H](O)[C@@H](CO)O5)O)[C@H]([C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JYJIGFIDKWBXDU-MNNPPOADSA-N 0.000 claims description 7
- 229940029339 inulin Drugs 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 238000001694 spray drying Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000003826 tablet Substances 0.000 claims description 3
- 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 claims description 2
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 claims description 2
- 229960004621 cinoxacin Drugs 0.000 claims description 2
- VDUWPHTZYNWKRN-UHFFFAOYSA-N cinoxacin Chemical compound C1=C2N(CC)N=C(C(O)=O)C(=O)C2=CC2=C1OCO2 VDUWPHTZYNWKRN-UHFFFAOYSA-N 0.000 claims description 2
- -1 cyprofloxacin Chemical compound 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 claims description 2
- 229960002549 enoxacin Drugs 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 229960003376 levofloxacin Drugs 0.000 claims description 2
- 229960000210 nalidixic acid Drugs 0.000 claims description 2
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 claims description 2
- 229960001699 ofloxacin Drugs 0.000 claims description 2
- 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 claims description 2
- 229960004236 pefloxacin Drugs 0.000 claims description 2
- 229960001732 pipemidic acid Drugs 0.000 claims description 2
- JOHZPMXAZQZXHR-UHFFFAOYSA-N pipemidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCNCC1 JOHZPMXAZQZXHR-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 1
- 239000007787 solid Substances 0.000 abstract description 8
- 230000001988 toxicity Effects 0.000 abstract description 4
- 231100000419 toxicity Toxicity 0.000 abstract description 4
- 230000000845 anti-microbial effect Effects 0.000 abstract description 3
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 description 8
- 125000001475 halogen functional group Chemical group 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 5
- 238000003760 magnetic stirring Methods 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 150000007660 quinolones Chemical class 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 4
- 239000005913 Maltodextrin Substances 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 230000003115 biocidal effect Effects 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 229940035034 maltodextrin Drugs 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 241000191967 Staphylococcus aureus Species 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 238000009631 Broth culture Methods 0.000 description 2
- 206010018612 Gonorrhoea Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000007515 enzymatic degradation Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229920005615 natural polymer Polymers 0.000 description 2
- 238000002663 nebulization Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000005063 solubilization Methods 0.000 description 2
- 230000007928 solubilization Effects 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229920001059 synthetic polymer Polymers 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- 239000001974 tryptic soy broth Substances 0.000 description 2
- 108010050327 trypticase-soy broth Proteins 0.000 description 2
- 230000002485 urinary effect Effects 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- DEXFNLNNUZKHNO-UHFFFAOYSA-N 6-[3-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-3-oxopropyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)C(CCC1=CC2=C(NC(O2)=O)C=C1)=O DEXFNLNNUZKHNO-UHFFFAOYSA-N 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 125000002353 D-glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000606790 Haemophilus Species 0.000 description 1
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 241000186781 Listeria Species 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- 241000588653 Neisseria Species 0.000 description 1
- 206010031252 Osteomyelitis Diseases 0.000 description 1
- 241001311547 Patina Species 0.000 description 1
- 108010093965 Polymyxin B Proteins 0.000 description 1
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 1
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 1
- 241000831652 Salinivibrio sharmensis Species 0.000 description 1
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 description 1
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 206010000269 abscess Diseases 0.000 description 1
- WQZGKKKJIJFFOK-DVKNGEFBSA-N alpha-D-glucose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-DVKNGEFBSA-N 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- 230000000721 bacterilogical effect Effects 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940041984 dextran 1 Drugs 0.000 description 1
- 229940000986 dextran 110 Drugs 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 208000001786 gonorrhea Diseases 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229920000024 polymyxin B Polymers 0.000 description 1
- 229960005266 polymyxin b Drugs 0.000 description 1
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention concerns adducts of natural polysaccharide polymers with active ingredients belonging to the class of quinolonic drugs with improved therapeutic activity.
- the polymer conjugated with the antibiotic can be active as such or, if the "linker” is biodegradable, it behaves as a prodrug that afterwards is bioactivated in vivo, releasing the antibiotic.
- this approach is expensive and complicated since it is necessary to chemically characterize the compound, in so far as it proves to be a new chemical product and therefore study once again its pharmacptoxicology, pharmacokinetics and clinical efficacy.
- SUMMARY OF THE INVENTION The Applicant has now surprisingly found some adducts of quinolonic antibacterial agents, characterized in that the percentage of said active ingredient is between 40 and 80% by weight calculated on the total weight of the adduct.
- the adducts according to the present invention are in powder form or in the form of an aqueous solution that preferably contains them in a concentration of between 0.1 and 1% by weight calculated on the total weight of the aqueous solution.
- the present invention further relates to the process for preparing the aforesaid adducts which, in particular, comprises the following steps: a) preparing the solution of the polysaccharide polymer in water in a percentage of ingredient of between 20 and 60% by weight on the total weight of the adduct and adding the active ingredient, thereby obtaining a concentration of the adduct being preferably comprised in the aforesaid intervals, b) filtering the aqueous solution thus obtained, in case the adduct in aqueous solution form is achieved, c) removing water thereby obtaining the adduct according to the present invention in powder form.
- the present invention further relates to pharmaceutical compositions containing the adducts according to the present invention in association with suitable ex
- the present invention represents an optimum form for administering both orally and parenterally quinolonic antibacterial drugs to be used in the treatment of infections caused by Gram-negative and Gram-positive bacteria.
- the present invention concerns adducts between an active ingredient, belonging to the class of Quinolones, and a natural biocompatible polysaccharide, able to interact without forming covalent and ionic bonds.
- the adducts can be administered both orally and parenterally, depending on the physical-chemical characteristics and the pharmacodynamic and pharmacokinetic profile of the active ingredient.
- the active ingredients used in the adducts according to the present invention are preferably nalidixic acid, pipemidic acid, cinoxacin, norfloxacin, cyprofloxacin, pefloxacin, enoxacin, ofloxacin and the levo form thereof levofloxacin. These are mainly used in the treatment of infections caused by Gram-negative and positive bacteria and their action mechanism consists in blocking DNA synthesis by inhibiting the DNA enzyme gyrase. More in detail, norfloxacin is effective in urinary, enteric and gonorrhea infections, at a dosage of 800-1200 mg/die through oral administration.
- Cyprofloxacin is suitable for urinary, respiratory, gastrointestinal and cutaneous infections and in osteomyelitis, since it is effective against Gram-negative organisms (E. Coli, Klebsiella, Salmonella typhi, Neisseria gonorrhoea et meningitidis, Haemophilus influentiae), Gram-positive (Staph. aureus et epidermidis, listeria) and Mycobacterium tubercolosis. It can be orally administered in the corresponding hydrochloride salt with daily doses of 500-1000 mg or, in more serious cases, intravenously in amount of 800-1200 mg/die in the corresponding lactate salt (A. Kucers et. N.Mck Bennett, The use of Antibiotics, 4 th ed., Heinemann Medical Books, 1989).
- the percentage of the quinolonic antibacterial agent calculated on the total weight of the adduct is 60%.
- the natural polysaccharide polymers dextrans are preferred, inulin and, for oral preparations, maltodextrins of pharmaceutical grade.
- Dextrans are polymers formed by linear chains of molecules of ⁇ -D- glucose and may exhibit very different molecular weights, ranging from 1000 Dalton (dextran 1 ) to 110000 Dalton (dextran 110) and do not undergo enzymatic degradation. Hydrophilia and therefore the solubility in water decreases with the increase of molecular weight.
- the dextrans with molecular weights lower than 4000 are completely excreted with urine within 48 hours, while those having higher molecular weights remain in circulation for longer periods of time.
- Preferred in the present invention are 4-70 dextrans.
- the maltodextrins consist of a branched polymer of maltose and dextrins in which the D-glucose units are mainly linked by ⁇ bond (1-4), but also (1-6) in the branched portions. They show a molecular weights ranging from 900 to 9000 Dalton. Also inulin is a natural polysaccharide linear structure constituted by fructose molecules with a molecular weight of 5000, it does not undergo enzymatic degradation and is excreted with urine, so that it is used in the medical field as a diagnostic means of renal functionality.
- the selected natural polysaccharides are biocompatible and inert and therefore their quinolones adducts do not present problems with quinolones insofar as it concerns toxicity and also from an immunological stand point.
- the preparation of the adducts envisages the solution of the polymer in water, in a percentage that may vary between 20 and 60% in weight, and the subsequent addition of the active ingredient, allowing the hydrophilic interaction of carboxylic and aminic groups of the antibacterial agent with those of the polymer. Weak hydrogen type bonds are thus formed with lower interaction forces if compared to covalent or ionic type bonds (Remington's Pharmaceutical Science 18 th ed. p. 186).
- the polymer and the drug are dissolved in distilled water (optionally with buffers and preservatives), filtering is performed to obtain a clear solution.
- filtering is performed to obtain a clear solution.
- the solvent is removed from the adduct through a process of freeze-drying or nebulization (spray drying) thereby obtaining the adduct in solid form.
- depyrogenated and sterile (w.f.p.) distilled water is used and the solution is filtered, with filters of from 0.1 to 0.2 ⁇ m porosity, then placed in depyrogenated and sterilized phialoids in a sterile environment, and preferably freeze-dried.
- the solution can be readily reconstituted by adding an aqueous solvent such as w.f.p. water or a physiological solution.
- Distilled water is used for the preparation of oral forms and the solution is filtered on filters of 0.45 ⁇ m porosity.
- the solvent is removed preferably through nebulization, and a solid porous adduct is obtained suitable for the preparation of pharmaceutical forms for oral use, such as tablets, capsules and granules.
- the titre of the active ingredient in the adduct was detected by HPLC, using a Perkin-Elmer LC75 chromatograph with an LC Pump 414-T Karitron Analytical injector, Waters detector-integrator and a Lichrosorb column RP18.
- an adduct with a polysaccharide of low molecular weight can increase the solubility of a poorly soluble antibacterial agent and accordingly, if orally administered the same adduct can increase its bioavailibility.
- an adduct with a high molecular weight polysaccharide can prolong the time the drug remains in circulation and therefore the same can prolong its effect.
- the presence of reduced active ingredient doses lowers the toxicity with equal antibacterial activity.
- the adducts in the form of aqueous solutions according to the present invention can be prepared with a process that in particular comprises the following steps: a') dissolving the active ingredient in distilled water, b') filtering the aqueous solution coming from the previous step, c') removing water, preferably by freeze-drying, from the product coming from in the previous step, d') reconstituting the aqueous solution by addition of water or other w.f.p. solvent, in which the polysaccharide polymer is dissolved, thereby obtaining a concentration of the adduct in said aqueous solution preferably comprised between 0.1 and 1% in weight.
- the adducts of the present invention were obtained with simple, quick and economic processes if compared to the traditional synthetic approaches, which envisage the formation of a covalent or saline bond between the antibacterial agent and the polymer, therefore resulting less expensive.
- 1.51 g of ivory coloured adduct are obtained in granular powder form, soluble in water and with a norfloxacin titre of 59.5% by weight.
- the adduct is suitable to be formulated in capsules, sachets, and after being compressed in tablets.
- EXAMPLE 2 Preparation of the solid adduct: 50% dextran - 50% norfloxacin 1 g of dextran 5 is dissolved in 1 L of distilled water and 1 g of norfloxacin is added to the solution, bringing the pH to the value of 4.8 by the addition of 1N HCI. The solution is filtered with a filter of 0.45 ⁇ m porosity and the solvent is removed by spraydrying as described in example 1. 1.87 g of whitish coloured adduct are obtained in the form of a light powder, with a norfloxacin titre of 49% in weight. The powder added with suitable excipients can be placed in sachets or formulated into capsules or directly compressed.
- the freezer-dryer is programmed to perform the freeze- drying cycle at the following temperatures: -35°C for prefreezing, -10°C during freeze-drying, +10°C for primary drying and +35°C for secondary drying, while maintaining the vacuum at 2.2 0 "2 mbar.
- 1.6 g of dextran 5 are dissolved in a volume of 800 ml of w.f.p. water under magnetic stirring 3.1 g of cyprofloxacin lactate equal to 2.43 g of cyprofloxacin are then added, while adjusting the pH with 1 N HCI until complete solution.
- the solution is brought to 1.5 L with w.f.p. water, filtered with a sterilizing filter with 0.2 ⁇ m porosity and placed in depyrogenated and sterilized vials, in a ratio of 37.5 ml/vial.
- the cyprofloxacin titre in the solution is 60.5%.
- EXAMPLE 6 PREPARATION OF THE SOLID ADDUCT: 40% DEXTRAN - 60% CYPROFLOXACIN
- the adduct solutions of example 5 are subjected to freeze-drying following the same cycle described in example 4.
- the freeze-dried substance obtained is compact with a cyprofloxacin titre of 60.4% by weight. It can be readily reconstituted by slow infusion with the addition of 30 ml of physiological solution.
- EXAMPLE 7 Preparation of the solution of the adduct: 40% inulin - 60% cyprofloxacin
- the inhibition halos were obtained with the diffusion method (FUI X ed., p. 135), using a Mueller-Hinton Medium Difco culture medium (with low thymine and thymidine content) conforming to the MG-P standards of the NCCLS in 9 cm diameter sterile Petri dishes and Tryptic soy broth (Difco).
- Small discs of filter paper were prepared for the sensitivity test, by soaking them in a quinolonic antibacterial agent at defined concentrations, and the corresponding adduct small discs were prepared, in which the total dose is the same, but the active ingredient content by weight is lower.
- Broth cultures were prepared placing a bacterial patina loop of a culture in agar of 12 h in a test tube containing 5 ml of Sterile Tryptic Soy Broth and then incubated at 37° C for 4 h. If necessary, the suspensions were diluted with sterile water to obtain a similar turbidity to the reference standard (0.5 Mc Fariand).
- EXAMPLE 9 Determination of the in vitro minimum inhibiting concentration (MIC)
- the MIC values were calculated with the method of dilutions in liquid medium (F. Pasquinelli, Manual for laboratory technicians, vol. II, pp. 1286-89, 1968), using a Mueller-Hinton broth at pH 7.4, sterilized at 120°C for 20 minutes.
- a series of test tubes containing a fixed medium volume of medium scalar concentrations by doubling the concentration of the active ingredient were added, from 0.1 ⁇ g/ml to 10 ⁇ g/ml.
- the same procedure was also followed for the adducts.
- a drop of 1 :10 dilution of the broth culture was added to all the test tubes and were incubated at 37°C for 18-24 hours. After this time, the test tube with the highest dilution in which turbidity was not observed was considered as the one containing the minimum inhibiting concentration.
- Table II The results obtained are contained in Table II.
- adducts of the present invention of quinolonic antibacterial agents and natural polysaccharide polymers show, in the in vitro and in vivo tests of antimicrobial activity in mice, a comparable activity or slightly higher than that of the active ingredient alone, although they contain it in lower amounts, thus reducing the cost of the therapy.
- these adducts are obtained with a quick, economic process which is suitable for the subsequent preparation of parenteral forms and, if combined with suitable excipients for the preparation, of oral forms for the treatment of infections due to Gram-positive and Gram-negative bacteria in animals and humans.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Compositions Of Macromolecular Compounds (AREA)
Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2002212631A AU2002212631A1 (en) | 2000-11-17 | 2001-11-16 | Adducts of quinolonic agents with natural polysaccharide polymers |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI2000A002476 | 2000-11-17 | ||
IT2000MI002476A IT1319664B1 (it) | 2000-11-17 | 2000-11-17 | Addotti di antibatterici chinolonici con polimeri polisaccaridicinaturali. |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2002039992A2 true WO2002039992A2 (fr) | 2002-05-23 |
WO2002039992A3 WO2002039992A3 (fr) | 2002-08-01 |
Family
ID=11446117
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2001/002171 WO2002039992A2 (fr) | 2000-11-17 | 2001-11-16 | Composes d'addition d'agents antibacteriens quinoloniques avec des polymeres de polysaccharides naturels |
Country Status (3)
Country | Link |
---|---|
AU (1) | AU2002212631A1 (fr) |
IT (1) | IT1319664B1 (fr) |
WO (1) | WO2002039992A2 (fr) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1459739A1 (fr) * | 2003-03-19 | 2004-09-22 | The Jordanian Pharmaceutical Manufacturing Co. Ltd. | Non hygroscopique Compositions pharmaceutiques contenant non-hydrate Quinilone acide carboxylique |
EP1930006A4 (fr) * | 2005-09-28 | 2010-10-13 | Daiichi Sankyo Co Ltd | Procédé de production de préparation lyophilisée contenant de la quinolone |
CN102824319A (zh) * | 2012-09-27 | 2012-12-19 | 西南大学 | 增效氧氟沙星冻干粉针剂及其制备方法 |
JP2013523676A (ja) * | 2010-03-29 | 2013-06-17 | フェリング ベスローテン フェンノートシャップ | 速溶解性医薬組成物 |
JP2014526483A (ja) * | 2011-09-16 | 2014-10-06 | フェリング ベスローテン フェンノートシャップ | 速溶性医薬組成物 |
CN110755374A (zh) * | 2019-11-22 | 2020-02-07 | 南京知和医药科技有限公司 | 一种左氧氟沙星注射液及制备工艺 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL80459A (en) * | 1986-10-30 | 1991-04-15 | Abic Ltd | Water-soluble adduct of norfloxacin and nicotinic acid |
IT1312110B1 (it) * | 1999-05-18 | 2002-04-04 | Istituto Biochimico Pavese Pha | Addotti antibiotico-polimero polisaccaridico naturale |
-
2000
- 2000-11-17 IT IT2000MI002476A patent/IT1319664B1/it active
-
2001
- 2001-11-16 AU AU2002212631A patent/AU2002212631A1/en not_active Abandoned
- 2001-11-16 WO PCT/IB2001/002171 patent/WO2002039992A2/fr not_active Application Discontinuation
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1459739A1 (fr) * | 2003-03-19 | 2004-09-22 | The Jordanian Pharmaceutical Manufacturing Co. Ltd. | Non hygroscopique Compositions pharmaceutiques contenant non-hydrate Quinilone acide carboxylique |
EP1930006A4 (fr) * | 2005-09-28 | 2010-10-13 | Daiichi Sankyo Co Ltd | Procédé de production de préparation lyophilisée contenant de la quinolone |
US8129533B2 (en) | 2005-09-28 | 2012-03-06 | Dalichi Sankyo Company, Limited | Method for production of quinolone-containing lyophilized preparation |
JP2013523676A (ja) * | 2010-03-29 | 2013-06-17 | フェリング ベスローテン フェンノートシャップ | 速溶解性医薬組成物 |
JP2014526483A (ja) * | 2011-09-16 | 2014-10-06 | フェリング ベスローテン フェンノートシャップ | 速溶性医薬組成物 |
US9731018B2 (en) | 2011-09-16 | 2017-08-15 | Ferring B.V. | Fast dissolving pharmaceutical composition |
CN102824319A (zh) * | 2012-09-27 | 2012-12-19 | 西南大学 | 增效氧氟沙星冻干粉针剂及其制备方法 |
CN110755374A (zh) * | 2019-11-22 | 2020-02-07 | 南京知和医药科技有限公司 | 一种左氧氟沙星注射液及制备工艺 |
Also Published As
Publication number | Publication date |
---|---|
ITMI20002476A1 (it) | 2002-05-17 |
AU2002212631A1 (en) | 2002-05-27 |
WO2002039992A3 (fr) | 2002-08-01 |
IT1319664B1 (it) | 2003-10-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20200297848A1 (en) | Metal chelating compositions and methods for controlling the growth or activities of a living cell or organism | |
Girard et al. | Correlation of the extravascular pharmacokinetics of azithromycin with in-vivo efficacy in models of localized infection | |
WO2011106993A1 (fr) | Nanoparticules d'or modifiées par un aminopyrimide, leur procédé de préparation et leur utilisation | |
Kadhum et al. | The synergistic effects of chitosan-alginate nanoparticles loaded with doxycycline antibiotic against multidrug resistant proteus mirabilis, Escherichia coli and enterococcus faecalis | |
CN113201082A (zh) | 一种壳聚糖-二氢卟吩e6抗菌剂及其制备方法 | |
EP0649437B1 (fr) | Procede de preparation de biopolymeres iodes ayant une activite desinfectante et cicatrisante, et biopolymeres iodes pouvant etre obtenus par ce procede | |
US8329155B2 (en) | Quaternary ammonium functionalized glycodendrimers, methods for the production and use thereof | |
WO2002039992A2 (fr) | Composes d'addition d'agents antibacteriens quinoloniques avec des polymeres de polysaccharides naturels | |
Kenawy et al. | Synthesis and biocidal activity of modified poly (vinyl alcohol) | |
KR20200009744A (ko) | Fab I 저해제를 포함하는 경구투여용 약제학적 조성물 및 그 제조방법 | |
CN101225093B (zh) | 氨基糖苷类衍生物 | |
WO2015010439A1 (fr) | Composé macromoléculaire pharmaceutique, soluble dans l'eau et antifongique | |
CN103784968B (zh) | 一种壳聚糖-抗生素共价复合物及其制备方法和应用 | |
JP2006520329A (ja) | 抗菌作用を有し、ジアミンをベースとするグアニジン誘導体 | |
US6821959B1 (en) | Antibiotic-natural polysaccharide polymer adducts | |
Cirillo et al. | Synthesis, characterization and antimicrobial activity of conjugates based on fluoroquinolon-type antibiotics and gelatin | |
EP1335748A1 (fr) | Adduits pour antibiotiques de polymeres de saccharides naturels sous forme de solutions aqueuses | |
US20040254366A1 (en) | Silver salts of sucrose-octasuphate | |
CN118852309B (zh) | 一种卡那霉素鹅去氧胆酸偶联物及其制备方法与应用 | |
CN114732785A (zh) | 一种大蒜素注射液及其制备方法 | |
Al-Hasnawi et al. | Evaluation of Chitosan and Nano-chitosan Gel with and without 1% Silver Sulfadiazine as an Alternative for Burn Wound InfectionsTreatment in Albino Mice | |
RU2435611C1 (ru) | Способ получения полимерного комплекса | |
CN117281797A (zh) | 一种载公英散提取物壳聚糖纳米粒及其制备方法 | |
CN119318718A (zh) | 一种pH/神经氨酸酶双响应载药纳米粒及其制备方法和应用 | |
CN110818684A (zh) | 一种抗金黄色葡萄球菌毒力和生物被膜形成的抑制剂Lo-SH及其用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
AK | Designated states |
Kind code of ref document: A3 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
122 | Ep: pct application non-entry in european phase | ||
NENP | Non-entry into the national phase |
Ref country code: JP |
|
WWW | Wipo information: withdrawn in national office |
Country of ref document: JP |