JP4290381B2 - Emulsion containing pyridonecarboxylic acid compound - Google Patents
Emulsion containing pyridonecarboxylic acid compound Download PDFInfo
- Publication number
- JP4290381B2 JP4290381B2 JP2002109585A JP2002109585A JP4290381B2 JP 4290381 B2 JP4290381 B2 JP 4290381B2 JP 2002109585 A JP2002109585 A JP 2002109585A JP 2002109585 A JP2002109585 A JP 2002109585A JP 4290381 B2 JP4290381 B2 JP 4290381B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- emulsion
- mol
- solution
- added
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 239000000839 emulsion Substances 0.000 title claims description 45
- -1 pyridonecarboxylic acid compound Chemical class 0.000 title description 19
- 239000003094 microcapsule Substances 0.000 claims description 40
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 20
- 239000003960 organic solvent Substances 0.000 claims description 20
- 229920001577 copolymer Polymers 0.000 claims description 16
- 239000011787 zinc oxide Substances 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 14
- 239000008346 aqueous phase Substances 0.000 claims description 12
- 239000006185 dispersion Substances 0.000 claims description 9
- 239000008363 phosphate buffer Substances 0.000 claims description 9
- 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 8
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 8
- 229960003376 levofloxacin Drugs 0.000 claims description 8
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 8
- 208000028169 periodontal disease Diseases 0.000 claims description 5
- 239000012071 phase Substances 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 4
- 238000001694 spray drying Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000005191 phase separation Methods 0.000 claims description 3
- XBBVURRQGJPTHH-UHFFFAOYSA-N 2-hydroxyacetic acid;2-hydroxypropanoic acid Chemical compound OCC(O)=O.CC(O)C(O)=O XBBVURRQGJPTHH-UHFFFAOYSA-N 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 235000002639 sodium chloride Nutrition 0.000 description 27
- 239000003814 drug Substances 0.000 description 25
- 229940079593 drug Drugs 0.000 description 25
- 150000003839 salts Chemical class 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- 125000001424 substituent group Chemical group 0.000 description 16
- 229920002988 biodegradable polymer Polymers 0.000 description 14
- 239000004621 biodegradable polymer Substances 0.000 description 14
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 14
- 239000000126 substance Substances 0.000 description 13
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Natural products OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 125000000217 alkyl group Chemical group 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- 239000007853 buffer solution Substances 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 238000005538 encapsulation Methods 0.000 description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
- 239000006228 supernatant Substances 0.000 description 8
- 239000004310 lactic acid Substances 0.000 description 7
- 235000014655 lactic acid Nutrition 0.000 description 7
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- YSLIPUSJNFIFAB-UHFFFAOYSA-N 2-oxopyridine-1-carboxylic acid Chemical class OC(=O)N1C=CC=CC1=O YSLIPUSJNFIFAB-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 238000013268 sustained release Methods 0.000 description 6
- 239000012730 sustained-release form Substances 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 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 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000004220 aggregation Methods 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 4
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 4
- 239000003405 delayed action preparation Substances 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 239000012086 standard solution Substances 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 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 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- CBOJBBMQJBVCMW-BTVCFUMJSA-N (2r,3r,4s,5r)-2-amino-3,4,5,6-tetrahydroxyhexanal;hydrochloride Chemical compound Cl.O=C[C@H](N)[C@@H](O)[C@H](O)[C@H](O)CO CBOJBBMQJBVCMW-BTVCFUMJSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- GJMPSRSMBJLKKB-UHFFFAOYSA-N 3-methylphenylacetic acid Chemical compound CC1=CC=CC(CC(O)=O)=C1 GJMPSRSMBJLKKB-UHFFFAOYSA-N 0.000 description 2
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 2
- MOMKYJPSVWEWPM-UHFFFAOYSA-N 4-(chloromethyl)-2-(4-methylphenyl)-1,3-thiazole Chemical compound C1=CC(C)=CC=C1C1=NC(CCl)=CS1 MOMKYJPSVWEWPM-UHFFFAOYSA-N 0.000 description 2
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 229930064664 L-arginine Natural products 0.000 description 2
- 235000014852 L-arginine Nutrition 0.000 description 2
- XAGMUUZPGZWTRP-ZETCQYMHSA-N LSM-5745 Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1C1(N)CC1 XAGMUUZPGZWTRP-ZETCQYMHSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229960002684 aminocaproic acid Drugs 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 2
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 2
- 239000001354 calcium citrate Substances 0.000 description 2
- 239000004227 calcium gluconate Substances 0.000 description 2
- 235000013927 calcium gluconate Nutrition 0.000 description 2
- 229960004494 calcium gluconate Drugs 0.000 description 2
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 229960004926 chlorobutanol Drugs 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 229940109239 creatinine Drugs 0.000 description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- 229940043237 diethanolamine Drugs 0.000 description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
- 235000019797 dipotassium phosphate Nutrition 0.000 description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 2
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 2
- 239000002526 disodium citrate Substances 0.000 description 2
- 235000019262 disodium citrate Nutrition 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- CEYULKASIQJZGP-UHFFFAOYSA-L disodium;2-(carboxymethyl)-2-hydroxybutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O CEYULKASIQJZGP-UHFFFAOYSA-L 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 229960001911 glucosamine hydrochloride Drugs 0.000 description 2
- 229960002989 glutamic acid Drugs 0.000 description 2
- 229960002449 glycine Drugs 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 235000011167 hydrochloric acid Nutrition 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 229960000448 lactic acid Drugs 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- RXMQCXCANMAVIO-CEOVSRFSSA-L magnesium;(2s)-2-amino-4-hydroxy-4-oxobutanoate Chemical compound [H+].[H+].[Mg+2].[O-]C(=O)[C@@H](N)CC([O-])=O.[O-]C(=O)[C@@H](N)CC([O-])=O RXMQCXCANMAVIO-CEOVSRFSSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 229960002625 pazufloxacin Drugs 0.000 description 2
- 229960004838 phosphoric acid Drugs 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- PSBAZVJEUNOIDU-UHFFFAOYSA-L potassium;sodium;diacetate Chemical compound [Na+].[K+].CC([O-])=O.CC([O-])=O PSBAZVJEUNOIDU-UHFFFAOYSA-L 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 229960004249 sodium acetate Drugs 0.000 description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 2
- 239000004299 sodium benzoate Substances 0.000 description 2
- 235000010234 sodium benzoate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 235000011083 sodium citrates Nutrition 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 239000001540 sodium lactate Substances 0.000 description 2
- 235000011088 sodium lactate Nutrition 0.000 description 2
- 229940005581 sodium lactate Drugs 0.000 description 2
- 235000019983 sodium metaphosphate Nutrition 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 235000019830 sodium polyphosphate Nutrition 0.000 description 2
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 229960001367 tartaric acid Drugs 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 235000013337 tricalcium citrate Nutrition 0.000 description 2
- 229940117957 triethanolamine hydrochloride Drugs 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- TYNPETUKPMFWQP-UHFFFAOYSA-K trisodium 2-[bis(2-hydroxyethyl)amino]ethanol phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O.OCCN(CCO)CCO TYNPETUKPMFWQP-UHFFFAOYSA-K 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 2
- 235000019801 trisodium phosphate Nutrition 0.000 description 2
- 229960004418 trolamine Drugs 0.000 description 2
- 229960000281 trometamol Drugs 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 1
- IEPMBYOIQGCVHO-UHFFFAOYSA-N 1-cyclopropyl-6-fluoro-5-methyl-7-(3-methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid;hydron;chloride Chemical compound Cl.C1CNC(C)CN1C(C(=C1C)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 IEPMBYOIQGCVHO-UHFFFAOYSA-N 0.000 description 1
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
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Images
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- Quinoline Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は、ｏ／ｗエマルションおよびこのエマルションを用いて製するマイクロカプセルに関する。
【０００２】
【従来の技術】
生体における消失速度が速く、有効性を得るためには頻回投与を必要とする薬物は、徐放製剤として製剤設計される試みがなされている。徐放製剤とすることで、持続的な薬効を示し、投与回数を減少させ、患者への負担を軽減することができる。
徐放製剤化の方法として、マイクロカプセル化が知られている。マイクロカプセルは、リザーバー型のものとモノシリック型のものに分類されるが、徐放製剤化においては、モノシリック型のものが適当である。
生理活性ポリペプチドについては、モノシリック型のマイクロカプセルとした方法が知られている。このものの一般的な製造方法は、生体分解性ポリマーを塩化メチレン等の有機溶媒に溶解し、生理活性ポリペプチド水溶液と撹拌、混合し、ｗ／ｏ型エマルションを調製し、このエマルションをポリビニルアルコール水溶液中に添加し、ｗ／ｏ／ｗ型エマルションを生成させ、次いで、油相である塩化メチレン等の有機溶媒を気化させるというものである。
【０００３】
この方法は、生理活性ポリペプチドがマイクロカプセル中に均一に分散したものが得られるという利点がある一方で、ｗ／ｏ／ｗ型エマルションを生成させる工程を経るため、マイクロカプセル中の生理活性ポリペプチドの含有量（薬物封入率）が低下しやすいという欠点がある。
水溶性薬物をマイクロカプセル化するに際し、内相に水溶性薬物を含有するエマルションを生成させる必要があるが、通常、水溶性薬物のエマルションとしては、ｓ／ｏ／ｗ型エマルション、ｗ／ｏ／ｗ型エマルションにならざるを得ない。
しかしながら、ｓ／ｏ／ｗ型エマルションは、含有させる水溶性薬物の粒子径の影響を受けやすいため、粒子径の制御が困難である。すなわち、微小なマイクロカプセルを製することができない。ｗ／ｏ／ｗ型エマルションは、上記生理活性ポリペプチドの例で示した欠点のほかに、製造工程が多いといった欠点がある。
【０００４】
【発明が解決しようとする課題】
ピリドンカルボン酸化合物またはその塩の徐放製剤化を意図したエマルション、マイクロカプセルを製するにあたり、薬物の粒子径の影響を受けずに、少ない工程で製造でき、また、エマルション、マイクロカプセル内へのピリドンカルボン酸化合物またはその塩の取り込み率（薬物封入率）の低さ、投与初期の過剰放出、長期にわたる安定した放出性、血中および／または患部での薬物濃度の長期間の保持などの問題点を解決するものである。
【０００５】
【課題を解決するための手段】
本発明者らは、鋭意研究した結果、ピリドンカルボン酸化合物またはその塩のｏ／ｗ型エマルションを調製し、このものを利用したマイクロカプセルが、前記問題点を解決し得る優れたものであることを見出し、本発明を完成した。
【０００６】
すなわち、本発明は、
（Ａ）油相がピリドンカルボン酸化合物またはその塩、生体内分解性ポリマーおよび酸化亜鉛を含有する有機溶媒分散液であるｏ／ｗ型エマルション、
（Ｂ）水相が緩衝液である上記（Ａ）記載のｏ／ｗ型エマルション、
（Ｃ）緩衝液が、アスコルビン酸、Ｌ−アスパラギン酸マグネシウム、アミノエチルスルホン酸、Ｌ−アルギニン、安息香酸、安息香酸ナトリウム、イプシロン−アミノカプロン酸、塩化アンモニウム、塩化カリウム、塩化ナトリウム、塩化ベンザルコニウム、塩酸アルギニン、塩酸グルコサミン、塩酸トリエタノールアミン、亜硫酸ナトリウム、炭酸ナトリウム、塩酸、クエン酸、クエン酸カルシウム、クエン酸ナトリウム、クエン酸二ナトリウム、グリシン、グルコン酸カルシウム、Ｌ−グルタミン酸、Ｌ−グルタミン酸ナトリウム、クレアチニン、クロロブタノール、リン酸、リン酸一水素ナトリウム、リン酸二水素ナトリウム、リン酸三ナトリウム、リン酸二カリウム、リン酸二水素カリウム、コハク酸二ナトリウム、酢酸、酢酸カリウム、酢酸ナトリウム、ジエタノールアミン、酒石酸、炭酸水素ナトリウム、トリエタノールアミン、トリエタノールアミンリン酸エステルナトリウム、トロメタモール、乳酸、乳酸ナトリウム、４−（２−ヒドロキシエチル）−１−ピペラジンエタンスルホン酸、ブドウ糖、ホウ酸、ポリリン酸ナトリウム、マレイン酸、メタリン酸ナトリウム、モノエタノールアミンおよびｄｌ−リンゴ酸からなる群より選ばれる１種または２種以上の緩衝剤を混合して製される緩衝液である上記（Ｂ）記載のｏ／ｗ型エマルション、
【０００７】
（Ｄ）緩衝液のｐＨがピリドンカルボン酸化合物の等電点−２〜等電点＋２の範囲である上記（Ｂ）または（Ｃ）記載のｏ／ｗ型エマルション、
（Ｅ）生体内分解性ポリマーが、ポリ乳酸および／または乳酸−グリコール酸共重合体である上記（Ａ）〜（Ｄ）いずれか１つに記載のｏ／ｗ型エマルション、（Ｆ）乳酸−グリコール酸共重合体の乳酸とグリコール酸組成比が、約９５：５〜約４０：６０（モル％）である上記（Ｅ）記載のｏ／ｗ型エマルション、
（Ｇ）乳酸−グリコール酸共重合体の質量平均分子量が、約３,０００〜約２０,０００である上記（Ｅ）または（Ｆ）記載のｏ／ｗ型エマルション、
（Ｈ）ピリドンカルボン酸またはその塩が、次の一般式（１）〜（４）で表されるものである上記（Ａ）〜（Ｇ）いずれか１つに記載のｏ／ｗ型エマルション。
【０００８】
【化２】
（式中、Ｒ1a、Ｒ1bおよびＲ1cはそれぞれ独立して、置換基を有することもあるＣ1−Ｃ6の直鎖状もしくは分枝状のアルキル基、置換基を有することもあるＣ3−Ｃ6の環状アルキル基、置換基を有することもあるアリール基または置換基を有することもあるヘテロアリール基を意味する。Ｒ2a、Ｒ2b、Ｒ2cおよびＲ2dはそれぞれ独立して、水素原子、置換基を有することもあるＣ1−Ｃ6の直鎖状もしくは分枝状のアルキル基またはアミノ基を意味する。Ｒ3a、Ｒ3b、Ｒ3cおよびＲ3dはそれぞれ独立して、水素原子またはハロゲン原子を意味する。Ｒ4aまたはＲ4cは、水素原子、ハロゲン原子、置換基を有することもあるＣ1−Ｃ6の直鎖状もしくは分枝状のアルキル基または置換基を有することもあるＣ1−Ｃ6の直鎖状もしくは分枝状のアルコキシル基を意味する。Ｒ5dは、水素原子または置換基を有することもあるＣ1−Ｃ6の直鎖状もしくは分枝状のアルキル基を意味する。Ｙa、Ｙb、ＹcおよびＹdはそれぞれ独立して含窒素基を意味する。）、
【００１０】
（Ｉ）ピリドンカルボン酸またはその塩が、オフロキサシン、レボフロキサシン、塩酸シプロフロキサシン、シタフロキサシン、ノルフロキサシン、スパルフロキサシン、トシル酸トスフロキサシン、塩酸モキシフロキサシン、エノキサシン、フレロキサシン、塩酸ロメフロキサシン、ＨＳＲ−９０３、ＣＳ−９４０、ガチフロキサシン、塩酸グレパフロキサシン、パズフロキサシン、プルリフロキサシン、メシル酸トロバフロキサシン、塩酸クリナフロキサシン、メシル酸アラトロフロキサシン、メシル酸パズフロキサシン、Ａ−９９０５８．Ｌ、エセノフロキサシン、塩酸ファンドフロキサシン、ＫＲＱ−１００１８、ＳＳ−７３２、Ｔ−３８１１、ＷＱ−３０３４、イルロキサシン、ＬＢ−２０３０４ａ、ＳＳ−７３４、ＷＱ−２７４３またはＹ−６８８である上記（Ａ）〜（Ｇ）いずれか１つに記載のｏ／ｗ型エマルション、
【００１１】
（Ｊ）上記（Ａ）〜（Ｉ）いずれか１つに記載のｏ／ｗ型エマルション中の有機溶媒を除去して得られるマイクロカプセル、
（Ｋ）有機溶媒の除去方法が水中乾燥法、相分離法または噴霧乾燥法である上記（Ｊ）記載のマイクロカプセル、
（Ｌ）徐放性マイクロカプセルである上記（Ｊ）または（Ｋ）記載のマイクロカプセル、
（Ｍ）歯周病治療用である上記（Ｊ）〜（Ｌ）いずれか１つに記載のマイクロカプセル、および
（Ｎ）上記（Ａ）〜（Ｉ）いずれか１つに記載のｏ／ｗ型エマルション中の有機溶媒を除去してマイクロカプセルを製造する方法に関する。
【００１２】
本発明において、生体内分解性ポリマーとしては、乳酸、グリコール酸等のα−ヒドロキシカルボン酸を単量体とする重合体および共重合体を挙げることができる。共重合体は、ランダム重合体、ブロック重合体、グラフト重合体のいずれの形態でもよい。本発明においては、ポリ乳酸、ポリグリコール酸、乳酸−グリコール酸共重合体等が好ましく、乳酸−グリコール酸共重合体が特に好ましい。乳酸−グリコール酸共重合体においては、組成比が約９５：５〜約５：９５（モル％）であるものが好ましく、約９５：５〜約４０：６０（モル％）であるものがさらに好ましい。生体内分解性ポリマーの質量平均分子量としては、約３,０００〜約２０,０００であるものが好ましい。上記のα−ヒドロキシカルボン酸を単量体とする重合体および共重合体は、種々のものが市販されており、容易に入手可能である。また、特開昭６１−２８５２１号公報に記載の方法またはこれに準じて製造することもできる。本発明のエマルション、マイクロカプセルを製するに際しては、生体内分解性ポリマーは、封入対象とする薬物や目標とする徐放期間などを考慮して、適宜検討すればよく、生体内分解性ポリマーは１種類のみならず、複数のものを組み合わせて用いてもよく、また、同一のポリマーであっても、質量平均分子量や組成比（共重合体の場合）が異なるものを適宜組み合わせて用いてもよい。
【００１３】
本発明のピリドンカルボン酸化合物またはその塩のｏ／ｗ型エマルションを製する際に、酸化亜鉛を添加すると、後記実施例から明らかなように、エマルション、マイクロカプセル内へのピリドンカルボン酸化合物またはその塩の取り込み率（薬物封入率）を向上させることができ、また投与初期の過剰放出を抑制することができる。酸化亜鉛は、エマルションの製造において、微粉状のものが好ましく、酸化亜鉛の粒子径としては、０．００１〜１０μｍのものが好ましい。酸化亜鉛の配合量は、ピリドンカルボン酸化合物またはその塩１モルに対し、０．０１〜２モル配合するのが好ましく、０．１〜１モル配合するのが特に好ましい。
【００１４】
本発明において、ｏ／ｗ型エマルションを製する際に用いる有機溶媒としては、ジクロロメタン、クロロホルム、四塩化炭素などのハロゲン化炭化水素、エタノール、メタノール、１,４−ブタンジオール、１,５−ペンタンジオールなどアルコール類、酢酸エチルエステルなどのエステル類、アセトニトリル、アセトンなどを挙げることができる。これら有機溶媒は、単独でも、２種以上を混合して用いてもよい。有機溶媒を単独で用いる場合、ジクロロメタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素、酢酸エチルエステル等のエステル類などが好ましい。また、混合溶媒としては、上述の好ましい有機溶媒に、アルコール類、アセトニトリルやアセトンを混合した混合溶媒を挙げることができ、中でもジクロロメタンとアセトンとの混合溶媒が好ましい。
【００１５】
本発明のｏ／ｗ型エマルション中に含有されるピリドンカルボン酸化合物またはその塩は、特に限定されるべきものではないが、ピリドンカルボン酸化合物またはその塩として好ましいものの一例として、合成抗菌薬として知られている、次の一般式（１）〜（４）で表されるピリドンカルボン酸化合物またはその塩を挙げることができる。
【００１６】
【化３】
（式中、Ｒ1a、Ｒ1bおよびＲ1cはそれぞれ独立して、置換基を有することもあるＣ1−Ｃ6の直鎖状もしくは分枝状のアルキル基、置換基を有することもあるＣ3−Ｃ6の環状アルキル基、置換基を有することもあるアリール基または置換基を有することもあるヘテロアリール基を意味する。Ｒ2a、Ｒ2b、Ｒ2cおよびＲ2dはそれぞれ独立して、水素原子、置換基を有することもあるＣ1−Ｃ6の直鎖状もしくは分枝状のアルキル基またはアミノ基を意味する。Ｒ3a、Ｒ3b、Ｒ3cおよびＲ3dはそれぞれ独立して、水素原子またはハロゲン原子を意味する。Ｒ4aまたはＲ4cは、水素原子、ハロゲン原子、置換基を有することもあるＣ1−Ｃ6の直鎖状もしくは分枝状のアルキル基または置換基を有することもあるＣ1−Ｃ6の直鎖状もしくは分枝状のアルコキシル基を意味する。Ｒ5dは、水素原子または置換基を有することもあるＣ1−Ｃ6の直鎖状もしくは分枝状のアルキル基を意味する。Ｙa、Ｙb、ＹcおよびＹdはそれぞれ独立して含窒素基を意味する。）
【００１８】
前記一般式（１）〜（４）で表されるピリドンカルボン酸化合物およびその塩は、特開昭５３−１４１２８６号公報、特開昭５５−３１０４２号公報、特開昭５７−４６９８６号公報、特開昭５７−７７６８３号公報、特開昭６０−３６４８２号公報、特開昭６０−６４９７９号公報、特開昭６０−２２８４７９号公報、特開昭６２−２５２７７２号公報、特開昭６２−２５２７９０号公報、特開昭６２−２７７３６２号公報、特開平１−２３０５５８号公報、特開平１−２５８６６６号公報、特開平１−２９４６８０号公報、特開平２−２８１７８号公報、特開平２−１２４８７３号公報、特開平２−２３１４７５号公報、特開平５−２７１２２９号公報、特開平７−３０９８６４号公報、特開平８−４１０５０号公報、ＷＯ９１／０２５２６号公報、ＷＯ９４／１４７９４号公報、ＷＯ９４／１５９３３号公報、ＷＯ９５／５３７３号公報、ＷＯ９６／３７４７５号公報、ＷＯ９６／３９４０７号公報、ＷＯ９７／２９１０２号公報、ＷＯ９７／１９０７２号公報、ＷＯ９７／４００３７号公報、ＷＯ９８／０２４３１号公報、ＷＯ９８／１３３７０号公報、ＷＯ９８／１８７８３号公報、ＷＯ９８／２４７８１号公報、ＷＯ９８／５２９３９号公報、ＷＯ９８／５４１６９号公報およびＷＯ９８／５８９２３号公報等に記載され、これら公報には製造方法も記載されている。
【００１９】
前記一般式（１）〜（４）で表される化合物は、不斉炭素を有する場合があり、光学異性体またはジアステレオ異性体が存在する場合もあるが、純粋な形態のこれらの異性体、これら異性体の任意の混合物、ラセミ体などはいずれも本発明に含まれる。また、前記一般式（１）〜（４）で表される化合物またはそられの塩は、水和物、溶媒和物として存在する場合もあるが、これらも本発明に含まれる。
【００２０】
前記一般式（１）〜（４）で表される化合物は、その分子中にカルボキシル基を有するため、酸化亜鉛における亜鉛原子と相互作用し、エマルション、マイクロカプセル内へのピリドンカルボン酸化合物またはその塩の取り込み率（薬物封入率）を向上させることができ、また投与初期の過剰放出を抑制することができるものと考えられる。したがって、分子内にカルボキシル基等の酸性基を有する化合物が、本発明のエマルションやマイクロカプセルへの封入対象薬物として、好ましいものと考えられる。
前記一般式（１）〜（４）で表される化合物またはその塩のうちの好ましい例としては、下記の化合物またはその塩が挙げられる。
【００２１】
【化４】
【化５】
【化６】
【化７】
【化８】
以下に、本発明のｏ／ｗエマルションおよびこのエマルションを用いて製するマイクロカプセルの製造方法について説明する。本発明のエマルションは、例えば、生体内分解性ポリマーを有機溶媒に溶解させた溶液中に酸化亜鉛およびピリドンカルボン酸化合物またはその塩を分散または溶解させ、この分散液（この分散液は、溶液も含むものを意味する。）をｏ／ｗエマルションの水相となり得る適当な緩衝液中に添加することにより得ることができる。
【００２７】
生体内分解性ポリマーを有機溶媒に溶解させた溶液は、生体内分解性ポリマーの質量平均分子量や組成比（共重合体の場合）、用いる有機溶媒の種類などによって、その製造条件は異なるが、生体内分解性ポリマーの有機溶媒溶液中濃度として、約０．１〜約８０％（ｗ／ｗ）、好ましくは、約１〜約７０％（ｗ／ｗ）、さらに好ましくは、約２〜約６０％（ｗ／ｗ）となるように製造すればよい。次いで、得られた生体内分解性ポリマー有機溶媒溶液中に、ピリドンカルボン酸化合物またはその塩、および酸化亜鉛を、それぞれ粉末として、あるいは適当な溶媒・分散媒を用いて製した溶液・分散液として添加して、ピリドンカルボン酸化合物またはその塩、生体内分解性ポリマーおよび酸化亜鉛を含有する有機溶媒分散液を製すればよい。
【００２８】
ピリドンカルボン酸化合物またはその塩の添加量は、生体内分解性ポリマーに対して、０．１〜５０％（ｗ／ｗ）質量部、好ましくは、１〜３０％（ｗ／ｗ）、さらに好ましくは、３〜２０％（ｗ／ｗ）とすればよく、また、酸化亜鉛の添加量は、ピリドンカルボン酸化合物またはその塩に対して、５〜３００％（ｗ／ｗ）、好ましくは、１０〜２００％（ｗ／ｗ）、さらに好ましくは、２０〜１００％（ｗ／ｗ）とすればよい。
得られた有機溶媒分散液は、ｏ／ｗエマルションの油相となり、この分散液を水相となり得る水または適当な水溶液（例えば、グルコース、乳糖、ショ糖などの糖水溶液、グリセリン、プロピレングリコールなどの多価アルコール水溶液、生理食塩水、緩衝液など）中に添加することにより、本発明のｏ／ｗエマルションを製することができる。本発明においては、水相として緩衝液が好ましい。緩衝液としては、アスコルビン酸、Ｌ−アスパラギン酸マグネシウム、アミノエチルスルホン酸、Ｌ−アルギニン、安息香酸、安息香酸ナトリウム、イプシロン−アミノカプロン酸、塩化アンモニウム、塩化カリウム、塩化ナトリウム、塩化ベンザルコニウム、塩酸アルギニン、塩酸グルコサミン、塩酸トリエタノールアミン、亜硫酸ナトリウム、炭酸ナトリウム、塩酸、クエン酸、クエン酸カルシウム、クエン酸ナトリウム、クエン酸二ナトリウム、グリシン、グルコン酸カルシウム、Ｌ−グルタミン酸、Ｌ−グルタミン酸ナトリウム、クレアチニン、クロロブタノール、リン酸、リン酸一水素ナトリウム、リン酸二水素ナトリウム、リン酸三ナトリウム、リン酸二カリウム、リン酸二水素カリウム、コハク酸二ナトリウム、酢酸、酢酸カリウム、酢酸ナトリウム、ジエタノールアミン、酒石酸、炭酸水素ナトリウム、トリエタノールアミン、トリエタノールアミンリン酸エステルナトリウム、トロメタモール、乳酸、乳酸ナトリウム、４−（２−ヒドロキシエチル）−１−ピペラジンエタンスルホン酸、ブドウ糖、ホウ酸、ポリリン酸ナトリウム、マレイン酸、メタリン酸ナトリウム、モノエタノールアミンおよびｄｌ−リンゴ酸からなる群より選ばれる１種または２種以上の緩衝剤を混合して製される緩衝液等を挙げることができ、緩衝液のｐＨはピリドンカルボン酸化合物またはその塩の等電点−２〜等電点＋２の範囲としたものが好ましく、等電点−１〜等電点＋１の範囲としたものがさらに好ましい。また、緩衝液の濃度としては、０．０００３〜０．１ｍｏｌ／ｌ、０．００１〜０．０５ｍｏｌ／ｌが好ましく、０．００３〜０．０３ｍｏｌ／ｌがさらに好ましい。
【００２９】
得られたｏ／ｗエマルションを、水中乾燥法（ｏ／ｗ法）、相分離法（コアセルベーション法）、噴霧乾燥法またはこれらに準じた方法を用いて、有機溶媒を除去し、必要に応じて洗浄することにより、マイクロカプセルを製することができる。好ましくは、水中乾燥法（ｏ／ｗ法）または噴霧乾燥法を用いて製する方法である。
マイクロカプセルを製する際、ｏ／ｗエマルションが凝集しているのは好ましくないため、凝集を抑制するために、ポリビニルアルコール、レシチン、ヒドロキシプロピルメチルセルロース、ノニオン性界面活性剤などの凝集抑制剤を、ｏ／ｗエマルションの水相となり得る水または適当な水溶液中に適当量加えるのが好ましい。凝集抑制剤の添加量は、生体内分解性ポリマー１質量部に対して、０．００１〜１０質量部、０．０１〜５質量部が好ましく、０．１〜２質量部がさらに好ましい。
【００３０】
得られたマイクロカプセルは、そのまま、またはマイクロカプセルを製剤原料として用いて種々の剤形として製剤化することができる。剤形としては、注射剤、軟膏剤、液剤、懸濁剤、貼付剤等の非経口製剤、散剤、顆粒剤、細粒剤、錠剤、カプセル剤等の経口製剤等を挙げることができる。これら製剤は、適宜製剤添加物を用いて、公知の方法で製剤化すればよい。
【００３１】
本発明のマイクロカプセルは、前記一般式（１）〜（４）の化合物またはその塩の徐放性製剤として使用されることが好適である。対象となる疾病としては、局所的に投与することにより、有効な治療効果等のメリットを得られる歯周病、慢性骨髄炎等を挙げることができる。
従来、歯周病の治療方法は、患部である歯周ポケット（歯と歯茎との間の隙間）に、抗菌剤や抗生物質の液剤、軟膏剤を、医師、歯科医師等が患部に投与することによりなされる。しかしながら、従来より用いられている製剤が徐放性ではないため、患者は治療（投薬）を受けるにあたり、医師、歯科医師等のもとに出向かなければならない。
したがって、本発明のマイクロカプセルを歯周病の治療を目的として投与すれば、治療効果が上がるのみならず、患者のメリットとなりうる。
【００３２】
【実施例】
以下に、実施例を挙げて本発明を更に詳細に説明するが、本発明はこれらのみに何ら限定されるべきものではない。
【００３３】
実施例１ 酸化亜鉛添加の検討
ガラスバイアル（容量２０ｍｌ）に乳酸−グリコール酸共重合体（ＰＬＧＡ，乳酸／グリコール酸組成比５０：５０，質量平均分子量７７００，和光純薬（株））３ｇを量り、ジクロロメタン（特級，和光純薬（株））３ｍｌを加え、約３分間振とうし、レボフロキサシン２００ｍｇを加え、約５分間振とうした。次いで、酸化亜鉛（０．０２μｍグレード，和光純薬（株））を設定した添加量となるように加え、約３分間振とうした。得られた分散液を、外水相（０．１％ポリビニルアルコール（以下、ＰＶＡ）含有０．０１ｍｏｌ／ｌリン酸塩緩衝液（ｐＨ７．５））１００ｍｌに、ホモジナイザー処理している中へ、シリンジを用いて徐々に添加した（機器：ＲＯＢＯ ＭＩＣＳ．，回転数３０００ｒｐｍ，処理時間２分，分散液注入時間１分）。得られた液を、プロペラ攪拌機にて２時間攪拌した（回転数：５００ｒｐｍ）。この液を遠沈管にとって遠心機処理を行い（回転数：１５００ｒｐｍ，時間：２分）、上清を取り除いた。得られた沈殿に対して洗浄処理（０．０１ｍｏｌ／ｌリン酸塩緩衝液（ｐＨ７．５）４０ｍｌで懸濁、遠心、上清の除去）を３回行った。得られた沈殿に、０．０１ｍｏｌ／ｌリン酸塩緩衝液（ｐＨ７．５）約２０ｍｌを加えて懸濁し、篩（メッシュサイズ：１２５μｍ）で篩過した。これに、２０％マンニトール溶液０．７ｍｌを加えた後、凍結乾燥を行い、マイクロカプセルを得た。
【００３４】
得られたマイクロカプセル約１５ｍｇを精密に量り、ジクロロメタン２ｍｌを加え、３０秒間激しく振とうした。次に０．１ｍｏｌ／ｌ塩酸２ｍｌを加え、３０秒間激しく振とうした。上層を一部取り、０．１ｍｏｌ／ｌ塩酸５０倍量を加えて試料溶液とした。別にレボフロキサシン約５ｍｇを精密に量り、０．１ｍｏｌ／ｌ塩酸１０ｍｌを加え溶解させ、この液２ｍｌにジクロロメタン２ｍｌを加え、３０秒間激しく振とうした。上層を一部取り、０．１ｍｏｌ／ｌ塩酸５０倍量を加えて標準溶液とした。試料溶液及び標準溶液の２９３ｎｍの紫外吸光度を測定し、製剤中の薬物含量を求め、薬物封入効率を算出した。結果を表1に示した。
【００３５】
【表１】
実施例２ 水相としての緩衝液濃度の検討
ガラスバイアル（容量２０ｍｌ）に乳酸−グリコール酸共重合体（ＰＬＧＡ，乳酸／グリコール酸組成比５０：５０，質量平均分子量６６００，和光純薬（株））１．５ｇを量り、ジクロロメタン（特級，和光純薬（株））１．５ｍｌを加え、約３分間振とうし溶解させた。この溶液にレボフロキサシン３００ｍｇを加え、約１０分間振とうした。さらに酸化亜鉛（０．０２μｍグレード，和光純薬（株））１１ｍｇを加え、約１０分間振とうした。得られた液に，外水相（設定された濃度の０．１％ＰＶＡ含有リン酸塩緩衝液（ｐＨ７．５））４．５ｍｌを加え、３０秒間激しく振とうした。これを外水相１００ｍｌに添加し、プロペラ攪拌機にて２時間攪拌した（回転数：２５０ｒｐｍ）。この液を遠沈管にとって遠心機処理を行い（回転数：１０００ｒｐｍ，時間：５分）、上清を取り除いた。得られた沈殿に対して洗浄処理（外水相として用いたものと同一のリン酸塩緩衝液（但し、ＰＶＡは含まない）約４０ｍｌで懸濁、遠心、上清の除去）を３回行った。得られた沈殿に同様のリン酸塩緩衝液約２０ｍｌを加え懸濁し、篩（メッスサイズ：１２５μｍ）で篩過した。篩過された液に、２０％マンニトール溶液０．４ｍｌを加えた後、凍結乾燥を行い、マイクロカプセルを得た。製造直後のマイクロカプセルの状態（凝集の有無）を観察し、実施例１と同様に、マイクロカプセルにおける薬物封入効率を求めた。また、１５ｍｌポリプロピレン製遠心チューブに、リン酸緩衝化生理食塩水（ｐＨ７．４）（以下、ＰＢＳ）１ｍｌを加え、マイクロカプセルおよそ１５ｍｇを加え、これを３７℃湯浴中振とう機で振とうした（機器：ＰＥＲＳＯＮＡＬ−１１ タイテック（株），振とう回数：９０往復／分）。振とう開始後経時的に遠心チューブを遠心し（回転数：２０００ｒｐｍ，時間：３分）、上清１ｍｌを採取し保存した。また、遠心管には新たにＰＢＳを加え、再び振とうを行った。保存した上清に０．１ｍｏｌ／ｌ塩酸適当量を加えて試料溶液とした。別に、レボフロキサシン約５ｍｇを精密に量り、０．１ｍｏｌ／ｌ塩酸１０ｍｌを加え溶解させた。この液を一部取り、０．１ｍｏｌ／ｌ塩酸５０倍量を加えて標準溶液とした。試料溶液及び標準溶液の２９３ｎｍの紫外吸光度を測定し、含まれていた薬物量を求めた。結果を表２に示した。
【００３７】
【表２】
尚、図１に緩衝液濃度０．０１ｍｏｌ／ｌにおけるマイクロカプセルからの経時的薬物放出の状況をグラフ化したものを示す。
【００３９】
実施例３ 水相としての緩衝液ｐＨの検討
ガラスバイアル（容量２０ｍｌ）に乳酸−グリコール酸共重合体（ＰＬＧＡ，乳酸／グリコール酸組成比５０：５０，質量平均分子量６６００，和光純薬（株））１．５ｇを量り、ジクロロメタン（特級，和光純薬（株））１．５ｍｌを加え、約３分間振とうして溶解させた。これにレボフロキサシン３００ｍｇを加え、約１０分間振とうした。さらに酸化亜鉛（０．０２μｍグレード，和光純薬（株））１１ｍｇを加え、約１０分間振とうした。得られた液に、外水相（設定されたｐＨの１．０％ＰＶＡ含有０．０１ｍｏｌ／ｌリン酸塩緩衝液４．５ｍｌを加え、３０秒間激しく振とうした。これを外水相１００ｍｌに添加し、プロペラ攪拌機にて２時間攪拌した（回転数：２５０ｒｐｍ）。この液を遠沈管にとり、遠心機処理を行い（回転数：１０００ｒｐｍ，時間：５分）、上清を取り除いた。得られた沈殿に対して洗浄処理（外水相として用いたものと同一のリン酸塩緩衝液（但し、ＰＶＡは含まない）約４０ｍｌで懸濁、遠心、上清の除去）を３回行った。得られた沈殿に同様のリン酸塩緩衝液約２０ｍｌを加え懸濁し、篩（篩サイズ：１２５μｍ）で篩過した。篩過された液に、２０％マンニトール溶液０．４ｍｌを加えた後、凍結乾燥を行い、マイクロカプセルを得た。実施例１と同様に、マイクロカプセルにおける薬物封入効率を求め、実施例２と同様に、撹拌直後のマイクロカプセルの状態を観察し、マイクロカプセルから放出された薬物量を求めた。結果を表３に示した。
【００４０】
【表３】
【発明の効果】
本発明は、エマルション、マイクロカプセル内へのピリドンカルボン酸化合物またはその塩の取り込み率（薬物封入率）を高くし、投与初期の過剰放出を抑制した、長期にわたる安定した徐放性が得られ、血中および／または患部での薬物濃度を長期間保持することができる製剤を提供し得る。
【図面の簡単な説明】
【図１】実施例２において、緩衝液濃度０．０１ｍｏｌ／ｌにおけるマイクロカプセルからの経時的薬物放出の状況をグラフ化したものを示す。尚、緩衝液ｐＨは７．５である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an o / w emulsion and a microcapsule produced using the emulsion.
[0002]
[Prior art]
Attempts have been made to design a drug as a sustained-release preparation for a drug that has a high elimination rate in a living body and requires frequent administration in order to obtain effectiveness. By making it a sustained-release preparation, it is possible to show a sustained drug effect, reduce the number of administrations, and reduce the burden on the patient.
Microencapsulation is known as a method for preparing a sustained release preparation. Microcapsules are classified into a reservoir type and a monolithic type, but a monolithic type is suitable for sustained release formulation.
As for the biologically active polypeptide, a method using monolithic microcapsules is known. A general production method for this is to dissolve a biodegradable polymer in an organic solvent such as methylene chloride, and stir and mix with a physiologically active polypeptide aqueous solution to prepare a w / o type emulsion. It is added to form a w / o / w type emulsion, and then an organic solvent such as methylene chloride as an oil phase is vaporized.
[0003]
While this method has an advantage that a physiologically active polypeptide is uniformly dispersed in the microcapsule, it has a step of forming a w / o / w type emulsion. There is a drawback that the peptide content (drug encapsulation rate) tends to decrease.
When microencapsulating a water-soluble drug, it is necessary to produce an emulsion containing the water-soluble drug in the internal phase. Usually, an emulsion of a water-soluble drug is an s / o / w type emulsion, w / o / It must be a w-type emulsion.
However, since the s / o / w type emulsion is easily affected by the particle size of the water-soluble drug to be contained, it is difficult to control the particle size. That is, a microcapsule cannot be manufactured. The w / o / w type emulsion has a drawback that it involves many production steps in addition to the drawbacks shown in the examples of the physiologically active polypeptide.
[0004]
[Problems to be solved by the invention]
When producing emulsions and microcapsules intended for the sustained release formulation of pyridonecarboxylic acid compounds or salts thereof, they can be manufactured with few steps without being affected by the particle size of the drug. Problems such as low uptake rate (drug encapsulation rate) of pyridonecarboxylic acid compounds or salts, excessive release at the beginning of administration, long-term stable release, long-term retention of drug concentration in the blood and / or affected area It solves the point.
[0005]
[Means for Solving the Problems]
As a result of diligent research, the present inventors have prepared an o / w emulsion of a pyridonecarboxylic acid compound or a salt thereof, and a microcapsule using this is an excellent solution that can solve the above problems. The present invention has been completed.
[0006]
That is, the present invention
(A) an o / w emulsion in which the oil phase is an organic solvent dispersion containing a pyridonecarboxylic acid compound or a salt thereof, a biodegradable polymer and zinc oxide,
(B) an o / w emulsion according to (A) above, wherein the aqueous phase is a buffer;
(C) The buffer solution is ascorbic acid, magnesium L-aspartate, aminoethylsulfonic acid, L-arginine, benzoic acid, sodium benzoate, epsilon-aminocaproic acid, ammonium chloride, potassium chloride, sodium chloride, benzalkonium chloride Arginine hydrochloride, glucosamine hydrochloride, triethanolamine hydrochloride, sodium sulfite, sodium carbonate, hydrochloric acid, citric acid, calcium citrate, sodium citrate, disodium citrate, glycine, calcium gluconate, L-glutamic acid, sodium L-glutamate , Creatinine, chlorobutanol, phosphoric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, potassium dihydrogen phosphate, disodium succinate, acetic acid, potassium acetate Sodium, sodium acetate, diethanolamine, tartaric acid, sodium bicarbonate, triethanolamine, sodium triethanolamine phosphate, trometamol, lactic acid, sodium lactate, 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid, glucose, The above-mentioned buffer solution prepared by mixing one or more buffering agents selected from the group consisting of boric acid, sodium polyphosphate, maleic acid, sodium metaphosphate, monoethanolamine and dl-malic acid ( B) o / w type emulsion according to the description,
[0007]
(D) The o / w emulsion according to (B) or (C) above, wherein the pH of the buffer solution is in the range of isoelectric point-2 to isoelectric point + 2 of the pyridonecarboxylic acid compound,
(E) The o / w emulsion according to any one of (A) to (D) above, wherein the biodegradable polymer is polylactic acid and / or lactic acid-glycolic acid copolymer, (F) lactic acid- O / w emulsion according to (E) above, wherein the glycolic acid copolymer has a lactic acid / glycolic acid composition ratio of about 95: 5 to about 40:60 (mol%),
(G) The o / w emulsion according to (E) or (F) above, wherein the lactic acid-glycolic acid copolymer has a mass average molecular weight of about 3,000 to about 20,000,
(H) The o / w emulsion according to any one of the above (A) to (G), wherein the pyridonecarboxylic acid or a salt thereof is represented by the following general formulas (1) to (4).
[0008]
[Chemical formula 2]
(Wherein R 1a , R 1b And R 1c Each independently may have a substituent. 1 -C 6 Or a linear or branched alkyl group, which may have a substituent Three -C 6 A cyclic alkyl group, an aryl group which may have a substituent, or a heteroaryl group which may have a substituent. R 2a , R 2b , R 2c And R 2d Each independently represents a hydrogen atom or a C which may have a substituent. 1 -C 6 A linear or branched alkyl group or amino group. R 3a , R 3b , R 3c And R 3d Each independently represents a hydrogen atom or a halogen atom. R 4a Or R 4c May have a hydrogen atom, a halogen atom or a substituent. 1 -C 6 May have a linear or branched alkyl group or a substituent 1 -C 6 A linear or branched alkoxyl group. R 5d May have a hydrogen atom or a substituent 1 -C 6 Or a linear or branched alkyl group. Y a , Y b , Y c And Y d Each independently represents a nitrogen-containing group. ),
[0010]
(I) Pyridonecarboxylic acid or a salt thereof is ofloxacin, levofloxacin, ciprofloxacin hydrochloride, sitafloxacin, norfloxacin, sparfloxacin, tosufloxacin tosylate, moxifloxacin hydrochloride, enoxacin, fleroxacin, lomefloxacin hydrochloride, HSR-903 CS-940, gatifloxacin, grepafloxacin hydrochloride, pazufloxacin, pullrifloxacin, trovafloxacin mesylate, clinafloxacin hydrochloride, alatrofloxacin mesylate, pazufloxacin mesylate, A-99058. L, ethenofloxacin, fundfloxacin hydrochloride, KRQ-10018, SS-732, T-3811, WQ-3034, irloxacin, LB-20304a, SS-734, WQ-2743 or Y-688 above ( A / W type emulsion according to any one of (A) to (G),
[0011]
(J) Microcapsules obtained by removing the organic solvent in the o / w emulsion according to any one of (A) to (I) above,
(K) The microcapsule according to (J) above, wherein the organic solvent removal method is an underwater drying method, a phase separation method or a spray drying method,
(L) The microcapsule according to (J) or (K), which is a sustained-release microcapsule,
(M) The microcapsule according to any one of (J) to (L) above, which is used for treatment of periodontal disease, and
(N) The present invention relates to a method for producing a microcapsule by removing the organic solvent in the o / w emulsion according to any one of (A) to (I) above.
[0012]
In the present invention, examples of the biodegradable polymer include polymers and copolymers having α-hydroxycarboxylic acid as a monomer such as lactic acid and glycolic acid. The copolymer may be in any form of a random polymer, a block polymer, and a graft polymer. In the present invention, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer and the like are preferable, and lactic acid-glycolic acid copolymer is particularly preferable. The lactic acid-glycolic acid copolymer preferably has a composition ratio of about 95: 5 to about 5:95 (mol%), more preferably about 95: 5 to about 40:60 (mol%). preferable. The biodegradable polymer preferably has a mass average molecular weight of about 3,000 to about 20,000. Various polymers and copolymers having the above α-hydroxycarboxylic acid as a monomer are commercially available and can be easily obtained. Moreover, it can also manufacture according to the method of Unexamined-Japanese-Patent No. 61-28521, or this. In producing the emulsion and microcapsule of the present invention, the biodegradable polymer may be appropriately examined in consideration of the drug to be encapsulated and the target sustained release period. Not only one type but also a plurality of types may be used in combination, or even the same polymer may be used in appropriate combination with different mass average molecular weights or composition ratios (in the case of copolymers). Good.
[0013]
When making an o / w emulsion of the pyridonecarboxylic acid compound of the present invention or a salt thereof, when zinc oxide is added, the pyridonecarboxylic acid compound in the emulsion or microcapsule or its emulsion is added, as will be apparent from the examples below. The salt uptake rate (drug encapsulation rate) can be improved, and excessive release at the initial administration can be suppressed. Zinc oxide is preferably in the form of fine powder in the production of an emulsion, and the particle diameter of zinc oxide is preferably 0.001 to 10 μm. The compounding amount of zinc oxide is preferably 0.01 to 2 mol, particularly preferably 0.1 to 1 mol, per 1 mol of pyridonecarboxylic acid compound or a salt thereof.
[0014]
In the present invention, the organic solvent used in producing the o / w emulsion includes halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, ethanol, methanol, 1,4-butanediol, and 1,5-pentane. Examples thereof include alcohols such as diol, esters such as ethyl acetate, acetonitrile, acetone and the like. These organic solvents may be used alone or in combination of two or more. When an organic solvent is used alone, halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride, and esters such as ethyl acetate are preferable. Moreover, as a mixed solvent, the mixed solvent which mixed alcohol, acetonitrile, and acetone with the above-mentioned preferable organic solvent can be mentioned, Among these, the mixed solvent of dichloromethane and acetone is preferable.
[0015]
The pyridone carboxylic acid compound or salt thereof contained in the o / w emulsion of the present invention is not particularly limited, but is known as a synthetic antibacterial agent as an example of a preferable pyridone carboxylic acid compound or salt thereof. The pyridonecarboxylic acid compounds represented by the following general formulas (1) to (4) or salts thereof can be mentioned.
[0016]
[Chemical 3]
(Wherein R 1a , R 1b And R 1c Each independently may have a substituent. 1 -C 6 A linear or branched alkyl group, which may have a substituent Three -C 6 A cyclic alkyl group, an aryl group which may have a substituent, or a heteroaryl group which may have a substituent. R 2a , R 2b , R 2c And R 2d Each independently represents a hydrogen atom or a C which may have a substituent. 1 -C 6 A linear or branched alkyl group or amino group. R 3a , R 3b , R 3c And R 3d Each independently represents a hydrogen atom or a halogen atom. R 4a Or R 4c May have a hydrogen atom, a halogen atom or a substituent. 1 -C 6 May have a linear or branched alkyl group or a substituent 1 -C 6 A linear or branched alkoxyl group. R 5d May have a hydrogen atom or a substituent 1 -C 6 Or a linear or branched alkyl group. Y a , Y b , Y c And Y d Each independently represents a nitrogen-containing group. )
[0018]
The pyridonecarboxylic acid compounds represented by the general formulas (1) to (4) and salts thereof are disclosed in JP-A Nos. 53-141286, 55-31042, 57-46986, JP-A-57-77683, JP-A-60-36482, JP-A-60-64979, JP-A-60-228479, JP-A-62-252772, JP-A-62-2 Nos. 252790, 62-277362, 1-230558, 1-258666, 1-294680, 2-28178, 2-124873 No. 2, JP-A-2-231475, JP-A-5-271229, JP-A-7-309864, JP-A-8-41050, WO91 / 025. No. 6, WO 94/14794, WO 94/15933, WO 95/5373, WO 96/37475, WO 96/39407, WO 97/29102, WO 97/19072, WO 97/40037 Publications, WO98 / 02431, WO98 / 13370, WO98 / 18783, WO98 / 24781, WO98 / 52939, WO98 / 54169, WO98 / 58923, etc. Describes the manufacturing method.
[0019]
The compounds represented by the general formulas (1) to (4) may have an asymmetric carbon and may have optical isomers or diastereoisomers, but these isomers in a pure form Any mixtures of these isomers, racemates and the like are included in the present invention. The compounds represented by the general formulas (1) to (4) or salts thereof may exist as hydrates or solvates, and these are also included in the present invention.
[0020]
Since the compound represented by the general formulas (1) to (4) has a carboxyl group in the molecule, it interacts with a zinc atom in zinc oxide, and the pyridonecarboxylic acid compound or its compound in an emulsion or a microcapsule. It is considered that the salt uptake rate (drug encapsulation rate) can be improved and excessive release at the initial administration can be suppressed. Therefore, a compound having an acidic group such as a carboxyl group in the molecule is considered preferable as a drug to be encapsulated in the emulsion or microcapsule of the present invention.
Preferable examples of the compounds represented by the general formulas (1) to (4) or salts thereof include the following compounds or salts thereof.
[0021]
[Formula 4]
[Chemical formula 5]
[Chemical 6]
[Chemical 7]
[Chemical 8]
Below, the o / w emulsion of this invention and the manufacturing method of the microcapsule manufactured using this emulsion are demonstrated. In the emulsion of the present invention, for example, zinc oxide and a pyridonecarboxylic acid compound or a salt thereof are dispersed or dissolved in a solution in which a biodegradable polymer is dissolved in an organic solvent, and this dispersion (this dispersion is also a solution). In a suitable buffer that can be the aqueous phase of the o / w emulsion.
[0027]
The solution in which the biodegradable polymer is dissolved in an organic solvent has different production conditions depending on the mass average molecular weight and composition ratio of the biodegradable polymer (in the case of a copolymer), the type of organic solvent used, etc. The concentration of the biodegradable polymer in the organic solvent solution is about 0.1 to about 80% (w / w), preferably about 1 to about 70% (w / w), more preferably about 2 to about What is necessary is just to manufacture so that it may become 60% (w / w). Next, in the obtained biodegradable polymer organic solvent solution, the pyridonecarboxylic acid compound or a salt thereof and zinc oxide are each used as a powder, or as a solution / dispersion solution produced using an appropriate solvent / dispersion medium. In addition, an organic solvent dispersion containing a pyridonecarboxylic acid compound or a salt thereof, a biodegradable polymer and zinc oxide may be produced.
[0028]
The addition amount of the pyridonecarboxylic acid compound or a salt thereof is 0.1 to 50% (w / w) by weight, preferably 1 to 30% (w / w), more preferably, with respect to the biodegradable polymer. May be 3 to 20% (w / w), and the addition amount of zinc oxide is 5 to 300% (w / w), preferably 10 to the pyridonecarboxylic acid compound or a salt thereof. ˜200% (w / w), more preferably 20˜100% (w / w).
The obtained organic solvent dispersion becomes an oil phase of an o / w emulsion, and water or an appropriate aqueous solution (for example, an aqueous sugar solution such as glucose, lactose, sucrose, glycerin, propylene glycol, etc.) In the polyhydric alcohol aqueous solution, physiological saline, buffer solution, etc.), the o / w emulsion of the present invention can be produced. In the present invention, a buffer solution is preferred as the aqueous phase. Buffers include ascorbic acid, magnesium L-aspartate, aminoethylsulfonic acid, L-arginine, benzoic acid, sodium benzoate, epsilon-aminocaproic acid, ammonium chloride, potassium chloride, sodium chloride, benzalkonium chloride, hydrochloric acid Arginine, glucosamine hydrochloride, triethanolamine hydrochloride, sodium sulfite, sodium carbonate, hydrochloric acid, citric acid, calcium citrate, sodium citrate, disodium citrate, glycine, calcium gluconate, L-glutamic acid, sodium L-glutamate, creatinine , Chlorobutanol, phosphoric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, potassium dihydrogen phosphate, disodium succinate, acetic acid, potassium acetate Sodium, sodium acetate, diethanolamine, tartaric acid, sodium bicarbonate, triethanolamine, sodium triethanolamine phosphate, trometamol, lactic acid, sodium lactate, 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid, glucose, Examples include a buffer solution prepared by mixing one or more buffering agents selected from the group consisting of boric acid, sodium polyphosphate, maleic acid, sodium metaphosphate, monoethanolamine and dl-malic acid. The pH of the buffer solution is preferably in the range of isoelectric point-2 to isoelectric point + 2 of the pyridone carboxylic acid compound or salt thereof, and is in the range of isoelectric point-1 to isoelectric point + 1. Further preferred. Moreover, as a density | concentration of a buffer solution, 0.0003-0.1 mol / l and 0.001-0.05 mol / l are preferable, and 0.003-0.03 mol / l is still more preferable.
[0029]
Using the obtained o / w emulsion, an organic solvent is removed by using an underwater drying method (o / w method), a phase separation method (coacervation method), a spray drying method, or a method similar thereto. Microcapsules can be produced by washing accordingly. Preferably, it is a method of producing using an underwater drying method (o / w method) or a spray drying method.
When producing microcapsules, it is not preferable that the o / w emulsion is aggregated. Therefore, in order to suppress aggregation, an aggregation inhibitor such as polyvinyl alcohol, lecithin, hydroxypropylmethylcellulose, and nonionic surfactant is used. It is preferable to add an appropriate amount to water or an appropriate aqueous solution that can form the aqueous phase of the o / w emulsion. 0.001-10 mass parts and 0.01-5 mass parts are preferable with respect to 1 mass part of biodegradable polymers, and, as for the addition amount of an aggregation inhibitor, 0.1-2 mass parts is more preferable.
[0030]
The obtained microcapsules can be formulated as various dosage forms as they are or using the microcapsules as a raw material for preparation. Examples of the dosage form include parenteral preparations such as injections, ointments, solutions, suspensions and patches, and oral preparations such as powders, granules, fine granules, tablets and capsules. These preparations may be formulated by known methods using appropriate formulation additives.
[0031]
The microcapsules of the present invention are preferably used as sustained release preparations of the compounds of the general formulas (1) to (4) or salts thereof. Examples of target diseases include periodontal diseases and chronic osteomyelitis, which can obtain merits such as effective therapeutic effects by local administration.
Conventionally, a method for treating periodontal disease is that a doctor, a dentist, or the like administers an antibacterial agent, an antibiotic solution, or an ointment to the affected periodontal pocket (the gap between the teeth and gums). Is made by However, since conventionally used preparations are not sustained-release, patients must go to a doctor, dentist, etc. to receive treatment (medication).
Therefore, if the microcapsules of the present invention are administered for the purpose of treating periodontal disease, not only the therapeutic effect can be improved, but also the patient can benefit.
[0032]
【Example】
Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention should not be limited to these examples.
[0033]
Example 1 Examination of zinc oxide addition
Weigh 3 g of lactic acid-glycolic acid copolymer (PLGA, lactic acid / glycolic acid composition ratio 50:50, mass average molecular weight 7700, Wako Pure Chemical Industries, Ltd.) in a glass vial (
[0034]
About 15 mg of the obtained microcapsules were accurately weighed, 2 ml of dichloromethane was added, and shaken vigorously for 30 seconds. Next, 2 ml of 0.1 mol / l hydrochloric acid was added and shaken vigorously for 30 seconds. A part of the upper layer was taken and 50 times the amount of 0.1 mol / l hydrochloric acid was added to prepare a sample solution. Separately, about 5 mg of levofloxacin was precisely weighed, 10 ml of 0.1 mol / l hydrochloric acid was added and dissolved, 2 ml of dichloromethane was added to 2 ml of this solution, and shaken vigorously for 30 seconds. A part of the upper layer was taken and 50 times the amount of 0.1 mol / l hydrochloric acid was added to obtain a standard solution. The UV absorbance at 293 nm of the sample solution and the standard solution was measured, the drug content in the preparation was determined, and the drug encapsulation efficiency was calculated. The results are shown in Table 1.
[0035]
[Table 1]
Example 2 Examination of buffer concentration as aqueous phase
In a glass vial (
[0037]
[Table 2]
FIG. 1 is a graph showing the state of drug release over time from microcapsules at a buffer concentration of 0.01 mol / l.
[0039]
Example 3 Examination of buffer pH as aqueous phase
In a glass vial (
[0040]
[Table 3]
【The invention's effect】
The present invention provides a stable and sustained release over a long period of time by increasing the uptake rate (drug encapsulation rate) of a pyridonecarboxylic acid compound or a salt thereof into an emulsion or microcapsule and suppressing excessive release at the initial stage of administration, A preparation capable of maintaining a drug concentration in blood and / or an affected area for a long period of time can be provided.
[Brief description of the drawings]
1 shows a graph of the state of drug release over time from microcapsules at a buffer concentration of 0.01 mol / l in Example 2. FIG. The buffer pH is 7.5.
Claims (3)
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| JP2002109585A JP4290381B2 (en) | 2002-04-11 | 2002-04-11 | Emulsion containing pyridonecarboxylic acid compound |
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| JP2002109585A JP4290381B2 (en) | 2002-04-11 | 2002-04-11 | Emulsion containing pyridonecarboxylic acid compound |
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| US7576216B2 (en) | 2004-07-30 | 2009-08-18 | Abbott Laboratories | Preparation of pyridonecarboxylic acid antibacterials |
| WO2006042034A2 (en) | 2004-10-08 | 2006-04-20 | Abbott Laboratories | Salt and crystalline forms thereof of a drug |
| PL1868581T3 (en) * | 2005-04-11 | 2012-08-31 | Abbvie Inc | Pharmaceutical compositions having improved dissolution profiles for poorly soluble drugs |
| US8546423B2 (en) | 2005-05-18 | 2013-10-01 | Mpex Pharmaceuticals, Inc. | Aerosolized fluoroquinolones and uses thereof |
| PT1901749T (en) * | 2005-05-18 | 2016-11-04 | Raptor Pharmaceuticals Inc | Aerosolized fluoroquinolones and uses thereof |
| CN100415212C (en) * | 2006-07-21 | 2008-09-03 | 哈药集团制药总厂 | An oral preparation containing caderofloxacin lactate |
| HUE050147T2 (en) | 2008-10-07 | 2020-11-30 | Horizon Orphan Llc | Inhalation of levofloxacin for reducing lung inflammation |
| MX345158B (en) | 2008-10-07 | 2017-01-18 | Raptor Pharmaceuticals Inc | Aerosol fluoroquinolone formulations for improved pharmacokinetics. |
| US8481526B2 (en) | 2009-03-25 | 2013-07-09 | Bausch & Lomb Incorporated | Fluoroquinolone carboxylic acid molecular crystals |
| AU2010289326B2 (en) | 2009-09-04 | 2015-09-24 | Horizon Therapeutics U.S. Holding Llc | Use of aerosolized levofloxacin for treating cystic fibrosis |
| CN102106842B (en) * | 2009-12-24 | 2014-03-05 | 杭州赛利药物研究所有限公司 | Levofloxacin hydrochloride micropill capsule and preparation method thereof |
| CN102210657B (en) * | 2010-04-01 | 2016-01-20 | 南京长澳医药科技有限公司 | A kind of prulifloxacin tablet and preparation technology thereof |
| CN102417162B (en) * | 2011-08-29 | 2013-06-26 | 浙江金壳生物化学有限公司 | Recycling method of hydrochloric acid-acetic acid waste liquid |
| CN106310286B (en) * | 2016-08-19 | 2020-04-10 | 珠海同源药业有限公司 | Tosufloxacin tosylate composition |
| CN115919761B (en) * | 2023-01-29 | 2023-07-21 | 浙江莎普爱思药业股份有限公司 | Pazufloxacin mesylate liquid preparation and preparation method thereof |
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| DE3033157A1 (en) * | 1980-09-03 | 1982-04-01 | Bayer Ag, 5090 Leverkusen | 7-AMINO-1-CYCLOPROPYL-4-OXO-1,4-DIHYDRO-NAPHTHYRIDINE-3-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE ANTIBACTERIAL AGENTS CONTAINING THEM |
| EP0349428B1 (en) * | 1988-06-30 | 1993-01-20 | Centre National De La Recherche Scientifique (Cnrs) | Process for preparing colloidal dispersive protein systems in the shape of nanoparticles |
| JPH107583A (en) * | 1995-06-27 | 1998-01-13 | Takeda Chem Ind Ltd | Production of sustained-release preparation |
| JP4459315B2 (en) * | 1996-12-20 | 2010-04-28 | 武田薬品工業株式会社 | Manufacturing method of sustained-release preparation |
| ES2388248T3 (en) * | 1997-03-31 | 2012-10-11 | Boston Scientific Scimed Limited | Dosage form comprising taxol in crystalline form |
| DE69838669T2 (en) * | 1997-04-30 | 2008-10-30 | Point Biomedical Corp., San Carlos | MICROPARTICLES, SUITABLE AS A CONTRASTANT IN ULTRASOUND AND FOR ACTIVITY IN THE BLOOD CIRCUIT |
| AU2660599A (en) * | 1998-02-06 | 1999-08-23 | Monsanto Company | Acid-stable and cationic-compatible cellulose compositions and methods of preparation |
| CA2319810C (en) * | 1998-02-10 | 2008-12-23 | Gensia Sicor Inc. | Propofol composition containing sulfite |
| KR20010010393A (en) * | 1999-07-20 | 2001-02-05 | 김윤 | Biodegradable Block Copolymer of Hydrophobic and Hydrophilic Polymers, and Composition for Drug Delivery Comprising Same |
| JP2001316296A (en) * | 2000-02-21 | 2001-11-13 | Takeda Chem Ind Ltd | Controlled release preparation for biologically active compound having poor solubility to water, method for producing the same and use thereof |
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