JPH10152433A - Film-forming antifungal composition - Google Patents
Film-forming antifungal compositionInfo
- Publication number
- JPH10152433A JPH10152433A JP27946497A JP27946497A JPH10152433A JP H10152433 A JPH10152433 A JP H10152433A JP 27946497 A JP27946497 A JP 27946497A JP 27946497 A JP27946497 A JP 27946497A JP H10152433 A JPH10152433 A JP H10152433A
- Authority
- JP
- Japan
- Prior art keywords
- film
- forming
- antifungal
- composition
- agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000012871 anti-fungal composition Substances 0.000 title claims description 44
- 229940121375 antifungal agent Drugs 0.000 claims abstract description 73
- 239000000203 mixture Substances 0.000 claims abstract description 72
- 239000003429 antifungal agent Substances 0.000 claims abstract description 64
- 239000000126 substance Substances 0.000 claims abstract description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 208000010195 Onychomycosis Diseases 0.000 claims abstract description 11
- 201000005882 tinea unguium Diseases 0.000 claims abstract description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 42
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical group CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 24
- 229960005279 amorolfine hydrochloride Drugs 0.000 claims description 19
- 239000004094 surface-active agent Substances 0.000 claims description 15
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims description 13
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 13
- 239000003410 keratolytic agent Substances 0.000 claims description 11
- 239000000080 wetting agent Substances 0.000 claims description 11
- 229920000178 Acrylic resin Polymers 0.000 claims description 10
- 239000004925 Acrylic resin Substances 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 8
- 239000004202 carbamide Substances 0.000 claims description 7
- 229920001577 copolymer Polymers 0.000 claims description 7
- 230000003472 neutralizing effect Effects 0.000 claims description 6
- 229940058015 1,3-butylene glycol Drugs 0.000 claims description 5
- 239000002280 amphoteric surfactant Substances 0.000 claims description 5
- 235000019437 butane-1,3-diol Nutrition 0.000 claims description 5
- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 claims description 5
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 claims description 5
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 229960004889 salicylic acid Drugs 0.000 claims description 4
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 claims description 3
- 239000003945 anionic surfactant Substances 0.000 claims description 3
- 229960001755 resorcinol Drugs 0.000 claims description 3
- 229960004025 sodium salicylate Drugs 0.000 claims description 3
- 229940045136 urea Drugs 0.000 claims description 3
- MQHLMHIZUIDKOO-AYHJJNSGSA-N amorolfine Chemical group C1=CC(C(C)(C)CC)=CC=C1CC(C)CN1C[C@@H](C)O[C@@H](C)C1 MQHLMHIZUIDKOO-AYHJJNSGSA-N 0.000 claims 1
- 241000894007 species Species 0.000 claims 1
- 230000035699 permeability Effects 0.000 abstract description 27
- 210000000434 stratum corneum Anatomy 0.000 abstract description 17
- 210000000282 nail Anatomy 0.000 description 84
- 239000003814 drug Substances 0.000 description 30
- 229940079593 drug Drugs 0.000 description 29
- 239000011248 coating agent Substances 0.000 description 27
- 238000000576 coating method Methods 0.000 description 27
- XZKWIPVTHGWDCF-KUZYQSSXSA-N amorolfine hydrochloride Chemical compound Cl.C1=CC(C(C)(C)CC)=CC=C1CC(C)CN1C[C@@H](C)O[C@@H](C)C1 XZKWIPVTHGWDCF-KUZYQSSXSA-N 0.000 description 26
- 238000012360 testing method Methods 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 17
- 102000011782 Keratins Human genes 0.000 description 16
- 108010076876 Keratins Proteins 0.000 description 16
- 230000035515 penetration Effects 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 13
- 210000000003 hoof Anatomy 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- -1 and specifically Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 230000000843 anti-fungal effect Effects 0.000 description 9
- 230000002209 hydrophobic effect Effects 0.000 description 9
- 230000001186 cumulative effect Effects 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 210000003491 skin Anatomy 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 6
- 229920000742 Cotton Polymers 0.000 description 5
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 description 4
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 4
- 229910002651 NO3 Inorganic materials 0.000 description 4
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 4
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 4
- SYELZBGXAIXKHU-UHFFFAOYSA-N dodecyldimethylamine N-oxide Chemical compound CCCCCCCCCCCC[N+](C)(C)[O-] SYELZBGXAIXKHU-UHFFFAOYSA-N 0.000 description 4
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 4
- 229960002867 griseofulvin Drugs 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000004014 plasticizer Substances 0.000 description 4
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 4
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 229920002126 Acrylic acid copolymer Polymers 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 241000223238 Trichophyton Species 0.000 description 3
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 3
- 238000013329 compounding Methods 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 238000009792 diffusion process Methods 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 3
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- OMNKZBIFPJNNIO-UHFFFAOYSA-N n-(2-methyl-4-oxopentan-2-yl)prop-2-enamide Chemical compound CC(=O)CC(C)(C)NC(=O)C=C OMNKZBIFPJNNIO-UHFFFAOYSA-N 0.000 description 3
- 239000011118 polyvinyl acetate Substances 0.000 description 3
- 229920002689 polyvinyl acetate Polymers 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- 239000001069 triethyl citrate Substances 0.000 description 3
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 3
- 235000013769 triethyl citrate Nutrition 0.000 description 3
- 230000037303 wrinkles Effects 0.000 description 3
- MCCACAIVAXEFAL-UHFFFAOYSA-N 1-[2-(2,4-dichlorophenyl)-2-[(2,4-dichlorophenyl)methoxy]ethyl]imidazole;nitric acid Chemical compound O[N+]([O-])=O.ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 MCCACAIVAXEFAL-UHFFFAOYSA-N 0.000 description 2
- 229940058020 2-amino-2-methyl-1-propanol Drugs 0.000 description 2
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 description 2
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 2
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 description 2
- 206010017533 Fungal infection Diseases 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000007605 air drying Methods 0.000 description 2
- 125000005250 alkyl acrylate group Chemical group 0.000 description 2
- CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 210000003298 dental enamel Anatomy 0.000 description 2
- 210000004207 dermis Anatomy 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000004299 exfoliation Methods 0.000 description 2
- 208000024386 fungal infectious disease Diseases 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000002563 ionic surfactant Substances 0.000 description 2
- 239000004922 lacquer Substances 0.000 description 2
- 150000002646 long chain fatty acid esters Chemical class 0.000 description 2
- 229960005040 miconazole nitrate Drugs 0.000 description 2
- 238000009782 nail-penetration test Methods 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- QJBZDBLBQWFTPZ-UHFFFAOYSA-N pyrrolnitrin Chemical compound [O-][N+](=O)C1=C(Cl)C=CC=C1C1=CNC=C1Cl QJBZDBLBQWFTPZ-UHFFFAOYSA-N 0.000 description 2
- 239000000344 soap Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 238000002834 transmittance Methods 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- GWHCXVQVJPWHRF-KTKRTIGZSA-N (15Z)-tetracosenoic acid Chemical compound CCCCCCCC\C=C/CCCCCCCCCCCCCC(O)=O GWHCXVQVJPWHRF-KTKRTIGZSA-N 0.000 description 1
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 1
- OCAPBUJLXMYKEJ-UHFFFAOYSA-N 1-[biphenyl-4-yl(phenyl)methyl]imidazole Chemical compound C1=NC=CN1C(C=1C=CC(=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 OCAPBUJLXMYKEJ-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N 1-propanol Substances CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 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
- AVPDLWTUGIZJLH-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C([O-])=O.C[NH+](C)CCOC(=O)C(C)=C AVPDLWTUGIZJLH-UHFFFAOYSA-N 0.000 description 1
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- MBRHNTMUYWQHMR-UHFFFAOYSA-N 2-aminoethanol;6-cyclohexyl-1-hydroxy-4-methylpyridin-2-one Chemical compound NCCO.ON1C(=O)C=C(C)C=C1C1CCCCC1 MBRHNTMUYWQHMR-UHFFFAOYSA-N 0.000 description 1
- SUMAWDZJEIQACJ-UHFFFAOYSA-N 2-methylpyridine-4-carbaldehyde Chemical compound CC1=CC(C=O)=CC=N1 SUMAWDZJEIQACJ-UHFFFAOYSA-N 0.000 description 1
- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 description 1
- SODWJACROGQSMM-UHFFFAOYSA-N 5,6,7,8-tetrahydronaphthalen-1-amine Chemical compound C1CCCC2=C1C=CC=C2N SODWJACROGQSMM-UHFFFAOYSA-N 0.000 description 1
- 101000773908 Archaeoglobus fulgidus (strain ATCC 49558 / DSM 4304 / JCM 9628 / NBRC 100126 / VC-16) Acetate-CoA ligase [ADP-forming] II Proteins 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical class NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- WHPAGCJNPTUGGD-UHFFFAOYSA-N Croconazole Chemical compound ClC1=CC=CC(COC=2C(=CC=CC=2)C(=C)N2C=NC=C2)=C1 WHPAGCJNPTUGGD-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 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 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- UNXHWFMMPAWVPI-QWWZWVQMSA-N D-threitol Chemical compound OC[C@@H](O)[C@H](O)CO UNXHWFMMPAWVPI-QWWZWVQMSA-N 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 229930091371 Fructose Natural products 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
- 241000282412 Homo Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010067125 Liver injury Diseases 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
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- UGGAILYEBCSZIV-ITJSPEIASA-N Siccanin Chemical compound C1CCC(C)(C)[C@@H]2CC[C@]3(C)OC4=CC(C)=CC(O)=C4[C@H]4[C@@H]3[C@@]21CO4 UGGAILYEBCSZIV-ITJSPEIASA-N 0.000 description 1
- UGGAILYEBCSZIV-UHFFFAOYSA-N Siccanin Natural products C1CCC(C)(C)C2CCC3(C)OC4=CC(C)=CC(O)=C4C4C3C21CO4 UGGAILYEBCSZIV-UHFFFAOYSA-N 0.000 description 1
- CRKGMGQUHDNAPB-UHFFFAOYSA-N Sulconazole nitrate Chemical compound O[N+]([O-])=O.C1=CC(Cl)=CC=C1CSC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 CRKGMGQUHDNAPB-UHFFFAOYSA-N 0.000 description 1
- 208000002474 Tinea Diseases 0.000 description 1
- 241000130764 Tinea Species 0.000 description 1
- SLINHMUFWFWBMU-UHFFFAOYSA-N Triisopropanolamine Chemical compound CC(O)CN(CC(C)O)CC(C)O SLINHMUFWFWBMU-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- FJWGYAHXMCUOOM-QHOUIDNNSA-N [(2s,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6s)-4,5-dinitrooxy-2-(nitrooxymethyl)-6-[(2r,3r,4s,5r,6s)-4,5,6-trinitrooxy-2-(nitrooxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-3,5-dinitrooxy-6-(nitrooxymethyl)oxan-4-yl] nitrate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](O[N+]([O-])=O)[C@H]1O[N+]([O-])=O)O[C@H]1[C@@H]([C@@H](O[N+]([O-])=O)[C@H](O[N+]([O-])=O)[C@@H](CO[N+]([O-])=O)O1)O[N+]([O-])=O)CO[N+](=O)[O-])[C@@H]1[C@@H](CO[N+]([O-])=O)O[C@@H](O[N+]([O-])=O)[C@H](O[N+]([O-])=O)[C@H]1O[N+]([O-])=O FJWGYAHXMCUOOM-QHOUIDNNSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001139 anti-pruritic effect Effects 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000003908 antipruritic agent Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- 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 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 229960002206 bifonazole Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229960003273 butenafine hydrochloride Drugs 0.000 description 1
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229960004375 ciclopirox olamine Drugs 0.000 description 1
- 229960004022 clotrimazole Drugs 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 229960002042 croconazole Drugs 0.000 description 1
- DNTGGZPQPQTDQF-XBXARRHUSA-N crotamiton Chemical compound C/C=C/C(=O)N(CC)C1=CC=CC=C1C DNTGGZPQPQTDQF-XBXARRHUSA-N 0.000 description 1
- 229960003338 crotamiton Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229940105990 diglycerin Drugs 0.000 description 1
- GPLRAVKSCUXZTP-UHFFFAOYSA-N diglycerol Chemical compound OCC(O)COCC(O)CO GPLRAVKSCUXZTP-UHFFFAOYSA-N 0.000 description 1
- 229940031578 diisopropyl adipate Drugs 0.000 description 1
- 229940031569 diisopropyl sebacate Drugs 0.000 description 1
- XFKBBSZEQRFVSL-UHFFFAOYSA-N dipropan-2-yl decanedioate Chemical compound CC(C)OC(=O)CCCCCCCCC(=O)OC(C)C XFKBBSZEQRFVSL-UHFFFAOYSA-N 0.000 description 1
- 229940113120 dipropylene glycol Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- GMSCBRSQMRDRCD-UHFFFAOYSA-N dodecyl 2-methylprop-2-enoate Chemical compound CCCCCCCCCCCCOC(=O)C(C)=C GMSCBRSQMRDRCD-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229960003645 econazole nitrate Drugs 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 229950010333 exalamide Drugs 0.000 description 1
- CKSJXOVLXUMMFF-UHFFFAOYSA-N exalamide Chemical compound CCCCCCOC1=CC=CC=C1C(N)=O CKSJXOVLXUMMFF-UHFFFAOYSA-N 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 210000004904 fingernail bed Anatomy 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 229960004007 isoconazole nitrate Drugs 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 150000002711 medium chain fatty acid esters Chemical class 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- XJRBAMWJDBPFIM-UHFFFAOYSA-N methyl vinyl ether Chemical compound COC=C XJRBAMWJDBPFIM-UHFFFAOYSA-N 0.000 description 1
- YWFWDNVOPHGWMX-UHFFFAOYSA-N n,n-dimethyldodecan-1-amine Chemical compound CCCCCCCCCCCCN(C)C YWFWDNVOPHGWMX-UHFFFAOYSA-N 0.000 description 1
- 229960004313 naftifine Drugs 0.000 description 1
- OZGNYLLQHRPOBR-DHZHZOJOSA-N naftifine Chemical compound C=1C=CC2=CC=CC=C2C=1CN(C)C\C=C\C1=CC=CC=C1 OZGNYLLQHRPOBR-DHZHZOJOSA-N 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- KSCKTBJJRVPGKM-UHFFFAOYSA-N octan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-] KSCKTBJJRVPGKM-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 229960004031 omoconazole Drugs 0.000 description 1
- JMFOSJNGKJCTMJ-ZHZULCJRSA-N omoconazole Chemical compound C1=CN=CN1C(/C)=C(C=1C(=CC(Cl)=CC=1)Cl)\OCCOC1=CC=C(Cl)C=C1 JMFOSJNGKJCTMJ-ZHZULCJRSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960003483 oxiconazole Drugs 0.000 description 1
- QRJJEGAJXVEBNE-MOHJPFBDSA-N oxiconazole Chemical compound ClC1=CC(Cl)=CC=C1CO\N=C(C=1C(=CC(Cl)=CC=1)Cl)\CN1C=NC=C1 QRJJEGAJXVEBNE-MOHJPFBDSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000036211 photosensitivity Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 229960002132 pyrrolnitrin Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229950008379 siccanin Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940080236 sodium cetyl sulfate Drugs 0.000 description 1
- GGHPAKFFUZUEKL-UHFFFAOYSA-M sodium;hexadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCOS([O-])(=O)=O GGHPAKFFUZUEKL-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 229960004718 sulconazole nitrate Drugs 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 description 1
- 229960000699 terbinafine hydrochloride Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 201000004647 tinea pedis Diseases 0.000 description 1
- 229960004880 tolnaftate Drugs 0.000 description 1
- FUSNMLFNXJSCDI-UHFFFAOYSA-N tolnaftate Chemical compound C=1C=C2C=CC=CC2=CC=1OC(=S)N(C)C1=CC=CC(C)=C1 FUSNMLFNXJSCDI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
(57)【要約】
【課題】 抗真菌剤の放出性及び角質層や爪に対する浸
透性が高い被膜を形成することができ、白癬症特に爪白
癬症の治療に有効な被膜形成性抗真菌剤組成物を提供す
る。
【解決手段】 親水性被膜形成物質、抗真菌剤及び水を
含有することを特徴とする。PROBLEM TO BE SOLVED: To provide a film-forming antifungal agent which is capable of forming a film having a high release property of an antifungal agent and a high permeability to the stratum corneum and nails, and which is effective for the treatment of tinea unguium, especially tinea unguium. A composition is provided. SOLUTION: It contains a hydrophilic film-forming substance, an antifungal agent and water.
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、爪及びその周辺の
真菌症の治療のための被膜形成性抗真菌剤組成物、特
に、被膜からの抗真菌剤の放出性及び角質層への浸透性
の改良に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a film-forming antifungal composition for the treatment of mycosis in and around the nail, and more particularly, to the release of the antifungal agent from the film and the penetration into the stratum corneum. Regarding improvement.
【０００２】[0002]
【従来の技術】従来、皮膚科領域における真菌症の治
療、特に爪白癬は外用剤による局所治療が困難であるこ
とが知られている。これは爪の角質層内部に繁殖してい
る白癬菌を局所的に外用剤を用いることにより処置しよ
うとしても、元々爪は外部からの異物の侵入に対する障
壁としての機能が大であり、角質層中へ抗真菌剤が浸透
しにくいことに起因する。従って、クリームや軟膏では
治療が極めて困難であり、爪白癬の治療法としてはグリ
セオフルビンの内服療法が一般的であった。2. Description of the Related Art It has been known that treatment of mycosis in the field of dermatology, in particular, tinea unguium, is difficult to locally treat with an external preparation. This is because even if an attempt is made to treat Trichophyton growing in the stratum corneum of the nail locally using an external preparation, the nail originally functions as a barrier against invasion of foreign substances from the outside. This is because the antifungal agent hardly penetrates the inside. Therefore, it is extremely difficult to treat with creams and ointments, and oral treatment with griseofulvin is generally used as a treatment for tinea unguium.
【０００３】しかしながら、グリセオフルビンの内服療
法には光過敏症、胃部不快感、腎臓障害、肝臓障害等の
副作用を生じることがあり、また、グリセオフルビン抵
抗性の菌株が存在すること、長期にわたる内服が必要で
あることなど、問題点が多い。また、外科的手法として
爪内部に存在する真菌を爪ごと除去する爪剥離手術が行
われる場合もある。しかし、爪白癬症の爪はもろく、患
部爪の破片が残る傾向にあり、治癒が完全でない。なに
より、この処置法は過激であり、また、治療後再生した
爪が感染していないという保証はない。[0003] However, oral treatment with griseofulvin may cause side effects such as photosensitivity, gastric discomfort, kidney damage, and liver damage. In addition, the existence of griseofulvin-resistant strains and the prolonged use of oral griseofulvin. There are many problems such as necessity. In addition, as a surgical technique, nail exfoliation surgery for removing fungi present inside the nail together with the nail may be performed. However, nails with tinea unguium tend to be brittle, tend to have fragments of the affected nail, and are not completely healed. Above all, this procedure is extreme and there is no guarantee that the regenerated nails will not be infected after treatment.
【０００４】こうした現状に対して、最近抗真菌剤によ
る外用療法の改善が試みられている。すなわち、従来か
らのクリームや軟膏基剤に代わって、爪に対して付着性
がよくコンプライアンスの高いネイルラッカー製剤やネ
イルエナメル製剤、マニキュア製剤等の被膜形成性組成
物が開発されている。[0004] Under these circumstances, attempts have recently been made to improve topical therapies with antifungal agents. That is, instead of conventional cream or ointment bases, film-forming compositions such as nail lacquer preparations, nail enamel preparations, and nail polish preparations having high adherence to nails and high compliance have been developed.
【０００５】例えば、特開平１−１１０６２０号公報に
は抗真菌剤とポリ酢酸ビニル、長鎖脂肪酸エステル、高
級アルコール、揮発性溶媒よりなる組成物が、特開平２
−２７９６２３号公報には抗真菌剤とポリ酢酸ビニル、
長鎖脂肪酸エステル、高級アルコール、多価アルコー
ル、溶媒よりなる組成物が、特開平１−１４９７２２号
公報にはトルナフテートと、メタクリル酸ジメチルアミ
ノエチル・メタクリル酸エステル共重合体、中鎖脂肪酸
エステル、アルコール系溶媒を含有する実質的に水を含
まない組成物が、特開平６−２１１６５１号公報には硝
酸オモコナゾール又は塩酸ブテナフィンを疎水性被膜形
成剤及び溶媒からなる基剤に配合した組成物が、特開平
７−２７７９７５号公報には２種以上の水溶性の低い被
膜形成物質、水、可塑剤、抗真菌剤及びアルコールを含
有する組成物等が開示されている。これらのネイルラッ
カー製剤やネイルエナメル製剤は、何れも被膜強度や耐
水性を得るために被膜形成物質として水不溶性（疎水
性）の被膜形成剤を用いるものであった。[0005] For example, JP-A-1-110620 discloses a composition comprising an antifungal agent and polyvinyl acetate, a long-chain fatty acid ester, a higher alcohol and a volatile solvent.
-279623 discloses an antifungal agent and polyvinyl acetate,
JP-A-1-149722 discloses a composition comprising a long-chain fatty acid ester, a higher alcohol, a polyhydric alcohol, and a solvent, which is disclosed in Japanese Patent Application Laid-Open No. 1-149722, with a copolymer of dimethylaminoethyl methacrylate-methacrylic acid ester, a medium-chain fatty acid ester, and an alcohol. Japanese Patent Application Laid-Open No. 6-211651 discloses a composition containing a system solvent and containing substantially no water, and a composition in which omoconazole nitrate or butenafine hydrochloride is blended with a base comprising a hydrophobic film-forming agent and a solvent. JP-A-7-277975 discloses a composition containing two or more kinds of film-forming substances having low water solubility, water, a plasticizer, an antifungal agent and an alcohol. Each of these nail lacquer preparations and nail enamel preparations uses a water-insoluble (hydrophobic) film-forming agent as a film-forming substance in order to obtain film strength and water resistance.
【０００６】[0006]
【発明が解決しようとする課題】しかしながら、このよ
うな水不溶性（疎水性）の被膜形成物質を用いた組成物
を爪に塗布した場合、塗布面上に形成された被膜中の網
状組織が抗真菌剤の被膜中での拡散を抑制し、被膜から
の抗真菌剤の放出や角質層への浸透が十分でないという
問題点があった。また、組成物中に用いられるアセトン
や酢酸エチル、トルエン等の有機溶剤は爪を脱水し、爪
を硬化させて抗真菌剤の浸透を遅くすることが知られて
いる。さらに、このような組成物を重ね塗りした際には
前に塗布した被膜の蓄積が新たに塗布した被膜中の抗真
菌剤の浸透の妨げ、継続的に使用しても十分な効果を得
ることができない。However, when a composition using such a water-insoluble (hydrophobic) film-forming substance is applied to a nail, the network in the film formed on the application surface has an adverse effect. There is a problem that the diffusion of the fungal agent in the coating is suppressed, and the release of the antifungal agent from the coating and the penetration into the stratum corneum are not sufficient. It is also known that organic solvents such as acetone, ethyl acetate, and toluene used in the composition dehydrate the nails, harden the nails and slow the penetration of the antifungal agent. Furthermore, when such a composition is overcoated, the accumulation of the previously applied film prevents the penetration of the antifungal agent into the newly applied film, and a sufficient effect can be obtained even when used continuously. Can not.
【０００７】一方、特開平１−１１０６２０号公報や特
開平２−２７９６２３号公報にはポリ酢酸ビニルを被膜
形成剤としたピールオフタイプの抗真菌剤組成物が報告
されているが、このようなピールオフタイプの組成物は
古くなった被膜を簡単にはがすことができるために重ね
塗りの問題はなく、常に新しい被膜を患部に接触させて
おくことができるものの、ピールオフ被膜は剥離の必要
性から爪に対する接着性が低いため、凹凸のある爪面上
に密着して被膜を形成することが難しく、このため被膜
からの抗真菌剤の放出や角質層への移行が十分に行われ
ないという問題点があった。本発明は前記従来技術の課
題に鑑みなされたものであり、その目的は被膜からの抗
真菌剤の放出性及び角質層への浸透性に優れ、白癬症特
に爪白癬の治療に効果的な被膜形成性抗真菌剤組成物を
提供することにある。On the other hand, in JP-A-1-110620 and JP-A-2-279623, a peel-off type antifungal composition using polyvinyl acetate as a film-forming agent is reported. This type of composition can easily remove the old film, so there is no problem of recoating.Although the new film can be kept in contact with the affected area at all times, the peel-off film needs to be peeled off from the nails. Due to the low adhesiveness, it is difficult to form a coating on the uneven nail surface, and the release of the antifungal agent from the coating and transfer to the stratum corneum are not performed sufficiently. there were. SUMMARY OF THE INVENTION The present invention has been made in view of the above-mentioned problems of the prior art, and has as its object an excellent release of an antifungal agent from a coating and excellent penetration into a stratum corneum, and an effective coating for the treatment of tinea unguium, especially tinea unguium It is an object of the present invention to provide a composition for forming fungi.
【０００８】[0008]
【課題を解決するための手段】前記目的を達成するため
に本発明者らが鋭意検討を進めた結果、被膜形成剤とし
て親水性の被膜形成物質を用い、この親水性被膜形成物
質とともに抗真菌剤及び水を配合した被膜形成性抗真菌
剤組成物が、患部に塗布することによって抗真菌剤の放
出性及び角質層への浸透性に非常に優れた被膜を形成す
ることを見出し、本発明を完成するに至った。すなわ
ち、本発明に係る被膜形成性抗真菌剤組成物は、親水性
被膜形成物質、抗真菌剤及び水を含有することを特徴と
する。Means for Solving the Problems As a result of intensive studies conducted by the present inventors to achieve the above object, a hydrophilic film-forming substance was used as a film-forming agent, and an antifungal was used together with the hydrophilic film-forming substance. The present invention has been found that a film-forming antifungal agent composition containing an antifungal agent and water forms a film having excellent release properties of the antifungal agent and excellent penetration into the stratum corneum by being applied to an affected area. Was completed. That is, the film-forming antifungal composition according to the present invention is characterized by containing a hydrophilic film-forming substance, an antifungal agent and water.
【０００９】なお、前記親水性被膜形成物質は室温で
０．１w/v％以上の濃度で水に溶解する物質であること
が好適であり、好ましくは０．５w/v％以上、さらに好
ましくは１．０w/v％以上の濃度で水に溶解する物質で
あることが好適である。特に、アクリル樹脂のアルカノ
ールアミン中和液、ポリビニルピロリドン、メトキシエ
チレン無水マレイン酸共重合体、コポリビドンから選ば
れる少なくとも１種以上の物質であることが好適であ
り、中でもアクリル樹脂のアルカノールアミン中和液が
好適である。The hydrophilic film-forming substance is preferably a substance that is soluble in water at room temperature at a concentration of 0.1 w / v% or more, preferably 0.5 w / v% or more, and more preferably 0.5 w / v% or more. It is preferable that the substance be soluble in water at a concentration of 1.0 w / v% or more. In particular, it is preferable that the alkanolamine neutralized solution of the acrylic resin, polyvinylpyrrolidone, methoxyethylene maleic anhydride copolymer, at least one or more substances selected from copolyvidone, and especially the alkanolamine neutralized solution of the acrylic resin Is preferred.
【００１０】また、本発明の被膜形成性抗真菌剤組成物
においては、低級アルコールを配合することが好適であ
り、低級アルコールとしてはエタノール及び／又はイソ
プロピルアルコールが好適である。また、本発明の被膜
形成性抗真菌剤組成物においては、湿潤剤を配合するこ
とが好適であり、前記湿潤剤としては特にプロピレング
リコール、ジプロピレングリコール、１，３−ブチレン
グリコールから選ばれる少なくとも１種以上であること
が好適である。[0010] Further, in the film-forming antifungal composition of the present invention, it is preferable to mix a lower alcohol, and as the lower alcohol, ethanol and / or isopropyl alcohol are preferable. Further, in the film-forming antifungal composition of the present invention, it is preferable to add a wetting agent, and the wetting agent is at least selected from propylene glycol, dipropylene glycol and 1,3-butylene glycol. It is preferable that at least one kind is used.
【００１１】また、本発明の被膜形成性抗真菌剤組成物
においては、角質溶解剤を配合することが好適であり、
前記角質溶解剤としては尿素、サリチル酸、サリチル酸
ナトリウム、レゾルシンから選ばれる少なくとも１種以
上であることが好適である。また、本発明の被膜形成性
抗真菌剤組成物においては、界面活性剤を配合すること
が好適であり、前記界面活性剤としてはアニオン性界面
活性剤の１種以上と両性界面活性剤の１種以上の組み合
わせであることが好適である。[0011] In the film-forming antifungal composition of the present invention, it is preferable to add a keratolytic agent.
The keratolytic agent is preferably at least one selected from urea, salicylic acid, sodium salicylate, and resorcinol. Further, in the film-forming antifungal composition of the present invention, it is preferable to add a surfactant, and as the surfactant, one or more anionic surfactants and one or more amphoteric surfactants are used. It is preferable that the combination is a combination of more than one kind.
【００１２】また、本発明の被膜形成性抗真菌剤組成物
においては、抗真菌剤が塩酸アモロルフィンであること
が好適である。また、本発明に係る被膜形成性抗真菌剤
組成物は非ピールオフタイプであることが好適である。
また、本発明に係る爪白癬治療剤は、前記何れかに記載
の被膜形成性抗真菌剤組成物からなることを特徴とす
る。In the film-forming antifungal composition of the present invention, the antifungal is preferably amorolfine hydrochloride. Further, the film-forming antifungal composition according to the present invention is preferably of a non-peel-off type.
Further, a therapeutic agent for tinea unguium according to the present invention is characterized by comprising the film-forming antifungal composition according to any of the above.
【００１３】[0013]
【発明の実施の形態】本発明において用いられる親水性
の被膜形成物質とは、水に対しある程度の溶解度を有す
るものであり、具体的には室温で０．１w/v％以上の濃
度で水に溶解するものを意味する。なお、好ましくは
０．５w/v％以上、特に好ましくは１．０w/v％以上の溶
解度を有するものである。BEST MODE FOR CARRYING OUT THE INVENTION The hydrophilic film-forming substance used in the present invention has a certain degree of solubility in water, and specifically, water at a concentration of 0.1 w / v% or more at room temperature. Means to be dissolved in It should be noted that the solvent preferably has a solubility of 0.5 w / v% or more, particularly preferably 1.0 w / v% or more.
【００１４】そして、本発明で用いる親水性被膜形成物
質としては、被膜形成性抗真菌剤組成物を爪等の患部に
塗布した場合に溶媒の揮発に伴って水分を包含した状態
で被膜を形成するものであって、該被膜がべたつきや他
の接触物に付着することが極めて少ない被膜であるこ
と、しかも、汗等により吸湿して被膜自体が膨潤した
り、破損・剥離したり、容易に流されたりということが
ないものが好ましい。このような被膜形成物質として
は、例えば、アクリル樹脂のアルカノールアミン中和液
（例えば、アクリル酸アルキルエステル・メタクリル酸
アルキルエステル・ジアセトンアクリルアミド・アクリ
ル酸・メタクリル酸共重合体の２−アミノ−２−メチル
−１−プロパノール中和液）や、ポリビニルピロリド
ン、メトキシエチレン無水マレイン酸共重合体（例え
ば、メチルビニルエーテル・無水マレイン酸の共重合
体）、コポリビドン（例えば、ポリビニルピロリドン・
ビニルアセテート（６０：４０）の共重合体）等から選
ばれる１種又は２種以上の被膜形成物質が挙げられる。
このうち、特に好ましいものはアクリル樹脂のアルカノ
ールアミン中和液である。As the hydrophilic film-forming substance used in the present invention, when a film-forming antifungal agent composition is applied to an affected area such as a nail, a film is formed in a state where water is included as the solvent volatilizes. The film is a film that adheres very little to sticky or other contact objects.Moreover, the film itself swells due to moisture absorption by sweat or the like, or is easily broken or peeled off. Those that are not washed away are preferred. As such a film-forming substance, for example, an alkanolamine neutralizing solution of an acrylic resin (for example, an alkyl acrylate / alkyl methacrylate / diacetone acrylamide / acrylic acid / methacrylic acid copolymer 2-amino-2) -Methyl-1-propanol neutralized solution), polyvinylpyrrolidone, methoxyethylene maleic anhydride copolymer (e.g., methyl vinyl ether / maleic anhydride copolymer), copolyvidone (e.g., polyvinyl pyrrolidone
One or more film-forming substances selected from vinyl acetate (copolymer of 60:40).
Of these, particularly preferred is an alkanolamine neutralized solution of an acrylic resin.
【００１５】前記のアクリル樹脂のアルカノールアミン
中和液はアクリル樹脂中に存在しているカルボキシル基
をアルカノールアミンにより中和したものである。アク
リル樹脂としてはアクリル酸アルキルエステル・メタク
リル酸アルキルエステル・ジアセトンアクリルアミド・
アクリル酸・メタクリル酸共重合体が好ましく、特にア
クリル酸ブチルエステル・メタクリル酸ラウリルエステ
ル・ジアセトンアクリルアミド・アクリル酸・メタクリ
ル酸共重合体が好適である。The alkanolamine neutralizing solution of the acrylic resin is obtained by neutralizing a carboxyl group present in the acrylic resin with an alkanolamine. As acrylic resin, alkyl acrylate, alkyl methacrylate, diacetone acrylamide,
Acrylic acid / methacrylic acid copolymer is preferred, and butyl acrylate / lauryl methacrylate / diacetone acrylamide / acrylic acid / methacrylic acid copolymer is particularly preferred.
【００１６】また、アルカノールアミンとしては特に限
定されないが２−アミノ−２−メチル−１，３−プロパ
ンジオール、２−アミノ−２−メチル−１−プロパノー
ル、トリエタノールアミン、トリイソプロパノールアミ
ン等が挙げられ、好ましくは２−アミノ−２−メチル−
１，３−プロパンジオール、２−アミノ−２−メチル−
１−プロパノールである。なお、前記アルカノールアミ
ンは１種又は２種以上を用いて中和してもよい。The alkanolamine is not particularly restricted but includes 2-amino-2-methyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, triethanolamine, triisopropanolamine and the like. And preferably 2-amino-2-methyl-
1,3-propanediol, 2-amino-2-methyl-
1-propanol. The alkanolamine may be neutralized by using one or more kinds.
【００１７】本発明で用いられるアクリル樹脂のアルカ
ノールアミン中和液としては、例えば、プラスサイズＬ
−５３Ｐ、プラスサイズＬ−３３Ｄ、プラスサイズＬ−
５３Ｄ（互応化学工業社製）等が好適に用いられる。本
発明において用いられる親水性の被膜形成物質の配合量
は組成物全量中、１〜３０w/v％、好ましくは２〜２０w
/v％、特に好ましくは３〜１５w/v％である。親水性被
膜形成物質の配合量が少ないと十分な被膜形成が成され
ず、また、被膜形成物質の配合量が多すぎると被膜中の
抗真菌剤の濃度が相対的に低くなり、好ましくない。The alkanolamine neutralizing solution of the acrylic resin used in the present invention includes, for example, Plus Size L
-53P, plus size L-33D, plus size L-
53D (manufactured by Goyo Chemical Industry Co., Ltd.) or the like is preferably used. The amount of the hydrophilic film-forming substance used in the present invention is 1 to 30 w / v%, preferably 2 to 20 w /% of the total amount of the composition.
/ v%, particularly preferably 3 to 15 w / v%. If the amount of the hydrophilic film-forming substance is too small, a sufficient film cannot be formed, and if the amount of the film-forming substance is too large, the concentration of the antifungal agent in the film becomes relatively low, which is not preferable.
【００１８】本発明の有効成分である抗真菌剤として
は、例えば塩酸アモロルフィン、塩酸テルビナフィン、
硝酸ミコナゾール、硝酸イソコナゾール、硝酸スルコナ
ゾール、硝酸オキシコナゾール、硝酸エコナゾール、硝
酸クロコナゾール、硝酸ナチコナゾール、トルナフター
ト、トルシクラート、リラナフタート、クロトリマゾー
ル、チオコナゾール、ビフォナゾール、ケトコナゾー
ル、シッカニン、ピロールニトリン、グリセオフルビ
ン、ウンデシレン酸、フルコナゾール、イトラコナゾー
ル、ナフチフィン、シクロピロックスオラミン、エキサ
ラミド等から選ばれる１種又は２種以上の抗真菌剤が挙
げられる。これらは塩酸塩、硝酸塩等の塩として用いる
のが好ましい。なお、被膜形成物質との相性等から、特
に好ましい抗真菌剤としては塩酸アモロルフィンが挙げ
られる。Examples of the antifungal agent as the active ingredient of the present invention include amorolfine hydrochloride, terbinafine hydrochloride,
Miconazole nitrate, isoconazole nitrate, sulconazole nitrate, oxyconazole nitrate, econazole nitrate, croconazole nitrate, naticonazole nitrate, tolnaftate, tolcyclate, rilanaftate, clotrimazole, thioconazole, bifonazole, ketoconazole, siccanin, pyrrolnitrin, griseofulin undeline And one or more antifungal agents selected from fluconazole, itraconazole, naftifine, ciclopirox olamine, exalamide and the like. These are preferably used as salts such as hydrochloride and nitrate. Amorolfine hydrochloride is particularly preferred as an antifungal agent in view of compatibility with the film-forming substance.
【００１９】本発明の被膜形成性抗真菌剤組成物におい
て、抗真菌剤の配合量は組成物全量に対して０．１〜１
０w/v％、好ましくは０．５〜８w/v％、特に好ましくは
１〜６w/v％である。抗真菌剤の配合量が少ないと十分
な抗菌活性が得られず、多すぎる場合には経済的な問題
や、安全性の問題、また、結晶の析出等安定性の問題等
を生じることがあるので好ましくない。本発明の必須成
分の一つである水の配合量は組成物全量に対して１〜３
０w/v％、好ましくは２〜１５w/v％、特に好ましくは３
〜１０w/v％である。水の配合量が少ないと爪や皮膚に
対する十分な柔軟効果や被膜からの抗真菌剤の放出性や
角質層への浸透性が十分に得られない。また、水が多す
ぎる場合には被膜が乾きにくく、また、抗真菌剤の溶解
性が悪くなるため、好ましくない。In the film-forming antifungal composition of the present invention, the amount of the antifungal agent is 0.1 to 1 with respect to the total amount of the composition.
0 w / v%, preferably 0.5 to 8 w / v%, particularly preferably 1 to 6 w / v%. If the amount of the antifungal agent is too small, sufficient antibacterial activity cannot be obtained.If the amount is too large, an economical problem, a safety problem, or a problem of stability such as precipitation of crystals may occur. It is not preferable. The amount of water, which is one of the essential components of the present invention, is 1 to 3 with respect to the total amount of the composition.
0 w / v%, preferably 2 to 15 w / v%, particularly preferably 3 w / v%
-10 w / v%. If the amount of water is small, a sufficient softening effect on nails and skin, release of an antifungal agent from a coating film, and permeability into a stratum corneum cannot be sufficiently obtained. On the other hand, if the amount of water is too large, it is not preferable because the coating film is difficult to dry and the solubility of the antifungal agent deteriorates.
【００２０】上記必須成分を含有するので、本発明の被
膜形成性抗真菌剤組成物を爪やその周辺の皮膚等に塗布
すれば、溶媒の揮発に伴って該被膜中に抗真菌剤及び水
を包含しながら被膜が形成される。本発明の被膜形成性
抗真菌剤組成物は患部に塗布した後に形成されるこの親
水性被膜に特徴がある。Since the above-mentioned essential components are contained, if the film-forming antifungal composition of the present invention is applied to nails and the skin around the nails, the antifungal agent and water are contained in the film as the solvent evaporates. The coating is formed while including the following. The film-forming antifungal composition of the present invention is characterized by this hydrophilic film formed after being applied to an affected area.
【００２１】従来のように疎水性の被膜形成性物質を用
いた場合には、塗布面上に疎水性被膜が形成されるが、
疎水性被膜中では抗真菌剤の拡散が起こりにくく、ま
た、疎水性被膜は爪等に対して親和性が低く、場合によ
っては爪を脱水することもあり、角質層の膨潤が十分行
われない。このため、被膜中の抗真菌剤は角質層へ十分
に浸透することができない。特開平１−１１０６２０及
び特開平７−２７７９７５には、水を組成物中に配合す
る被膜形成性抗真菌剤組成物も報告されているが、何れ
も被膜形成物質として水溶性の低い（疎水性の）被膜形
成物質を用いているために、角質層への浸透性に問題が
あった。When a hydrophobic film-forming substance is used as in the prior art, a hydrophobic film is formed on the coated surface.
The diffusion of the antifungal agent hardly occurs in the hydrophobic film, and the hydrophobic film has low affinity for nails and the like, and in some cases, dehydrates the nails, so that the stratum corneum does not swell sufficiently . Therefore, the antifungal agent in the coating cannot penetrate the stratum corneum sufficiently. JP-A-1-110620 and JP-A-7-277975 also report a film-forming antifungal composition in which water is incorporated into the composition, but all of them have low water solubility (hydrophobicity) as a film-forming substance. However, there is a problem in permeability into the stratum corneum due to the use of a film-forming substance.
【００２２】また、特開平１−１１０６２０の酢酸ビニ
ルを被膜形成物質としたピールオフタイプの被膜形成性
抗真菌剤組成物では、後に剥がすピールオフタイプであ
ることから爪に対する接着性が劣っており、前述のよう
に凹凸のある爪面上に密着した被膜を形成することが難
しく、やはり十分な抗真菌剤の浸透性は得られなかっ
た。In addition, the peel-off type film-forming antifungal composition using vinyl acetate as a film-forming substance disclosed in JP-A-1-110620 has poor adhesion to nails because it is a peel-off type that is peeled off later. Thus, it was difficult to form a tightly adhered film on the uneven nail surface, and sufficient antifungal permeability could not be obtained.
【００２３】これに対して、本発明の被膜形成性抗真菌
剤組成物においては親水性の被膜形成物質を用いること
により、抗真菌剤の放出性や角質層への浸透性を著しく
改善することができる。すなわち、本発明の親水性被膜
は爪や皮膚に対して親和性、密着性が非常に高く、容易
にはがれることがないために、該被膜中からの抗真菌剤
の放出性や角質層に対する浸透性が高い。さらに、患部
が親水性被膜に覆われるため、いわゆるＯＤＴ法（密封
包帯法）での適用であると同時に、被膜自身が親水性で
且つ水分も包含しているため、固い爪甲も十分な保湿作
用を受けて膨潤し、抗真菌剤が被膜から爪に非常に移行
しやすい状態とすることができるので、抗真菌剤の浸透
が促進される。そして、該親水性被膜の患部に接触して
いる部分の抗真菌剤が爪に移行すると、膜中の抗真菌剤
が爪の方へと移行し、徐々に患部に抗真菌剤が浸透し
て、角質層中における高い抗真菌剤濃度を得ることがで
きるものと考えられる。また、本発明の親水性被膜は乾
燥後はべとついたり、接触物に対して付着することがな
いので、衣服等を汚さない。On the other hand, in the film-forming antifungal composition of the present invention, by using a hydrophilic film-forming substance, the releasability of the antifungal agent and the permeability into the stratum corneum are remarkably improved. Can be. That is, since the hydrophilic coating of the present invention has a very high affinity and adhesion to nails and skin and does not easily come off, the release of the antifungal agent from the coating and the penetration into the stratum corneum are prevented. High in nature. Furthermore, since the affected area is covered with a hydrophilic film, the application is the so-called ODT method (sealing dressing method). At the same time, since the film itself is hydrophilic and contains moisture, the hard nail plate is also sufficiently moisturized. The swelling under action allows the antifungal agent to be very easily transferred from the coating to the nail, thereby promoting the penetration of the antifungal agent. Then, when the antifungal agent in the portion of the hydrophilic film that is in contact with the affected part moves to the nail, the antifungal agent in the film moves toward the nail, and the antifungal agent gradually penetrates into the affected part. It is considered that a high antifungal agent concentration in the stratum corneum can be obtained. In addition, the hydrophilic coating of the present invention does not stick after drying and does not adhere to contact objects, so that clothes and the like are not stained.
【００２４】本発明で用いる被膜形成性物質は水に対す
る溶解度が極めて高いというわけではないが、親水性物
質であるため、入浴や水洗いを繰り返すことにより洗い
流すことができる。使用方法としては特に制限されない
が、繰り返し塗布が必要である場合には、常に高濃度の
抗真菌剤を患部に接触させるために疾患の程度によって
一日１回〜数回被膜を水で洗い流した後、患部に該組成
物を再塗布することが好ましい。なお、本発明の親水性
被膜は爪や皮膚に対して非常に密着性がよいので、ピー
ルオフタイプには適さない。また、本組成物を爪等に塗
布した後、包帯やラップフィルム等で巻いてもよい。Although the film-forming substance used in the present invention does not have extremely high solubility in water, it is a hydrophilic substance and can be washed away by repeating bathing and washing with water. The method of use is not particularly limited, but when repeated application is necessary, the coating was washed with water once to several times a day depending on the degree of the disease in order to always contact a high concentration antifungal agent to the affected area. Thereafter, it is preferable to reapply the composition to the affected area. The hydrophilic coating of the present invention has very good adhesion to nails and skin, and is not suitable for a peel-off type. After the composition is applied to nails or the like, the composition may be wound with a bandage, wrap film, or the like.
【００２５】本発明の被膜形成性抗真菌剤組成物には上
記必須成分の他に、低級アルコールを配合することが好
適である。低級アルコールは速やかな被膜の形成に寄与
し、溶媒としての機能を有するものであれば特に限定さ
れないが、好ましくはエタノール及び／又はイソプロピ
ルアルコールである。配合量としては目的とする組成物
の性状、抗真菌剤や被膜形成物質の配合量等により適宜
調製して配合することができるが、通常１５〜８６w/v
％、好ましくは３０〜８０w/v％、さらに好ましくは５
０〜７５w/v％である。また、本発明に係る被膜形成性
抗真菌剤組成物には、上記必須成分の他に角質層への抗
真菌剤の浸透性を高めるために湿潤剤、角質溶解剤、界
面活性剤を配合することができる。The film-forming antifungal composition of the present invention preferably contains a lower alcohol in addition to the above essential components. The lower alcohol is not particularly limited as long as it contributes to rapid formation of a film and has a function as a solvent, but is preferably ethanol and / or isopropyl alcohol. The compounding amount can be appropriately adjusted according to the properties of the target composition, the compounding amount of the antifungal agent or the film-forming substance and the like, and is usually 15 to 86 w / v.
%, Preferably 30 to 80 w / v%, more preferably 5%
0 to 75 w / v%. In addition, the film-forming antifungal composition according to the present invention contains a wetting agent, a keratolytic agent, and a surfactant in order to enhance the penetration of the antifungal agent into the stratum corneum in addition to the above essential components. be able to.
【００２６】湿潤剤としては、例えば、プロピレングリ
コール、ジプロピレングリコール、１，３−ブチレング
リコール、グリセリン、ジグリセリン、トリグリセリ
ン、ポリエチレングリコール、ソルビトール、グルコー
ス、フルクトース、マルトース、キシリトール、エリス
リトール、スレイトール、マビット、マンニット等が挙
げられ、これら湿潤剤のうち、１種又は２種以上を用い
ることができる。特に好ましくはプロピレングリコー
ル、ジプロピレングリコール、1，３−ブチレングリコ
ールである。湿潤剤は爪や皮膚を柔軟にし、抗真菌剤の
浸透性を高める効果を有する。Examples of the wetting agent include propylene glycol, dipropylene glycol, 1,3-butylene glycol, glycerin, diglycerin, triglycerin, polyethylene glycol, sorbitol, glucose, fructose, maltose, xylitol, erythritol, threitol, mabit And mannitol, and one or more of these wetting agents can be used. Particularly preferred are propylene glycol, dipropylene glycol and 1,3-butylene glycol. Wetting agents have the effect of softening nails and skin and increasing the permeability of antifungal agents.
【００２７】本発明における湿潤剤の配合量は、組成物
全量に対して１〜２０w/v％、好ましくは２〜１５w/v
％、特に好ましくは５〜１０w/v％である。湿潤剤が少
ないと爪に対する十分な柔軟効果が得られず、薬剤浸透
性の明らかな向上が認められない。また、多すぎる場合
には被膜が乾燥しにくくべたつきが大となるので好まし
くない。The compounding amount of the wetting agent in the present invention is 1 to 20 w / v%, preferably 2 to 15 w / v% based on the total amount of the composition.
%, Particularly preferably 5 to 10 w / v%. If the amount of the humectant is small, a sufficient softening effect on the nail is not obtained, and no clear improvement in drug permeability is observed. On the other hand, if the amount is too large, it is not preferable because the coating is difficult to dry and the stickiness becomes large.
【００２８】また、角質溶解剤としては、例えば尿素、
サリチル酸、サリチル酸ナトリウム、レゾルシン等が挙
げられ、これらは単独でも任意の混合物としても使用す
ることができる。角質溶解剤は爪表面の角質層を軟化
し、抗真菌剤の浸透を高めることができる。本発明にお
いて角質溶解剤の配合量は組成物全量に対して０．２〜
１０w/v％、好ましくは０．５〜５w/v％、特に好ましく
は１〜３w/v％である。角質溶解剤の配合量が少ないと
爪に対する十分な薬剤浸透性が得られず、また、多すぎ
る場合には被膜が乾きにくくべたつきが大きくなるため
に好ましくない。As the keratolytic agent, for example, urea,
Salicylic acid, sodium salicylate, resorcin and the like can be mentioned, and these can be used alone or as an arbitrary mixture. The keratolytic agent softens the stratum corneum on the nail surface and can enhance the penetration of antifungal agents. In the present invention, the blending amount of the keratolytic agent is from 0.2 to the total amount of the composition.
It is 10 w / v%, preferably 0.5 to 5 w / v%, particularly preferably 1 to 3 w / v%. If the amount of the keratolytic agent is too small, sufficient drug permeability to the nail cannot be obtained, and if it is too large, the coating is difficult to dry and the stickiness becomes large, which is not preferable.
【００２９】本発明において用いられる界面活性剤は特
に限定されないが、好ましくは親水性界面活性剤が良
い。親水性界面活性剤としては非イオン性界面活性剤、
イオン性界面活性剤、両性界面活性剤の何れでも良く、
これらの界面活性剤を単独又は任意の混合物として使用
することができる。非イオン性界面活性剤としては例え
ばポリオキシアルキレン系、ポリグリセリン脂肪酸エス
テル、トゥイーン系、シュガーエステル系のものが挙げ
られ、また、イオン性界面活性剤としては例えば脂肪酸
セッケン、アルキルスルホン酸塩、エーテルリン酸塩、
塩基性アミノ酸の脂肪酸塩、トリエタノールアミン石
鹸、アルキル四級アンモニウム塩等が、両性界面活性剤
としては例えばベタイン、アミノカルボン酸塩、アルキ
ルジメチルアミンオキシド等が挙げられる。好ましくは
アニオン性界面活性剤と両性界面活性剤の組み合わせが
良い。界面活性剤は爪の角質表面を活性化し、薬物の爪
への浸透性を高めることができる。The surfactant used in the present invention is not particularly limited, but is preferably a hydrophilic surfactant. Nonionic surfactants as hydrophilic surfactants,
Any of an ionic surfactant and an amphoteric surfactant may be used,
These surfactants can be used alone or as an arbitrary mixture. Nonionic surfactants include, for example, polyoxyalkylenes, polyglycerin fatty acid esters, tweens, and sugar esters, and ionic surfactants include fatty acid soaps, alkyl sulfonates, and ethers. Phosphates,
Fatty acid salts of basic amino acids, triethanolamine soaps, alkyl quaternary ammonium salts and the like, and amphoteric surfactants include, for example, betaines, aminocarboxylates, alkyldimethylamine oxides and the like. Preferably, a combination of an anionic surfactant and an amphoteric surfactant is good. Surfactants can activate the keratinous surface of the nail and increase drug penetration into the nail.
【００３０】本発明において用いられる界面活性剤の配
合量は、０．２〜５w/v％、好ましくは０．５〜３w/v
％、特に好ましくは１〜２w/v％である。界面活性剤の
配合量が少ないと爪に対する十分な薬剤浸透性が得られ
ず、また、界面活性剤の配合量が多すぎると被膜が乾き
にくくべたつきが大となる。本発明にかかる被膜形成性
抗真菌剤組成物には、この他必要に応じ他の薬物（例え
ば、抗ヒスタミン剤、鎮痒剤、抗炎症剤、局所麻酔剤
等）、吸収促進剤、可塑剤、緩衝剤、清涼剤、抗酸化
剤、ゲル化剤、中和剤、キレート剤、油分、溶媒、高分
子、香料、色剤など本発明の効果を損なわない範囲で配
合することができる。The amount of the surfactant used in the present invention is 0.2 to 5% w / v, preferably 0.5 to 3% w / v.
%, Particularly preferably 1-2 w / v%. If the amount of the surfactant is small, sufficient drug permeability to the nail cannot be obtained, and if the amount of the surfactant is too large, the coating is difficult to dry and the stickiness becomes large. The film-forming antifungal composition according to the present invention may further contain other drugs (for example, antihistamines, antipruritics, anti-inflammatory agents, local anesthetics, etc.), absorption enhancers, plasticizers, and buffers as necessary. , A cooling agent, an antioxidant, a gelling agent, a neutralizing agent, a chelating agent, an oil, a solvent, a polymer, a fragrance, a coloring agent, etc., within a range not impairing the effects of the present invention.
【００３１】前記可塑剤としては例えば炭酸エチレン、
炭酸プロピレン、クエン酸トリエチル、トリアセチン、
クロタミトン、セバシン酸ジイソプロピル、セバシン酸
ジエチル、アジピン酸ジイソプロピル等が挙げられる。
これら可塑剤のうち、１種または２種以上を用いること
ができ、特に好ましくは炭酸エチレン、炭酸プロピレン
である。本発明の被膜形成性抗真菌剤組成物は剤型とし
て粘性の低い液状製剤から粘性の高いゲル状製剤まで任
意の粘性をもつ組成物として調製が可能である。Examples of the plasticizer include ethylene carbonate,
Propylene carbonate, triethyl citrate, triacetin,
Crotamiton, diisopropyl sebacate, diethyl sebacate, diisopropyl adipate and the like.
One or more of these plasticizers can be used, and ethylene carbonate and propylene carbonate are particularly preferred. The film-forming antifungal composition of the present invention can be prepared as a composition having any viscosity from a low-viscosity liquid formulation to a highly viscous gel-like formulation as a dosage form.
【００３２】本発明の被膜形成性抗真菌剤組成物を患部
に塗布する方法としては、特に限定されないが、ハケ塗
り、綿棒やへら等の塗布具での塗布、ロールオンタイプ
での塗布、容器からの直接塗布、スプレー塗布等が可能
である。以下、具体例として、抗真菌剤として塩酸アモ
ロルフィン、親水性被膜形成物質としてプラスサイズＬ
−５３Ｐを用いて本発明の実施の形態を説明する。な
お、配合量は特に指定のない場合は重量（ｇ）で示す。The method of applying the film-forming antifungal agent composition of the present invention to the affected area is not particularly limited, but may be, for example, brush application, application using an applicator such as a cotton swab or a spatula, application using a roll-on type, or use of a container. Direct coating, spray coating, etc. are possible. Hereinafter, as specific examples, amorolfine hydrochloride as an antifungal agent and Plus Size L as a hydrophilic film-forming substance will be described.
An embodiment of the present invention will be described using -53P. The blending amount is indicated by weight (g) unless otherwise specified.
【００３３】試験例１ まず、本発明の被膜形成性抗真菌剤組成物のべたつき、
爪への密着性、角質浸透性について調べた。サンプルと
しては、下記表１の被膜形成性抗真菌剤組成物を用い
た。調製方法は成分（９）の一部に成分（１）〜（８）
を順に溶解せしめ、最終的に（９）で合計１００ｍｌに
して液状の組成物を得た。なお、各試験方法は次の通
り。 Test Example 1 First, the film-forming antifungal composition of the present invention was tacky.
The adhesion to the nail and the keratin penetration were examined. As samples, the film-forming antifungal compositions shown in Table 1 below were used. The preparation method is as follows: components (1) to (8)
Were dissolved in order, and finally, a total of 100 ml was obtained using (9) to obtain a liquid composition. In addition, each test method is as follows.
【００３４】べたつき 試料を爪に塗布し、自然乾燥後の被膜のべたつきを以下
の基準に従って評価した。 ◎…べたつきが全くなし ○…べたつきがほとんどない △…べたつきが少し感じられる ×…べたつきがはっきり感じられるThe sticky sample was applied to a nail, and the stickiness of the film after air drying was evaluated according to the following criteria. ◎: No stickiness at all ○: Almost no stickiness △: Some stickiness is felt ×: Stickiness is clearly felt
【００３５】爪への密着性 試料を爪に塗布し、自然乾燥後の被膜の状態を肉眼観察
して以下の基準に従って爪への密着性を評価した。 ◎…密着性が高い（被膜に全くしわがよらない） ○…密着性がかなり高い（被膜に僅かにしわがよる） △…密着性が低い（被膜にしわがよる） ×…密着性なし（被膜が爪上から容易に剥離する） Adhesion to nail The sample was applied to the nail, and the state of the film after air drying was visually observed, and the adhesion to the nail was evaluated according to the following criteria. ◎… High adhesion (no wrinkles on the coating) ○… Quite high adhesion (slightly wrinkles on the coating) △… Low adhesion (wrinkles on the coating) ×… No adhesion (no coating on the coating) Easily peels off from nails)
【００３６】角質浸透性試験 ８週齢雄性ヘアレスマウスの背部摘出皮膚をフランツ型
拡散セルに装着した。レセプター溶液として生理食塩液
を用い、試料０．１５ｍｌを開放系で２４時間適用し
た。皮膚を透過して、レセプター溶液中に移行した抗真
菌剤量を調べるため、レセプター溶液を経時的にサンプ
リングし、レセプター溶液中の抗真菌剤濃度をＨＰＬＣ
法により測定した。２４時間後のレセプター溶液中の抗
真菌剤濃度により下記の基準に従って角質浸透性を評価
した。 ◎…抗真菌剤濃度が５μｇ／ｍｌ以上 ○…抗真菌剤濃度が３μｇ／ｍｌ以上５μｇ／ｍｌ未満 △…抗真菌剤濃度が１μｇ／ｍｌ以上３μｇ／ｍｌ未満 ×…抗真菌剤濃度が１μｇ／ｍｌ未満Exfoliation test of keratin The skin from the back of an 8-week-old male hairless mouse was attached to a Franz diffusion cell. Using a physiological saline solution as the receptor solution, 0.15 ml of the sample was applied in an open system for 24 hours. The receptor solution was sampled over time to determine the amount of the antifungal agent that passed through the skin and transferred into the receptor solution, and the concentration of the antifungal agent in the receptor solution was determined by HPLC.
It was measured by the method. The keratin permeability was evaluated according to the following criteria based on the concentration of the antifungal agent in the receptor solution after 24 hours. …: Antifungal concentration of 5 μg / ml or more ○: Antifungal concentration of 3 μg / ml or more and less than 5 μg / ml △: Antifungal concentration of 1 μg / ml or more and less than 3 μg / ml ×: Antifungal concentration of 1 μg / ml less than ml
【００３７】[0037]
【表１】 ──────────────────────────────────── サンプルＮｏ． 構 成 成 分 １ ２ ３ ４ ５ ６ ──────────────────────────────────── (1)塩酸アモロルフィン ５ ５ ５ ５ ５ ５ (2)プラスサイズＬ−５３Ｐ ８ ８ ８ ８ ８ ８ (3)精製水 ５ ５ ５ ５ ５ − (4)炭酸プロピレン １ １ １ １ １ １ (5)プロピレングリコール − ６ − − ６ − (6)尿素 − − １ − １ − (7)ラウリルシ゛メチルアミンオキシト゛ − − − ０.３ ０.３ − (8)ラウリル硫酸ナトリウム − − − ０.１ ０.１ − (9)９５％エタノール 適量 適量 適量 適量 適量 適量 ──────────────────────────────────── 合計 100ml 100ml 100ml 100ml 100ml 100ml ──────────────────────────────────── べたつき ◎ ◎ ◎ ◎ ◎ ◎ 爪への密着性 ◎ ◎ ◎ ◎ ◎ ◎ 角質浸透性 ○ ◎ ◎ ◎ ◎ × ────────────────────────────────────[Table 1] ──────────────────────────────────── Sample No. Composition 1 2 3 4 5 6 ──────────────────────────────────── (1) Hydrochloric acid Amorolfin 55 55 55 55 (2) Plus size L-53P 88 88 88 88 (3) Purified water 55 55 55- (4) Propylene carbonate 11 11 11 11 (5) Propylene glycol 6 --6-(6) Urea--1-1-(7) Lauryldimethylamine oxyto---0.3 0.3-(8) Sodium lauryl sulfate---0.1 0.1-(9) 95% ethanol qs qq qq qq qq qs ──────────────────────────────────── total 100ml 100ml 100ml 100ml 100ml 100ml ──────────────────────────────────── Sticky ◎ ◎ ◎ ◎ ◎ ◎ Adhesion to nail ◎ ◎ ◎ ◎ ◎ horny permeability ○ ◎ ◎ ◎ ◎ × ────────────────────────────────────
【００３８】何れの組成物も爪に塗布した場合には溶媒
の揮発に伴って親水性の被膜を形成し、該被膜はべたつ
きや被接触物に対する付着が極めて少なく、また、十分
な物理的強度を備えていた。そして、サンプル１〜５の
組成物は、角質浸透性試験において該被膜から抗真菌剤
が放出され、角質に浸透していることが示された。特
に、サンプル２〜５のように湿潤剤（プロピレングリコ
ール）、角質溶解剤（尿素）、界面活性剤（ラウリルジ
メチルアミンオキシド、ラウリル硫酸ナトリウム）を配
合すれば抗真菌剤の角質浸透性がさらに促進されること
が理解される。一方、サンプル６のように組成物中に水
を配合しなかった場合には角質浸透性は非常に低かっ
た。When any of the compositions is applied to nails, a hydrophilic film is formed as the solvent evaporates, and the film has very little stickiness or adhesion to a contacted object, and has a sufficient physical strength. It was equipped. The compositions of Samples 1 to 5 showed that the antifungal agent was released from the coating in the keratin penetration test, and the compositions penetrated the keratin. In particular, if a wetting agent (propylene glycol), a keratolytic agent (urea), and a surfactant (lauryl dimethylamine oxide, sodium lauryl sulfate) are added as in samples 2 to 5, the keratin permeability of the antifungal agent is further promoted. It will be understood that On the other hand, when water was not added to the composition as in Sample 6, the keratin permeability was extremely low.
【００３９】比較例１ ＜製法＞（５）及び（６）と（７）の一部の混合物に
（１）〜（４）を順に溶解せしめ、最終的に（７）で合
計１００ｍｌにして目的とする被膜形成性抗真菌剤組成
物を得た。 Comparative Example 1 <Production method> (5) and (1) to (4) were dissolved in a partial mixture of (6) and (7) in order, and finally (7) was added to a total of 100 ml to obtain the desired film-forming agent. A fungicidal composition was obtained.
【００４０】比較例２ ＜製法＞（５）の一部に（１）〜（４）を順に溶解せし
めて、最終的に（５）で合計１００ｍｌにして目的とす
る被膜形成性抗真菌剤組成物を得た。 Comparative Example 2 <Production method> (1) to (4) were sequentially dissolved in a part of (5), and finally (5) was made up to a total of 100 ml to obtain a desired film-forming antifungal composition.
【００４１】比較例３ ＜製法＞（１）〜（５）及び（６）の一部を８０℃に加
熱撹拌して溶解させ、冷却して最終的に（６）で合計１
００ｍｌにして目的とする被膜形成性抗真菌剤組成物を
得た。 Comparative Example 3 <Production method> A part of (1) to (5) and (6) was heated and stirred at 80 ° C. to dissolve, cooled, and finally cooled to a total of 1 in (6).
The solution was made up to 00 ml to obtain the desired film-forming antifungal composition.
【００４２】比較例１〜比較例３についても前記試験例
１と同様に試験を行った。結果を表２に示す。The same tests as in Test Example 1 were conducted for Comparative Examples 1 to 3. Table 2 shows the results.
【表２】 ────────────────────────────────── 試験項目 比較例１ 比較例２ 比較例３ ────────────────────────────────── べたつき ◎ ◎ ◎ 爪への密着性 ◎ △ ◎ 角質浸透性 × △ × ────────────────────────────────── [Table 2] Test items Comparative example 1 Comparative example 2 Comparative example 3 Sticky ◎ ◎ ◎ Adhesion to nails ◎ △ ◎ Permeability of keratin × △ × ──────────────────────────────────
【００４３】表２から明らかなように、疎水性の被膜形
成性物質（ニトロセルロース、酢酸ビニル、エチルセル
ロース、メタアクリル酸メタアクリル酸メチルコポリマ
ー）を用いた比較例１〜比較例３の組成物では何れもべ
たつきのない被膜が得られ、また、比較例１及び比較例
３の被膜では爪への密着性が高い被膜が得られるが、比
較例２では爪への密着性が低く、また、比較例１〜比較
例３の何れも角質浸透性が非常に悪いことが理解され
る。As is clear from Table 2, the compositions of Comparative Examples 1 to 3 using hydrophobic film-forming substances (nitrocellulose, vinyl acetate, ethyl cellulose, and methacrylic acid methyl methacrylate copolymer) were used. In each case, a film having no stickiness was obtained, and in the films of Comparative Examples 1 and 3, a film having high adhesion to the nail was obtained, but in Comparative Example 2, the adhesion to the nail was low. It is understood that all of Example 1 to Comparative Example 3 have very poor keratin permeability.
【００４４】図１は前記試験例１のサンプル１、サンプ
ル５及び比較例１の皮膚透過量を経時的にプロットした
ものである。疎水性被膜形成物質を用いた比較例１の組
成物では角質浸透性がほとんど認められなかったのに対
して、本発明の被膜形成性抗真菌剤組成物であるサンプ
ル１及びサンプル５では親水性被膜から抗真菌剤が経時
的に放出され、角質浸透性が高いことがわかる。特に、
サンプル５では湿潤剤、角質溶解剤、界面活性剤の配合
により角質浸透性が著しく向上している。FIG. 1 is a plot of the skin permeation amount of Sample 1, Sample 5 of Test Example 1 and Comparative Example 1 with time. In the composition of Comparative Example 1 using a hydrophobic film-forming substance, almost no keratin permeability was recognized, whereas in the film-forming antifungal compositions of the present invention, Sample 1 and Sample 5, which were hydrophilic, It can be seen that the antifungal agent is released from the coating over time, and the keratin permeability is high. Especially,
In sample 5, the keratin permeability is remarkably improved by blending a wetting agent, a keratolytic agent and a surfactant.
【００４５】試験例２ 次に、ブタの爪（蹄壁）を用いて、本発明の被膜形成性
抗真菌剤組成物を塗布した際の塩酸アモロルフィンの爪
内濃度、及び爪透過量について調べた。試験方法は次の
通り。 Test Example 2 Next, using a pig's nail (hoof wall), the concentration of amorolfine hydrochloride in the nail and the amount of nail penetration when the film-forming antifungal composition of the present invention was applied were examined. . The test method is as follows.
【００４６】爪浸透性試験 １）ブタ蹄壁切片の作製 豚足から蹄壁を摘出し、円形（直径１．１ｃｍ）に打ち
抜き、コールドトーム（ＣＭ−５０１、サクラ精機
（株））で蹄真皮を削り、厚さ２．０ｍｍの蹄壁切片を
作製した。 Nail penetration test 1) Preparation of pig hoof wall section A hoof wall was excised from a pig foot, punched into a circular shape (1.1 cm in diameter), and cut with a cold tome (CM-501, Sakura Seiki Co., Ltd.). And a 2.0 mm thick hoof wall section was prepared.
【００４７】 ２）被験抗真菌剤組成物の調製 ＜処方＞ （１）14Ｃ-塩酸アモロルフィン ０．５、２．０又は５．０ｇ （２）プラスサイズＬ−５３Ｐ ６．０ｇ （３）炭酸プロピレン １．０ｇ （４）プロピレングリコール ５．０ｇ （５）尿素 １．０ｇ （６）ラウリル硫酸ナトリウム ０．１ｇ （７）ラウリルジメチルアミンオキシド １．０ｇ （８）精製水 ３．０ｇ （９）９５％エタノール 適 量 合計 １００ｍｌ2) Preparation of Test Antifungal Agent Composition <Formulation> (1) 14 C-Amorolfine hydrochloride 0.5, 2.0 or 5.0 g (2) Plus size L-53P 6.0 g (3) Carbonic acid Propylene 1.0 g (4) Propylene glycol 5.0 g (5) Urea 1.0 g (6) Sodium lauryl sulfate 0.1 g (7) Lauryl dimethylamine oxide 1.0 g (8) Purified water 3.0 g (9) 95 % Ethanol qs 100ml
【００４８】＜製法＞（９）の一部に成分（１）〜
（８）を順に溶解せしめ、最終的に（９）で合計１００
ｍｌにして、０．５、２、５w/v％14Ｃ-塩酸アモロルフ
ィン含有組成物をそれぞれ調製した。なお、14Ｃ-塩酸
アモロルフィンの比放射能は３．４２ＭＢｑ／ｍｇ、放
射化学的純度は９８％以上であった。<Production method> Components (1) to (9)
(8) was dissolved in order, and finally (9)
Then, 0.5, 2, and 5 w / v% 14 C-amololfin hydrochloride-containing compositions were prepared. The specific radioactivity of 14 C-amololfin hydrochloride was 3.42 MBq / mg, and the radiochemical purity was 98% or more.
【００４９】３）方法 ブタ蹄壁切片の外層側に直径５ｍｍの円形の印をつけ、
その中に０．５、２、５w/v％14Ｃ-塩酸アモロルフィン
含有組成物をそれぞれ５μｌ（薬剤塗布量としてそれぞ
れ２５、１００、又は２５０μｇ／切片）均一に塗布し
た。図２のように、バイアル内に１／１５Ｍリン酸緩衝
溶液（ｐＨ７．４）０．５ｍｌで湿らせたコンバストパ
ッド（パッカード社製）を入れ、その上に被験組成物を
塗布した蹄壁切片を真皮側を下にして静置した。バイア
ルを開放系にて２５℃で放置し、一定時間毎にコンバス
トパッドとバイアルを新しいものに交換した。なお、試
験は単回塗布、及び反復塗布にて行った。反復塗布の場
合には、塗布後２４時間毎に７０％エタノールを含ませ
た脱脂綿で塗布面に残存している薬剤を除去し、新たに
被験組成物を塗布する方法で一日一回、５日間連続塗布
した。3) Method A circular mark having a diameter of 5 mm was placed on the outer layer side of the pig hoof wall section.
5 μl of each of the compositions containing 0.5, 2, 5 w / v% 14 C-amololfin hydrochloride (25, 100, or 250 μg / drug as a drug application amount) was uniformly applied thereto. As shown in FIG. 2, a combust pad (manufactured by Packard) moistened with 0.5 ml of a 1/15 M phosphate buffer solution (pH 7.4) was placed in a vial, and a hoof wall section on which a test composition was applied was placed thereon. Was left standing with the dermis side down. The vial was left at 25 ° C. in an open system, and the combust pad and the vial were replaced with new ones at regular intervals. In addition, the test was performed by single application and repeated application. In the case of repeated application, every 24 hours after application, the drug remaining on the application surface is removed with absorbent cotton containing 70% ethanol, and the test composition is applied once a day by applying a new test composition. It was applied continuously for days.
【００５０】塩酸アモロルフィンの透過量は、使用済み
のコンバストパッドから、メタノールで薬剤を抽出し、
その一部にＡＣＳ−II（Amersham International plc)
５ｍｌを加え、放射能を液体シンチレーションアナライ
ザー（Tri-Carb 2000CA、パッカード社製）で測定する
ことにより算出した。塩酸アモロルフィンの爪内濃度
は、次のように算出した。すなわち、単回塗布の場合に
は塗布後２４時間、反復塗布の場合には最終塗布後２４
時間の蹄壁切片について、その表面を７０％エタノール
をしみ込ませた脱脂綿にて拭き取り、蹄壁切片表面に残
存する薬剤を除去した。その後、蹄壁切片をコールドト
ームで外層側から４分割し、それぞれの蹄壁画分をサン
プルオキシダイザー（３０６型、パッカード社製）で燃
焼処理し、同様に放射能を測定することにより、各蹄壁
画分内に存在している薬剤の爪内濃度を算出した。な
お、試験はそれぞれｎ＝３で行った。The amount of permeation of amorolfin hydrochloride can be determined by extracting the drug from the used combust pad with methanol,
Some of them are ACS-II (Amersham International plc)
5 ml was added, and the radioactivity was calculated by measuring with a liquid scintillation analyzer (Tri-Carb 2000CA, manufactured by Packard). The concentration of amorolfin hydrochloride in the nail was calculated as follows. That is, in the case of single application, 24 hours after application, and in the case of repeated application, 24 hours after final application.
The surface of the hoof wall section was wiped with absorbent cotton impregnated with 70% ethanol to remove the drug remaining on the hoof wall section surface. Thereafter, the hoof wall section is divided into four sections from the outer layer side by a cold tome, and each of the hoof wall fractions is subjected to combustion treatment with a sample oxidizer (Type 306, manufactured by Packard), and the radioactivity is measured in the same manner. The concentration of the drug present in the wall fraction in the nail was calculated. In addition, each test was performed with n = 3.
【００５１】４）結果 図３は単回塗布時の14Ｃ-塩酸アモロルフィンの累積透
過量を示す図、図４は反復塗布時の14Ｃ-塩酸アモロル
フィンの累積透過量を示す図である。単回投与時では、
何れの薬剤濃度においても経時的に透過量が増加し、製
剤中の塩酸アモロルフィン濃度が高い程、薬剤の透過量
は多くなることがわかる。反復塗布時でも単回投与と同
様の傾向があったが、日数が多くなるにつれて累積透過
量はやや頭打ちとなる傾向が認められた。4) Results FIG. 3 is a diagram showing the cumulative permeation amount of 14 C-amololfin hydrochloride in a single application, and FIG. 4 is a diagram showing the cumulative permeation amount of 14 C-amololfin hydrochloride in a repeated application. At the time of single dose,
It can be seen that the amount of permeation increases with time at any drug concentration, and the higher the concentration of amorolfine hydrochloride in the preparation, the greater the amount of permeation of the drug. Even during repeated application, there was a tendency similar to that of single administration, but as the number of days increased, the cumulative permeation amount tended to slightly peak.
【００５２】[0052]
【表３】 ──────────────────────────────────── 塗布側からの距離(mm) 製剤中の薬剤濃度（ｗ／ｖ％） ０．５ ２ ５ ──────────────────────────────────── 単回塗布時（塗布後２４時間） ０ 〜０．５ 70.7±5.8 678±228 1173±375 ０．５〜１．０ 0.77±0.40 1.60±0.44 11.2±4.0 １．０〜１．５ 0.12±0.05 0.93±0.23 3.18±1.10 １．５〜２．０ 0.09±0.02 0.44±0.12 2.19±0.70 ──────────────────────────────────── 反復塗布時（最終塗布後２４時間） ０ 〜０．５ 169±48 456±109 1533±417 ０．５〜１．０ 3.18±1.23 4.79±1.41 12.9±3.1 １．０〜１．５ 0.72±0.19 1.96±0.40 7.94±0.98 １．５〜２．０ 0.51±0.20 1.61±0.54 3.72±0.31 ──────────────────────────────────── （単位：μｇ／ｇ）[Table 3] 距離 Distance from application side (mm) In formulation Drug concentration (w / v%) of 0.5 25 Single application (24 hours after application) 0 to 0.5 70.7 ± 5.8 678 ± 228 1173 ± 375 0.5 to 1.0 0.77 ± 0.40 1.60 ± 0.44 11.2 ± 4.0 1.0 to 1.5 0.12 ± 0.05 0.93 ± 0.23 3.18 ± 1.10 1.5 ~ 2.0 0.09 ± 0.02 0.44 ± 0.12 2.19 ± 0.70 ────────────────────────────時 During repeated application (24 hours after final application) 0 to 0.5 169 ± 48 456 ± 109 1533 ± 417 0.5 to 1.0 3.18 ± 1.23 4.79 ± 1.41 12.9 ± 3.1 0 to 1.5 0.72 ± 0.19 1.96 ± 0.40 7.94 ± 0.98 1.5 to 2.0 0.51 ± 0.20 1.61 ± 0.54 3.72 ± 0.31 ──────────────────── ──────────────── (Unit: μg / g)
【００５３】表３は、単回塗布時、及び反復塗布時の塩
酸アモロルフィンの各画分における爪内濃度（爪１ｇ当
たりに存在する薬剤量、μｇ／ｇ）の結果である。何れ
の薬剤濃度においても最深部（１．５〜２．０ｍｍ画
分）まで薬剤が浸透しており、蹄壁内の薬剤濃度は塗布
側に近いほど高く、真皮側に向かって減少していた。ま
た、薬剤の爪内濃度は、製剤中の薬剤濃度や製剤の反復
塗布によって高めることができる。Table 3 shows the results of the concentration of amorolfine hydrochloride in the nails (the amount of drug per g of nail, μg / g) in each fraction at the time of single application and at the time of repeated application. In all drug concentrations, the drug penetrated to the deepest part (1.5-2.0 mm fraction), and the drug concentration in the hoof wall was higher near the application side and decreased toward the dermis side. . In addition, the concentration of the drug in the nail can be increased by the drug concentration in the preparation or by repeated application of the preparation.
【００５４】塩酸アモロルフィンの白癬菌に対する幾何
平均最小阻止濃度は、Tricophytonrubrum（３２株）で
０．００１μｇ／ｍｌ、Tricophyton mentagrophtes
（２３株）で０．０１１μｇ／ｍｌである（Polak A.,
et al., Sabonuraudia, 21, 205(1983)）。このことか
ら塩酸アモロルフィン濃度が０．５％の製剤の単回塗布
でも、爪内及びネイルベット付近の白癬菌に対して有効
性が期待でき、製剤中の薬剤濃度を高めたり、反復塗布
を行うことによって、さらに有効性が高められるものと
考えられる。The geometric mean minimum inhibitory concentration of amorolfine hydrochloride against Trichophyton was 0.001 μg / ml in Tricophytonrubrum (32 strains) and Tricophyton mentagrophtes.
(23 strains) and 0.011 μg / ml (Polak A.,
et al., Sabonuraudia, 21 , 205 (1983)). From this, even with a single application of a formulation having an amorolfine hydrochloride concentration of 0.5%, it can be expected to be effective against Trichophyton in the nail and near the nail bed, and the drug concentration in the formulation can be increased or repeated application is performed. It is thought that this will further enhance the effectiveness.
【００５５】試験例３ 次に、健常なヒトの爪に対する浸透性を試験例２の方法
に準じて調べた。なお、サンプル塗布は、前記試験例２
の５w/v％14Ｃ−塩酸アモロルフィン含有組成物２μｌ
（薬剤投与量１００μｇ／切片）を、ヒト爪切片の外層
側直径２．５ｍｍの円内に塗布した。試験は、密閉系、
単回塗布にて行い、爪内に存在する塩酸アモロルフィン
量は、塗布後１６８時間の爪切片を７０％エタノールを
含ませた脱脂綿で表面に残存する薬剤を拭き取り、その
後爪切片を分割することなく処理し、測定した。また、
拭き取りに用いた脱脂綿に含まれる薬剤をメタノールで
抽出し、同様に測定を行って、爪切片表面に残存してい
た塩酸アモロルフィン量も算出した。 Test Example 3 Next, the permeability into healthy human nails was examined in accordance with the method of Test Example 2. The sample was applied in the same manner as in Test Example 2 described above.
2 μl of a composition containing 5 w / v% of 14 C-amololfin hydrochloride
(Drug dose of 100 μg / section) was applied to a circle having a diameter of 2.5 mm on the outer layer side of a human nail section. The test was performed on a closed system,
Performed in a single application, the amount of amorolfin hydrochloride present in the nail was determined by wiping the nail section 168 hours after application with a cotton wool impregnated with 70% ethanol to remove the remaining drug on the surface, and then dividing the nail section. Processed and measured. Also,
The drug contained in the absorbent cotton used for the wiping was extracted with methanol, and the same measurement was carried out to calculate the amount of amorolfine hydrochloride remaining on the nail section surface.
【００５６】図５〜６は、ヒト爪切片に対する塩酸アモ
ロルフィンの累積透過率（塗布後０〜８時間及び０〜１
６８時間）をそれぞれ示している。ヒト爪に対しても製
剤中の塩酸アモロルフィンが経時的に浸透し、その透過
量が増大することがわかる。また、図７は、塗布後１６
８時間の塩酸アモロルフィンの分布を示している。ヒト
爪切片に塗布された製剤中の塩酸アモロルフィンの内、
２１．８％が爪内に貯留し、６．７７％が爪を透過して
おり、製剤中の塩酸アモロルフィンの約３０％が被膜中
から爪内に移行している。このことから、本発明の被膜
形成性抗真菌剤組成物は、ヒトの爪に対する浸透性にも
優れることが理解される。FIGS. 5 and 6 show the cumulative permeability of amorolfine hydrochloride to human nail sections (from 0 to 8 hours after application and from 0 to 1 hour).
68 hours). It can be seen that amorolfine hydrochloride in the preparation permeates into the human nail over time, and the amount of permeation increases. Also, FIG.
8 shows the distribution of amorolfine hydrochloride for 8 hours. Of the amorolfine hydrochloride in the formulation applied to human nail sections,
21.8% are stored in the nails, 6.77% have penetrated the nails, and about 30% of the amorolfine hydrochloride in the formulation has migrated from the capsule into the nails. From this, it is understood that the film-forming antifungal composition of the present invention is excellent in permeability to human nails.
【００５７】以上のように、本発明の被膜形成性抗真菌
剤組成物によれば、塗布により抗真菌剤の放出性、角質
浸透性、爪浸透性に優れた親水性被膜を形成することが
でき、ヒトやその他の哺乳動物の白癬症特に爪白癬を効
果的に治療することができる。As described above, according to the film-forming antifungal composition of the present invention, it is possible to form a hydrophilic film excellent in antifungal release, keratin permeability and nail permeability by application. It is possible to effectively treat tinea pedis in humans and other mammals, especially tinea unguium.
【００５８】[0058]
【実施例】以下、実施例により本発明を具体的に説明す
るが本発明はこれらに限定されるものではない。EXAMPLES The present invention will be described below in detail with reference to examples, but the present invention is not limited to these examples.
【００５９】 ＜製法＞（５）の一部に成分（１）〜（４）を順に溶解
せしめ、最終的に（５）で合計１００ｍｌにして目的と
する被膜形成性抗真菌剤組成物を得た。[0059] <Production method> Components (1) to (4) were sequentially dissolved in a part of (5), and finally, the total amount of (5) was adjusted to 100 ml to obtain a desired film-forming antifungal agent composition.
【００６０】実施例２ 液状製剤 （１）硝酸ミコナゾール ２ ｇ （２）プラスサイズＬ−５３Ｐ ８ ｇ （３）クエン酸トリエチル ２ ｇ （４）１，３−ブチレングリコール １０ ｇ （５）サリチル酸 ０．５ｇ （６）精製水 １０ ｇ （７）アルキルジメチルアミンオキシド １．５ｇ （８）セチル硫酸ナトリウム ０．５ｇ （９）９５％エタノール 適量 合計 １００ｍｌ ＜製法＞（９）の一部に成分（１）〜（８）を順に溶解
せしめ、最終的に（９）で合計１００ｍｌにして目的と
する被膜形成性抗真菌剤組成物を得た。 Example 2 Liquid preparation (1) 2 g of miconazole nitrate (2) 8 g of plus size L-53P (3) 2 g of triethyl citrate (4) 10 g of 1,3-butylene glycol (5) Salicylic acid 5 g (6) Purified water 10 g (7) Alkyl dimethylamine oxide 1.5 g (8) Sodium cetyl sulfate 0.5 g (9) 95% ethanol qs 100 ml <Production method> Component (1) as part of (9) To (8) were sequentially dissolved, and finally (9) was made up to a total of 100 ml to obtain the desired film-forming antifungal composition.
【００６１】実施例３ ゲル状製剤 （１）塩酸アモロルフィン ３ ｇ （２）プラスサイズＬ−５３Ｐ ６ ｇ （３）クエン酸トリエチル ２．５ｇ （４）ジプロピレングリコール ３ ｇ （５）尿素 ２ ｇ （６）ヒドロキシプロピルセルロース ３ ｇ （７）精製水 １０ ｇ （８）ラウリルジメチルアミンオキシド １ ｇ （９）ラウリル硫酸ナトリウム ０．１ｇ （１０）９５％エタノール 適量 合計 １００ｍｌ Example 3 Gel preparation (1) Amorolfine hydrochloride 3 g (2) Plus size L-53P 6 g (3) Triethyl citrate 2.5 g (4) Dipropylene glycol 3 g (5) Urea 2 g ( 6) Hydroxypropylcellulose 3 g (7) Purified water 10 g (8) Lauryl dimethylamine oxide 1 g (9) Sodium lauryl sulfate 0.1 g (10) 95% ethanol Suitable amount Total 100 ml
【００６２】＜製法＞（１０）の一部に成分（１）〜
（９）を順に溶解せしめ、最終的に（１０）で合計１０
０ｍｌにして目的とする被膜形成性抗真菌剤組成物を得
た。<Production method> Components (1) to (10)
(9) was dissolved in order, and finally (10) resulted in a total of 10
0 ml to obtain the desired film-forming antifungal composition.
【００６３】実施例４ 液状製剤 （１）塩酸アモロルフィン ５ ｇ （２）プラスサイズＬ−５３Ｐ ８ ｇ （３）精製水 ５ ｇ （４）炭酸プロピレン １ ｇ （５）プロピレングリコール ６ ｇ （６）尿素 １ ｇ （７）ラウリルジメチルアミンオキシド ０．３ｇ （８）ラウリル硫酸ナトリウム ０．１ｇ （９）９５％エタノール 適量 合計 １００ｍｌ Example 4 Liquid preparation (1) 5 g of amorolfine hydrochloride (2) 8 g of plus size L-53P (3) 5 g of purified water (4) 1 g of propylene carbonate (5) 6 g of propylene glycol (6) urea 1 g (7) Lauryl dimethylamine oxide 0.3 g (8) Sodium lauryl sulfate 0.1 g (9) 95% ethanol suitable amount total 100 ml
【００６４】＜製法＞（９）の一部に成分（１）〜
（８）を順に溶解せしめ、最終的に（９）で合計１００
ｍｌにして目的とする被膜形成性抗真菌剤組成物を得
た。<Production method> Components (1) to (9)
(8) was dissolved in order, and finally (9)
to obtain a desired film-forming antifungal composition.
【００６５】以上実施例１〜４の被膜形成性抗真菌剤組
成物を爪に塗布したところ、何れも爪に対して密着性の
よい被膜が形成された。また、べたつきや爪への密着
性、角質浸透性について前記のように評価したところ、
何れの組成物もべたつき◎、爪への密着性◎であり、角
質浸透性は実施例１が○、実施例２、実施例３及び実施
例４が◎であった。When the film-forming antifungal compositions of Examples 1 to 4 were applied to nails, films having good adhesion to nails were formed. In addition, the adhesiveness to the sticky and nails, when evaluated for keratin permeability as described above,
All of the compositions were sticky 密 着 and adhesion to nails 角, and the keratin permeability was ○ in Example 1 and ◎ in Examples 2, 3 and 4.
【００６６】[0066]
【発明の効果】以上説明したように本発明にかかる被膜
形成性抗真菌剤組成物は、親水性被膜形成物質、抗真菌
剤及び水を含有し、これを患部に該組成物を塗布するこ
とにより抗真菌剤の放出性及び角質層や爪に対する浸透
性が高い親水性被膜を形成することができ、白癬症特に
爪白癬症を効果的に治療することができる。As described above, the film-forming antifungal composition according to the present invention comprises a hydrophilic film-forming substance, an antifungal agent and water, and the composition is applied to the affected area. As a result, it is possible to form a hydrophilic film having a high antifungal release property and a high permeability to the stratum corneum and nails, and it is possible to effectively treat tinea, especially tinea unguium.
【図面の簡単な説明】[Brief description of the drawings]
【図１】本発明の一実施例にかかる被膜形成性抗真菌剤
組成物の角質浸透性を示す図である。FIG. 1 is a graph showing keratin permeability of a film-forming antifungal agent composition according to one example of the present invention.
【図２】本発明の爪浸透性試験の試験方法を示す図であ
る。FIG. 2 is a view showing a test method of a nail penetration test of the present invention.
【図３】本発明の一実施例にかかる被膜形成性抗真菌剤
組成物の単回塗布におけるブタ蹄壁に対する薬剤の累積
透過量を示す図である。FIG. 3 is a graph showing the cumulative amount of drug permeating the hoof wall of a pig in a single application of the film-forming antifungal agent composition according to one example of the present invention.
【図４】本発明の一実施例にかかる被膜形成性抗真菌剤
組成物の反復塗布におけるブタ蹄壁に対する薬剤の累積
透過量を示す図である。FIG. 4 is a graph showing the cumulative amount of a drug permeating into a pig hoof wall when a film-forming antifungal agent composition according to one embodiment of the present invention is repeatedly applied.
【図５】本発明の一実施例にかかる被膜形成性抗真菌剤
組成物の単回塗布におけるヒト爪に対する薬剤の累積透
過率を示す図である。FIG. 5 is a graph showing the cumulative transmittance of a drug to a human nail in a single application of the film-forming antifungal agent composition according to one example of the present invention.
【図６】本発明の一実施例にかかる被膜形成性抗真菌剤
組成物の単回塗布におけるヒト爪に対する薬剤の累積透
過率を示す図である。FIG. 6 is a graph showing the cumulative transmittance of a drug to a human nail in a single application of the film-forming antifungal agent composition according to one example of the present invention.
【図７】本発明の一実施例にかかる被膜形成性抗真菌剤
組成物をヒト爪に単回塗布した時の、塗布後１６８時間
における薬剤の分布を示す図である。FIG. 7 is a graph showing the distribution of a drug at 168 hours after application when a single film-forming antifungal agent composition according to one example of the present invention was applied to human nails.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 鈴木 喬 神奈川県横浜市金沢区福浦２−12−１ 株 式会社資生堂第二リサーチセンター内 (72)発明者 小室 正勝 栃木県下都賀郡野木町友沼5905−58 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Takashi Suzuki 2-12-1 Fukuura, Kanazawa-ku, Yokohama-shi, Kanagawa Prefecture Inside Shiseido Second Research Center Co., Ltd. −58
Claims (15)
含有することを特徴とする被膜形成性抗真菌剤組成物。1. A film-forming antifungal composition comprising a hydrophilic film-forming substance, an antifungal agent and water.
被膜形成物質が室温で０．１w/v％以上の濃度で水に溶
解する物質であることを特徴とする被膜形成性抗真菌剤
組成物。2. The composition according to claim 1, wherein the hydrophilic film-forming substance is a substance soluble in water at room temperature at a concentration of 0.1% w / v or more. Composition.
て、親水性被膜形成物質が、アクリル樹脂のアルカノー
ルアミン中和液、ポリビニルピロリドン、メトキシエチ
レン無水マレイン酸共重合体、コポリビドンから選ばれ
る少なくとも１種以上の物質であることを特徴とする被
膜形成性抗真菌剤組成物。3. The composition according to claim 1, wherein the hydrophilic film-forming substance is at least one selected from an alkanolamine neutralized solution of an acrylic resin, polyvinylpyrrolidone, a methoxyethylene maleic anhydride copolymer, and copolyvidone. A film-forming antifungal composition comprising at least one kind of substance.
被膜形成物質が、アクリル樹脂のアルカノールアミン中
和液であることを特徴とする被膜形成性抗真菌剤組成
物。4. The film-forming antifungal composition according to claim 3, wherein the hydrophilic film-forming substance is an alkanolamine neutralizing solution of an acrylic resin.
おいて、低級アルコールを配合することを特徴とする被
膜形成性抗真菌剤組成物。5. The film-forming antifungal composition according to claim 1, further comprising a lower alcohol.
ルコールがエタノール及び／又はイソプロピルアルコー
ルであることを特徴とする被膜形成性抗真菌剤組成物。6. The film-forming antifungal composition according to claim 5, wherein the lower alcohol is ethanol and / or isopropyl alcohol.
おいて、湿潤剤を配合することを特徴とする被膜形成性
抗真菌剤組成物。7. A film-forming antifungal composition according to claim 1, further comprising a wetting agent.
がプロピレングリコール、ジプロピレングリコール、
１，３−ブチレングリコールから選ばれる少なくとも１
種以上であることを特徴とする被膜形成性抗真菌剤組成
物。8. The composition according to claim 7, wherein the wetting agent is propylene glycol, dipropylene glycol,
At least one selected from 1,3-butylene glycol
A film-forming antifungal composition comprising at least one species.
おいて、角質溶解剤を配合することを特徴とする被膜形
成性抗真菌剤組成物。9. A film-forming antifungal agent composition according to claim 1, further comprising a keratolytic agent.
溶解剤が尿素、サリチル酸、サリチル酸ナトリウム、レ
ゾルシンから選ばれる少なくとも１種以上であることを
特徴とする被膜形成性抗真菌剤組成物。10. The film-forming antifungal composition according to claim 9, wherein the keratolytic agent is at least one selected from urea, salicylic acid, sodium salicylate, and resorcinol.
物において、界面活性剤を配合することを特徴とする被
膜形成性抗真菌剤組成物。11. A film-forming antifungal composition comprising the composition according to claim 1 and a surfactant.
面活性剤がアニオン性界面活性剤の１種以上と両性界面
活性剤の１種以上の組み合わせであることを特徴とする
被膜形成性抗真菌剤組成物。12. The composition of claim 11, wherein the surfactant is a combination of one or more anionic surfactants and one or more amphoteric surfactants. Composition.
物において、抗真菌剤が塩酸アモロルフィンであること
を特徴とする被膜形成性抗真菌剤組成物。13. The composition according to claim 1, wherein the antifungal agent is amorolfine hydrochloride.
物において、該組成物が非ピールオフタイプであること
を特徴とする被膜形成性抗真菌剤組成物。14. A film-forming antifungal composition according to claim 1, wherein the composition is a non-peel-off type.
形成性抗真菌剤組成物からなる爪白癬治療剤。15. An agent for treating tinea unguium, comprising the film-forming antifungal agent composition according to any one of claims 1 to 14.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27946497A JP4253047B2 (en) | 1996-09-27 | 1997-09-26 | Film-forming antifungal composition |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27698096 | 1996-09-27 | ||
| JP8-276980 | 1996-09-27 | ||
| JP27946497A JP4253047B2 (en) | 1996-09-27 | 1997-09-26 | Film-forming antifungal composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH10152433A true JPH10152433A (en) | 1998-06-09 |
| JP4253047B2 JP4253047B2 (en) | 2009-04-08 |
Family
ID=26552195
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP27946497A Expired - Fee Related JP4253047B2 (en) | 1996-09-27 | 1997-09-26 | Film-forming antifungal composition |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP4253047B2 (en) |
Cited By (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2785537A1 (en) * | 1999-03-26 | 2000-05-12 | Blue Skin Sa | Antiseptic composition in gel form for disinfecting the skin without using water or soap comprises ethyl alcohol, isopropyl alcohol and a carbomer with gel-forming capability |
| JP2002068974A (en) * | 2000-08-25 | 2002-03-08 | Pola Chem Ind Inc | Antifungal medicine composition |
| JP2002068975A (en) * | 2000-08-25 | 2002-03-08 | Pola Chem Ind Inc | Antifungal medicine composition |
| JP2003321396A (en) * | 2002-04-25 | 2003-11-11 | Sekisui Chem Co Ltd | External preparation |
| JP2004149508A (en) * | 2002-03-08 | 2004-05-27 | Sankyo Co Ltd | Composition having increased antimycotic activity and method for increasing antimycotic activity |
| JP2005104918A (en) * | 2003-09-30 | 2005-04-21 | Kobayashi Pharmaceut Co Ltd | Antifungal composition |
| JPWO2003086433A1 (en) * | 2002-04-15 | 2005-08-18 | 哲夫 山東 | Dermatitis treatment cream |
| JPWO2003086432A1 (en) * | 2002-04-15 | 2005-08-18 | 哲夫 山東 | Dermatitis lotion |
| JP2006232856A (en) * | 2006-06-05 | 2006-09-07 | Kobayashi Pharmaceut Co Ltd | Antifungal composition |
| WO2007077806A1 (en) * | 2005-12-28 | 2007-07-12 | Teikoku Seiyaku Co., Ltd. | Pharmaceutical composition for application to nail |
| WO2007102241A1 (en) | 2006-03-08 | 2007-09-13 | Nihon Nohyaku Co., Ltd. | External pharmaceutical composition |
| JP2009511553A (en) * | 2005-10-14 | 2009-03-19 | ガルデルマ・ソシエテ・アノニム | Pharmaceutical composition based on amorolfine and a water-soluble film-forming agent for application to and around the nail |
| WO2009125667A1 (en) | 2008-04-08 | 2009-10-15 | 帝國製薬株式会社 | Water-based adhesive skin patch containing butenafine hydrochloride |
| US8058303B2 (en) | 2006-03-08 | 2011-11-15 | Nihon Nohyaku Co, Ltd | Pharmaceutical composition for external use |
| US8349882B2 (en) | 2006-03-08 | 2013-01-08 | Nihon Nohyaku Co., Ltd. | Pharmaceutical composition for external use |
| US8513296B2 (en) | 2007-09-05 | 2013-08-20 | Pola Pharma Inc. | Pharmaceutical composition |
| US8697753B1 (en) | 2013-02-07 | 2014-04-15 | Polichem Sa | Method of treating onychomycosis |
| US8952044B2 (en) | 2009-08-25 | 2015-02-10 | Pola Pharma Inc. | Antimycotic pharmaceutical composition |
| US9050271B2 (en) | 2009-04-09 | 2015-06-09 | Pola Pharma Inc. | Antimycotic pharmaceutical composition |
| US9480678B2 (en) | 2007-09-05 | 2016-11-01 | Pola Pharma Inc. | Antifungal pharmaceutical composition |
| US9968591B2 (en) | 2007-09-05 | 2018-05-15 | Pola Pharma Inc. | Antifungal composition |
| US10130610B2 (en) | 2009-04-09 | 2018-11-20 | Pola Pharma Inc. | Antimycotic pharmaceutical composition |
| US10898470B1 (en) | 2019-08-13 | 2021-01-26 | Sato Pharmaceutical Co., Ltd. | Pharmaceutical composition containing antifungal agent as active ingredient |
-
1997
- 1997-09-26 JP JP27946497A patent/JP4253047B2/en not_active Expired - Fee Related
Cited By (31)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2785537A1 (en) * | 1999-03-26 | 2000-05-12 | Blue Skin Sa | Antiseptic composition in gel form for disinfecting the skin without using water or soap comprises ethyl alcohol, isopropyl alcohol and a carbomer with gel-forming capability |
| JP2002068974A (en) * | 2000-08-25 | 2002-03-08 | Pola Chem Ind Inc | Antifungal medicine composition |
| JP2002068975A (en) * | 2000-08-25 | 2002-03-08 | Pola Chem Ind Inc | Antifungal medicine composition |
| JP2004149508A (en) * | 2002-03-08 | 2004-05-27 | Sankyo Co Ltd | Composition having increased antimycotic activity and method for increasing antimycotic activity |
| US7572469B2 (en) | 2002-04-15 | 2009-08-11 | Tetsuo Santo | Therapeutic lotion for dermatitis |
| JPWO2003086433A1 (en) * | 2002-04-15 | 2005-08-18 | 哲夫 山東 | Dermatitis treatment cream |
| JPWO2003086432A1 (en) * | 2002-04-15 | 2005-08-18 | 哲夫 山東 | Dermatitis lotion |
| JP2003321396A (en) * | 2002-04-25 | 2003-11-11 | Sekisui Chem Co Ltd | External preparation |
| JP2005104918A (en) * | 2003-09-30 | 2005-04-21 | Kobayashi Pharmaceut Co Ltd | Antifungal composition |
| JP2009511553A (en) * | 2005-10-14 | 2009-03-19 | ガルデルマ・ソシエテ・アノニム | Pharmaceutical composition based on amorolfine and a water-soluble film-forming agent for application to and around the nail |
| US9579297B2 (en) | 2005-12-28 | 2017-02-28 | Teikoku Seiyaku Co., Ltd. | Pharmaceutical composition for application to nail |
| WO2007077806A1 (en) * | 2005-12-28 | 2007-07-12 | Teikoku Seiyaku Co., Ltd. | Pharmaceutical composition for application to nail |
| US8058303B2 (en) | 2006-03-08 | 2011-11-15 | Nihon Nohyaku Co, Ltd | Pharmaceutical composition for external use |
| WO2007102241A1 (en) | 2006-03-08 | 2007-09-13 | Nihon Nohyaku Co., Ltd. | External pharmaceutical composition |
| US8268876B2 (en) | 2006-03-08 | 2012-09-18 | Nihon Nohyaku Co., Ltd. | Pharmaceutical composition for external use |
| US8349882B2 (en) | 2006-03-08 | 2013-01-08 | Nihon Nohyaku Co., Ltd. | Pharmaceutical composition for external use |
| JP2006232856A (en) * | 2006-06-05 | 2006-09-07 | Kobayashi Pharmaceut Co Ltd | Antifungal composition |
| US9480678B2 (en) | 2007-09-05 | 2016-11-01 | Pola Pharma Inc. | Antifungal pharmaceutical composition |
| US8513296B2 (en) | 2007-09-05 | 2013-08-20 | Pola Pharma Inc. | Pharmaceutical composition |
| US9968591B2 (en) | 2007-09-05 | 2018-05-15 | Pola Pharma Inc. | Antifungal composition |
| WO2009125667A1 (en) | 2008-04-08 | 2009-10-15 | 帝國製薬株式会社 | Water-based adhesive skin patch containing butenafine hydrochloride |
| US10130610B2 (en) | 2009-04-09 | 2018-11-20 | Pola Pharma Inc. | Antimycotic pharmaceutical composition |
| US9050271B2 (en) | 2009-04-09 | 2015-06-09 | Pola Pharma Inc. | Antimycotic pharmaceutical composition |
| US8952044B2 (en) | 2009-08-25 | 2015-02-10 | Pola Pharma Inc. | Antimycotic pharmaceutical composition |
| US9107877B2 (en) | 2013-02-07 | 2015-08-18 | Polichem Sa | Method of treating onychomycosis |
| US8697753B1 (en) | 2013-02-07 | 2014-04-15 | Polichem Sa | Method of treating onychomycosis |
| US10172811B2 (en) | 2013-02-07 | 2019-01-08 | Polichem Sa | Topical antifungal composition for treating onychomycosis |
| US10898470B1 (en) | 2019-08-13 | 2021-01-26 | Sato Pharmaceutical Co., Ltd. | Pharmaceutical composition containing antifungal agent as active ingredient |
| WO2021029350A1 (en) * | 2019-08-13 | 2021-02-18 | 佐藤製薬株式会社 | Pharmaceutical composition containing antifungal agent as active ingredient |
| JP6888180B1 (en) * | 2019-08-13 | 2021-06-16 | 佐藤製薬株式会社 | Pharmaceutical composition containing an antifungal drug as an active ingredient |
| US11738006B2 (en) | 2019-08-13 | 2023-08-29 | Sato Pharmaceutical Co., Ltd. | Pharmaceutical composition containing antifungal agent as active ingredient |
Also Published As
| Publication number | Publication date |
|---|---|
| JP4253047B2 (en) | 2009-04-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4227677B2 (en) | Film-forming antifungal composition | |
| JP4253047B2 (en) | Film-forming antifungal composition | |
| US8741332B2 (en) | Compositions and methods for dermally treating neuropathic pain | |
| US5346692A (en) | Nail lacquer for the treatment of onychomycosis | |
| JP5290582B2 (en) | Pharmaceutical composition for nail | |
| US7198800B1 (en) | Compositions and methods | |
| US5807568A (en) | Enhanced delivery of topical compositions containing flurbiprofen | |
| RU2519664C2 (en) | Compositions and methods of treating nail diseases | |
| AU2006326018B2 (en) | Compositions and methods for dermally treating pain | |
| CA2633489C (en) | Compositions and methods for treating dermatological conditions | |
| US7094422B2 (en) | Topical delivery of antifungal agents | |
| US20070189980A1 (en) | Compositions and methods for treating alopecia | |
| US20070189978A1 (en) | Compositions and methods for dermally treating musculoskeletal pain | |
| US20080019927A1 (en) | Compositions and methods for dermally treating neuropathy with minoxidil | |
| US20070196293A1 (en) | Compositions and methods for treating photo damaged skin | |
| JP3803393B2 (en) | Nail ringworm treatment composition | |
| JP2014001218A (en) | Adhesive peel formation formulation for dermal delivery of drug and method using the same | |
| JP2005503318A (en) | Pharmaceutical composition | |
| US11865217B2 (en) | Transdermal drug delivery system | |
| KR101333892B1 (en) | Antifungal composition | |
| CA2747845C (en) | Compositions and methods for dermally treating pain | |
| WO1994015591A1 (en) | Onychomycosis remedy composition | |
| JP4359140B2 (en) | Formulation for removing abnormal keratinous substances | |
| WO2011061155A1 (en) | Antifungal formulations and their use | |
| JP2001097848A (en) | Preparation composition for external use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20040818 |
|
| A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20050325 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20050325 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20080415 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20080612 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20080612 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20080715 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20080911 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20081028 |
|
| A911 | Transfer of reconsideration by examiner before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20081201 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20090106 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20090123 |
|
| R150 | Certificate of patent (=grant) or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120130 Year of fee payment: 3 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120130 Year of fee payment: 3 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130130 Year of fee payment: 4 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130130 Year of fee payment: 4 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20140130 Year of fee payment: 5 |
|
| S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| LAPS | Cancellation because of no payment of annual fees |