JPH0335288B2 - - Google Patents
Info
- Publication number
- JPH0335288B2 JPH0335288B2 JP58196504A JP19650483A JPH0335288B2 JP H0335288 B2 JPH0335288 B2 JP H0335288B2 JP 58196504 A JP58196504 A JP 58196504A JP 19650483 A JP19650483 A JP 19650483A JP H0335288 B2 JPH0335288 B2 JP H0335288B2
- Authority
- JP
- Japan
- Prior art keywords
- imidazole
- water
- preparation
- chlorobenzyl
- oxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000002360 preparation method Methods 0.000 claims description 33
- -1 polyoxyethylene stearate Polymers 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 25
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 238000009472 formulation Methods 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 229920002125 Sokalan® Polymers 0.000 claims description 7
- 229940121375 antifungal agent Drugs 0.000 claims description 6
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 claims description 5
- 230000000843 anti-fungal effect Effects 0.000 claims description 5
- 239000002736 nonionic surfactant Substances 0.000 claims description 5
- 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 claims description 4
- 239000000839 emulsion Substances 0.000 claims description 4
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 claims description 3
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 3
- 229960000541 cetyl alcohol Drugs 0.000 claims description 3
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 claims description 3
- 239000001587 sorbitan monostearate Substances 0.000 claims description 3
- 235000011076 sorbitan monostearate Nutrition 0.000 claims description 3
- 229940035048 sorbitan monostearate Drugs 0.000 claims description 3
- 239000003381 stabilizer Substances 0.000 claims description 3
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims description 2
- LWJUIYYIILPRRI-UHFFFAOYSA-N 1-[1-[2-[(3-chlorophenyl)methoxy]phenyl]ethenyl]imidazole;hydron;chloride Chemical compound Cl.ClC1=CC=CC(COC=2C(=CC=CC=2)C(=C)N2C=NC=C2)=C1 LWJUIYYIILPRRI-UHFFFAOYSA-N 0.000 claims description 2
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 claims description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 2
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 2
- 229940057838 polyethylene glycol 4000 Drugs 0.000 claims description 2
- 239000012190 activator Substances 0.000 claims 1
- 238000012360 testing method Methods 0.000 description 11
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 239000006071 cream Substances 0.000 description 8
- 235000014113 dietary fatty acids Nutrition 0.000 description 8
- 239000000194 fatty acid Substances 0.000 description 8
- 229930195729 fatty acid Natural products 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000000872 buffer Substances 0.000 description 5
- 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 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 229920001214 Polysorbate 60 Polymers 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000000600 sorbitol Substances 0.000 description 4
- 230000008961 swelling Effects 0.000 description 4
- 206010040880 Skin irritation Diseases 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000036556 skin irritation Effects 0.000 description 3
- 231100000475 skin irritation Toxicity 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- JVTIXNMXDLQEJE-UHFFFAOYSA-N 2-decanoyloxypropyl decanoate 2-octanoyloxypropyl octanoate Chemical compound C(CCCCCCC)(=O)OCC(C)OC(CCCCCCC)=O.C(=O)(CCCCCCCCC)OCC(C)OC(=O)CCCCCCCCC JVTIXNMXDLQEJE-UHFFFAOYSA-N 0.000 description 2
- BGRXBNZMPMGLQI-UHFFFAOYSA-N 2-octyldodecyl tetradecanoate Chemical compound CCCCCCCCCCCCCC(=O)OCC(CCCCCCCC)CCCCCCCCCC BGRXBNZMPMGLQI-UHFFFAOYSA-N 0.000 description 2
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- LLEMOWNGBBNAJR-UHFFFAOYSA-N biphenyl-2-ol Chemical compound OC1=CC=CC=C1C1=CC=CC=C1 LLEMOWNGBBNAJR-UHFFFAOYSA-N 0.000 description 2
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 229960004022 clotrimazole Drugs 0.000 description 2
- 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 2
- 150000001875 compounds Chemical class 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- HCZKYJDFEPMADG-TXEJJXNPSA-N masoprocol Chemical compound C([C@H](C)[C@H](C)CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-TXEJJXNPSA-N 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 229950011392 sorbitan stearate Drugs 0.000 description 2
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- DSEKYWAQQVUQTP-XEWMWGOFSA-N (2r,4r,4as,6as,6as,6br,8ar,12ar,14as,14bs)-2-hydroxy-4,4a,6a,6b,8a,11,11,14a-octamethyl-2,4,5,6,6a,7,8,9,10,12,12a,13,14,14b-tetradecahydro-1h-picen-3-one Chemical compound C([C@H]1[C@]2(C)CC[C@@]34C)C(C)(C)CC[C@]1(C)CC[C@]2(C)[C@H]4CC[C@@]1(C)[C@H]3C[C@@H](O)C(=O)[C@@H]1C DSEKYWAQQVUQTP-XEWMWGOFSA-N 0.000 description 1
- PAFJZWHXMSQJKV-UQZRNVAESA-N (3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol;octadecanoic acid Chemical compound OC[C@@H](O)C1OC[C@H](O)[C@H]1O.OC[C@@H](O)C1OC[C@H](O)[C@H]1O.OC[C@@H](O)C1OC[C@H](O)[C@H]1O.CCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O PAFJZWHXMSQJKV-UQZRNVAESA-N 0.000 description 1
- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 description 1
- ZWVMLYRJXORSEP-UHFFFAOYSA-N 1,2,6-Hexanetriol Chemical compound OCCCCC(O)CO ZWVMLYRJXORSEP-UHFFFAOYSA-N 0.000 description 1
- LEZWWPYKPKIXLL-UHFFFAOYSA-N 1-{2-(4-chlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound C1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 LEZWWPYKPKIXLL-UHFFFAOYSA-N 0.000 description 1
- FKOKUHFZNIUSLW-UHFFFAOYSA-N 2-Hydroxypropyl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(C)O FKOKUHFZNIUSLW-UHFFFAOYSA-N 0.000 description 1
- XULHFMYCBKQGEE-UHFFFAOYSA-N 2-hexyl-1-Decanol Chemical compound CCCCCCCCC(CO)CCCCCC XULHFMYCBKQGEE-UHFFFAOYSA-N 0.000 description 1
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 1
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
- ODJQKYXPKWQWNK-UHFFFAOYSA-N 3,3'-Thiobispropanoic acid Chemical compound OC(=O)CCSCCC(O)=O ODJQKYXPKWQWNK-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
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- 125000005274 4-hydroxybenzoic acid group Chemical class 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- 239000004287 Dehydroacetic acid Substances 0.000 description 1
- 241000233866 Fungi Species 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- 239000004163 Spermaceti wax Substances 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000003490 Thiodipropionic acid Substances 0.000 description 1
- 208000002474 Tinea Diseases 0.000 description 1
- 241000223238 Trichophyton Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- LNTHITQWFMADLM-UHFFFAOYSA-N anhydrous gallic acid Natural products OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 description 1
- 235000019258 dehydroacetic acid Nutrition 0.000 description 1
- 229940061632 dehydroacetic acid Drugs 0.000 description 1
- JEQRBTDTEKWZBW-UHFFFAOYSA-N dehydroacetic acid Chemical compound CC(=O)C1=C(O)OC(C)=CC1=O JEQRBTDTEKWZBW-UHFFFAOYSA-N 0.000 description 1
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Natural products CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940031578 diisopropyl adipate Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229960003913 econazole Drugs 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- HCZKYJDFEPMADG-UHFFFAOYSA-N erythro-nordihydroguaiaretic acid Natural products C=1C=C(O)C(O)=CC=1CC(C)C(C)CC1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229940074391 gallic acid Drugs 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- XXMIOPMDWAUFGU-UHFFFAOYSA-N hexane-1,6-diol Chemical compound OCCCCCCO XXMIOPMDWAUFGU-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 229960003951 masoprocol Drugs 0.000 description 1
- 229960002509 miconazole Drugs 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 235000019808 microcrystalline wax Nutrition 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 235000010292 orthophenyl phenol Nutrition 0.000 description 1
- 239000004306 orthophenyl phenol Substances 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 1
- 229940113115 polyethylene glycol 200 Drugs 0.000 description 1
- 229940068886 polyethylene glycol 300 Drugs 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229940057847 polyethylene glycol 600 Drugs 0.000 description 1
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 229940093625 propylene glycol monostearate Drugs 0.000 description 1
- 238000011076 safety test Methods 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 239000001570 sorbitan monopalmitate Substances 0.000 description 1
- 235000011071 sorbitan monopalmitate Nutrition 0.000 description 1
- 229940031953 sorbitan monopalmitate Drugs 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 235000019385 spermaceti wax Nutrition 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 235000019303 thiodipropionic acid Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明はイミダゾール系抗真菌性外用乳化製剤
に関するものであり、さらに詳しくは１−［１−
［２−［（３−クロロベンジル）オキシ］フエニル］
ビニル］−1H−イミダゾールまたはその製薬上許
容される塩を有効成分として含有する乳化製剤に
関するものである。
イミダゾール系抗真菌性外用剤として、クロト
マゾール、ミコナゾールおよびエコナゾールなど
がクリームまたは液剤の剤型で現在市販されてい
るが、本発明者らはイミダゾール系抗真菌薬とし
て最近開発された１−［１−［２−［（３−クロロベ
ンジル）オキシ］フエニル］ビニル］−1H−イミ
ダゾールまたはその製薬上許容される塩を有効成
分とする外用製剤の創製を試みた。その結果、１
−［１−［２−［（３−クロロベンジル）オキシ］フ
エニル］ビニル］−1H−イミダゾールまたはその
製薬上許容される塩（以下主薬と記載する）、油
性物質、非イオン性界面活性剤、を一定比率で含
んでおりかつ水を組成々分として含有する乳化製
剤が上記の市販抗真菌性外用剤に比較して安全性
に優れておりかつ製剤としての物理的安定性も良
好であることを見い出し、本発明を完成した。
本発明の乳化製剤の組成は以下のとおりであ
る。なお、本明細書におけるパーセント（％）は
重量パーセント（重量／重量）を意味する。
主 薬 0.2〜2.0％
油性物質 １〜50％
非イオン性界面活性剤 0.5〜15％
水 適量
を含有する製剤。
本発明は上記組成を有する乳化製剤すべてを包
含するが、上記組成は特に、ローシヨンやクリー
ムに適している。
上記組成を有する乳化製剤の具体例として好ま
しい補助成分およびその組成比を以下に示す。
主 薬 0.2〜2.0％
油性物質 １〜50％
非イオン性界面活性剤 0.5〜15％
カルボキシビニルポリマー 0.1〜2.5％
C2〜C6の一乃至三価アルコール ０〜30％
平均分子量200〜4000のポリエチレングリコー
ル ０〜30％
安定剤 適量
水 必要量（全量で100％とする）。
次に本発明にかかる乳化製剤の各組成分につい
て記載する。
主薬である１−［１−［２−［（３−クロロベンジ
ル）オキシ］フエニル］ビニル］−1H−イミダゾ
ールは特開昭55−164677号公報およびJ.Med.
Chem.26巻768頁（1983年）に記載されている化
合物で下記の構造式を有する。
本発明においては上記化合物またはその製薬上
許容される塩、例えば、塩酸塩、硝酸塩、硫酸
塩、蓚酸塩、コハク酸塩、などが用いられ、製剤
全量に対して約0.2〜２重量％が有効成分として
含有される。
油性物質としては具体的には、２−ヘキシルデ
カノール、２−オクチルドデカノールなどの液状
の高級アルコール類、セチルアルコール、ステア
リルアルコールなどの固型の高級アルコール類、
パルミチン酸、ステアリン酸などの高級脂肪酸、
ミリスチン酸イソプロピル、ミリスチン酸２−オ
クチルドデシル、セパシン酸ジエチル、アジピン
酸ジイソプロピルなどのエステル類、スクワラ
ン、流動パラフイン、各種パラフイン、ワセリ
ン、ミクロクリスタリンワツクス、セレシンなど
の液状、半固型、固型の炭化水素類、蜜ろう、鯨
ろう、カルナウバろうなどのろう類、ヒマシ油、
オリーブ油などの天然の脂肪酸トリグリセリド
類、合成トリグリセリド類、ジグリセリド類なら
びに高級脂肪酸モノグリセリド類などを挙げるこ
とができる。
使用する油性物質の種類、混合比、およびその
製剤全重量に対する割合は使用する主薬の性状、
外用製剤の剤型などに左右されるが、一般に製剤
全量の１〜50重量％、好ましくはクリームで10〜
35重量％、ローシヨンで２〜10重量％が用いられ
る。
非イオン性界面活性剤は、ソルビタン脂肪酸エ
ステル、ソルビトール脂肪酸エステル、ポリオキ
シエチレンソルビタン脂肪酸エステル、ポリオキ
シエチレン脂肪酸エステル、ポリオキシエチレン
アルキルエーテル、ポリオキシエチレン硬化ヒマ
シ油誘導体、ポリオキシエチレンポリオキシプロ
ピレンアルキルエーテルなどで具体的にはモノラ
ウリン酸ソルビタン、モノパルミチン酸ソルビタ
ン、モノステアリン酸ソルビタン、セスキステア
リン酸ソルビタン、モノラウリン酸ポリオキシエ
チレンソルビタン、モノパルミチン酸ポリオキシ
エチレンソルビタン、モノステアリン酸ポリオキ
シエチレンソルビタン、トリステアリン酸ポリオ
キシエチレンソルビタン、モノオレイン酸ポリオ
キシエチレンソルビタン、トリオレイン酸ポリオ
キシエチレンソルビタン、モノラウリン酸ポリオ
キシエチレンソルビトール、ヘキサステアリン酸
ポリオキシエチレンソルビトール、テトラオレイ
ン酸ポリオキシエチレンソルビトール、ポリオキ
シエチレンラウリルエステル、ポリオキシエチレ
ンステアリルエステル、ポリオキシエチレンオレ
イルエステル、ポリオキシエチレンラウリルエー
テル、ポリオキシエチレンセチルエーテル、ポリ
オキシエチレンステアリルエーテル、ポリオキシ
エチレンオレイルエーテル、ポリオキシエチレン
ヘキサデシルエーテル、モノステアリン酸プロピ
レングリコール、ポリオキシプロピレンポリオキ
シエチレンセチルエーテルなどとして例示するこ
とができる。これらの界面活性剤は単独でも、ま
た混合して使用してもよく、製剤全量に対し0.5
〜15重量％好ましくは１〜10重量％の割合で使用
される。
カルボキシビニルポリマーとしては、市販のカ
ーボポール（Carbopol）934（グツドリツチ・ケ
ミカル社製）、同940、同941、ハイビスワコー
（HIVISWAKO）103（和光純薬社製）、同104、同
105などが例示される。カルボキシビニルポリマ
ーは製剤全量に対して0.1〜2.5重量％、より好ま
しくは0.2〜1.0重量％の割合で用いられる。
C2〜C6の一乃至三価アルコールとは、炭素数
２〜６の直鎖状または分枝状の一乃至三価アルコ
ールを意味し、具体的にはエタノール、イソプロ
パノール、エチレングリコール肪酸、プロピレン
グリコール、トリエチレングリコール、１，３−
ブタンジオール、１，４−ブタンジオール、１，
５−ペンタンジオール、１，６−ヘキサンジオー
ル、グリセリン、１，２，６−ヘキサントリオー
ルなどが例示される。これらのアルコール類は製
剤全重量に対し、０〜30重量％、好ましくは０〜
10重量％の割合で用いられる。
他の補助成分として挙げた平均分子量約200〜
4000のポリエチレングリコールはポリエチレング
リコール200、同300、同400、同600、同1000、同
1500、同1540、同4000などとして例示される。こ
れらは製剤全重量に対し０〜30重量％が用いられ
る。
安定剤としては、通常外用製剤に用いられる酸
化防止剤、防腐剤、キレート剤、緩衝剤などが包
含され、酸化防止剤としては、例えば、没食子酸
アルキルエステル、ブチルヒドロキシアニソー
ル、ブチルヒドロキシトルエン、トコフエロー
ル、チオジプロピオン酸、ノルジヒドログアイア
レチン酸（nordihydroguaiaretic acid）などが、
防腐剤としては、例えば、パラヒドロキシ安息香
酸エステル類、デヒドロ酢酸、オルトフエニルフ
エノール、ソルビタン酸などが、またキレート剤
としてはエチレンジアミン四酢酸ジナトリウムな
どが、常法に従つて用いられる。緩衝剤として
は、リン酸緩衝液などの外用製剤に通常用いられ
るものを使用し、最終製剤のPHが約４〜７になる
ようにする。
本発明の乳化製剤のうちで、特に好ましいクリ
ーム製剤の組成々分は、１−［１−［２−［（３−ク
ロロベンジル）オキシ］フエニル］ビニル］−1H
−イミダゾール塩酸塩、セチルアルコール、ミリ
スチン酸２−オクチルドデシル、モノステアリン
酸ソルビタン、ステアリン酸ポリオキシエチレン
ソルビタン、カルボキシビニルポリマー、エチレ
ンジアミン四酢酸ジナトリウム、ｐ−ヒドロキシ
安息香酸メチル、ｐ−ヒドロキシ安息香酸ブチル
および水よりなり、緩衝剤でPH4.0〜7.0に調整す
る。
本発明の乳化製剤の調製は、主薬の溶解性に応
じて常法に従つて行なう。例えば、主薬が水溶性
の場合は加温した水に溶かし、主薬が水に難溶ま
たは不溶の場合は必要により加温した水、C2〜
C6の一乃至三価アルコールおよび／またはポリ
エチレングリコールの混合液に主薬を溶解または
分散する。別に他の成分を混合、加温、混和し、
ここへ上記の主薬混合物を加えて撹拌、乳化す
る。ついで緩衝剤を加えて撹拌しながら室温まで
冷却すると所望の乳化製剤が得られる。
かくして得られた乳化製剤は主薬が基剤に適度
に溶解しているために主薬の皮膚への放出が良好
で、主薬が皮膚より吸収される割合が極めて高
く、治療効果が優れている。また皮膚刺激が少な
く、物理的安定性においても優れた製剤である。
以下に市販のイミダゾール系抗真菌性外用剤を
対照に用いて行なつた本発明のクリーム製剤の安
全性および有効性試験の結果を示す。なお、試験
製剤の処方は対応する番号の実施例に示す。
(1) 安全性試験（皮膚刺激試験）
ａ 試験方法
マウス７匹を１群とし、それぞれの右耳殻
に試験製剤0.1ｇを朝夕、１日２回、４日間
または11日間にわたり塗布する。塗布最終日
の翌日に右耳殻を先端より９mmで切断して秤
量する。別に無塗布対照群を設け、同様に右
耳殻重量を測定して腫脹比を求めた。
腫脹比＝塗布群耳殻重量／無塗布群耳殻重量×100
ｂ 試験結果
表１に示す。なお、表中に示した数値は市
販のクロトリマゾールクリーム製剤（商品
名、エンペミドクリーム）塗布による腫脹比
を100として算出した試験製剤の腫脹比の相
対値であり、数値が小さい程、皮膚刺激が弱
く安全性が高いことを示す。
(2) 有効性試験（抗白癬症試験）
ａ 試験方法
モルモツトの背部４箇所を抜毛し、白癬菌
（Trichophyton asteroides）の胞子液を接
種し、菌感染２日後より３箇所に被験製剤を
１日１回８日間連続塗布し、１箇所を感染対
照とする。最終治療の翌日にモルモツトを屠
殺し、治療箇所の皮膚面を切除し、細切して
シクロヘキサマイド500μｇ／mlおよびペニ
シリンG100μｇ／mlを含むサブロー・グルコ
ース寒天培地に28℃、７日間培養後菌生育の
有無を判定し、菌陰性率を算出した。
ｂ 試験結果
表１に示す。表中の数値は安定性試験と同
様にクロトリマゾールクリーム製剤の菌陰性
率を100として算出した相対値であり、数値
が大きい程有効性が高いことを示す。
The present invention relates to imidazole-based antifungal emulsions for external use, and more specifically, 1-[1-
[2-[(3-chlorobenzyl)oxy]phenyl]
The present invention relates to an emulsified preparation containing vinyl]-1H-imidazole or a pharmaceutically acceptable salt thereof as an active ingredient. Clotomazole, miconazole, and econazole are currently commercially available as imidazole antifungal agents for external use in the form of creams or liquids. An attempt was made to create an external preparation containing [2-[(3-chlorobenzyl)oxy]phenyl]vinyl]-1H-imidazole or a pharmaceutically acceptable salt thereof as an active ingredient. As a result, 1
-[1-[2-[(3-chlorobenzyl)oxy]phenyl]vinyl]-1H-imidazole or a pharmaceutically acceptable salt thereof (hereinafter referred to as the active ingredient), an oily substance, a nonionic surfactant, The emulsified formulation containing a certain proportion of the above-mentioned water and water as a constituent is superior in safety and has good physical stability as a formulation compared to the above-mentioned commercially available antifungal external preparations. They discovered this and completed the present invention. The composition of the emulsified preparation of the present invention is as follows. Note that percentage (%) in this specification means weight percent (weight/weight). Main drug 0.2-2.0% Oily substance 1-50% Non-ionic surfactant 0.5-15% Water Preparation containing appropriate amount. Although the present invention encompasses all emulsified preparations having the above composition, the above composition is particularly suitable for lotions and creams. Preferred auxiliary components and their composition ratios are shown below as specific examples of emulsified preparations having the above composition. Main drug 0.2-2.0% Oily substance 1-50% Nonionic surfactant 0.5-15% Carboxyvinyl polymer 0.1-2.5% C2 - C6 mono- or trihydric alcohol 0-30% Average molecular weight 200-4000 Polyethylene glycol 0-30% Stabilizer Appropriate amount Water Required amount (total amount is 100%). Next, each component of the emulsified preparation according to the present invention will be described. The main drug, 1-[1-[2-[(3-chlorobenzyl)oxy]phenyl]vinyl]-1H-imidazole, is disclosed in JP-A-55-164677 and J.Med.
It is a compound described in Chem. Vol. 26, p. 768 (1983) and has the following structural formula. In the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof, such as hydrochloride, nitrate, sulfate, oxalate, succinate, etc., is used, and is effective in an amount of about 0.2 to 2% by weight based on the total amount of the preparation. Contained as an ingredient. Specifically, the oily substances include liquid higher alcohols such as 2-hexyldecanol and 2-octyldodecanol, solid higher alcohols such as cetyl alcohol and stearyl alcohol,
Higher fatty acids such as palmitic acid and stearic acid,
Esters such as isopropyl myristate, 2-octyldodecyl myristate, diethyl sepacate, diisopropyl adipate, squalane, liquid paraffin, various paraffins, petrolatum, microcrystalline wax, ceresin, etc. in liquid, semi-solid, and solid form. Hydrocarbons, waxes such as beeswax, spermaceti wax, carnauba wax, castor oil,
Examples include natural fatty acid triglycerides such as olive oil, synthetic triglycerides, diglycerides, and higher fatty acid monoglycerides. The type of oil-based substance used, the mixing ratio, and its proportion to the total weight of the formulation depend on the properties of the main drug used,
Although it depends on the dosage form of the external preparation, it is generally 1 to 50% by weight of the total amount of the preparation, preferably 10 to 50% for creams.
35% by weight, 2-10% by weight in lotions. Nonionic surfactants include sorbitan fatty acid ester, sorbitol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil derivative, polyoxyethylene polyoxypropylene alkyl Examples of ethers include sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquistearate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, and ethers. Polyoxyethylene sorbitan stearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan trioleate, polyoxyethylene sorbitol monolaurate, polyoxyethylene sorbitol hexastearate, polyoxyethylene sorbitol tetraoleate, polyoxyethylene lauryl Ester, polyoxyethylene stearyl ester, polyoxyethylene oleyl ester, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene hexadecyl ether, propylene glycol monostearate , polyoxypropylene polyoxyethylene cetyl ether, and the like. These surfactants may be used alone or in combination, and should be added at a concentration of 0.5 to the total amount of the preparation.
It is used in proportions of up to 15% by weight, preferably 1 to 10% by weight. As carboxyvinyl polymers, commercially available Carbopol 934 (manufactured by Gutsudoritsuchi Chemical Co., Ltd.), Carbopol 940, Carbopol 941, HIVISWAKO 103 (made by Wako Pure Chemical Industries, Ltd.), Carbopol 104, Carbopol 941, HIVISWAKO 103 (made by Wako Pure Chemical Industries),
105 etc. are exemplified. The carboxyvinyl polymer is used in an amount of 0.1 to 2.5% by weight, more preferably 0.2 to 1.0% by weight, based on the total amount of the preparation. C2 - C6 mono- to trihydric alcohol means a linear or branched mono- to trihydric alcohol having 2 to 6 carbon atoms, and specifically includes ethanol, isopropanol, ethylene glycol fatty acid, Propylene glycol, triethylene glycol, 1,3-
Butanediol, 1,4-butanediol, 1,
Examples include 5-pentanediol, 1,6-hexanediol, glycerin, and 1,2,6-hexanetriol. These alcohols are contained in an amount of 0 to 30% by weight, preferably 0 to 30% by weight based on the total weight of the preparation.
It is used in a proportion of 10% by weight. Average molecular weight listed as other auxiliary ingredients: approximately 200~
Polyethylene glycol 4000 is polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, polyethylene glycol
Examples include 1500, 1540, 4000, etc. These are used in an amount of 0 to 30% by weight based on the total weight of the preparation. Stabilizers include antioxidants, preservatives, chelating agents, buffers, etc. that are commonly used in external preparations, and examples of antioxidants include gallic acid alkyl esters, butylated hydroxyanisole, butylated hydroxytoluene, and tocopherols. , thiodipropionic acid, nordihydroguaiaretic acid, etc.
As the preservative, for example, parahydroxybenzoic acid esters, dehydroacetic acid, orthophenylphenol, sorbitan acid, etc. are used, and as the chelating agent, disodium ethylenediaminetetraacetate and the like are used in a conventional manner. As a buffer, one commonly used for external preparations, such as a phosphate buffer, is used, and the pH of the final preparation is adjusted to about 4 to 7. Among the emulsified preparations of the present invention, a particularly preferred composition of the cream preparation is 1-[1-[2-[(3-chlorobenzyl)oxy]phenyl]vinyl]-1H
- Imidazole hydrochloride, cetyl alcohol, 2-octyldodecyl myristate, sorbitan monostearate, polyoxyethylene sorbitan stearate, carboxyvinyl polymer, disodium ethylenediaminetetraacetate, methyl p-hydroxybenzoate, butyl p-hydroxybenzoate and water, and adjust the pH to 4.0 to 7.0 with a buffer. The emulsion preparation of the present invention is prepared according to conventional methods depending on the solubility of the main drug. For example, if the active ingredient is water-soluble, dissolve it in heated water, and if the active ingredient is sparingly soluble or insoluble in water, use warmed water if necessary .
The main drug is dissolved or dispersed in a mixture of C6 mono- to trihydric alcohol and/or polyethylene glycol. Separately mix, warm, and mix other ingredients,
The above active ingredient mixture is added to this and stirred to emulsify. Then, a buffer is added and the mixture is cooled to room temperature while stirring to obtain the desired emulsified formulation. In the emulsified preparation thus obtained, the main drug is appropriately dissolved in the base, so the main drug is released well into the skin, and the rate of absorption of the main drug through the skin is extremely high, resulting in excellent therapeutic effects. It is also a formulation with little skin irritation and excellent physical stability. The results of a safety and efficacy test of the cream formulation of the present invention using a commercially available imidazole antifungal external preparation as a control are shown below. The formulation of the test preparation is shown in the correspondingly numbered Examples. (1) Safety test (skin irritation test) a Test method A group of 7 mice is made, and 0.1 g of the test preparation is applied to the right ear shell of each group, twice a day in the morning and evening for 4 or 11 days. On the day after the last day of application, cut the right ear shell 9 mm from the tip and weigh it. A separate non-application control group was established, and the weight of the right ear shell was similarly measured to determine the swelling ratio. Swelling ratio=Ear shell weight of applied group/Ear shell weight of non-applied group x 100b Test results are shown in Table 1. The values shown in the table are relative values of the swelling ratio of the test preparation, which was calculated by setting the swelling ratio due to the application of a commercially available clotrimazole cream preparation (trade name, Empemid Cream) as 100. Indicates low stimulation and high safety. (2) Efficacy test (anti-ringworm test) a Test method Hair was removed from 4 areas on the back of guinea pigs, inoculated with Trichophyton asteroides spore solution, and the test preparation was applied to 3 areas for 1 day starting 2 days after infection with the fungus. Apply once for 8 consecutive days, and use one area as an infection control. The day after the final treatment, the guinea pigs were sacrificed, the skin surface of the treated area was excised, cut into small pieces, and cultured on Sabouraud glucose agar containing 500 μg/ml of cyclohexamide and 100 μg/ml of penicillin G at 28°C for 7 days. The presence or absence of growth was determined, and the bacterial negative rate was calculated. b Test results are shown in Table 1. The numerical values in the table are relative values calculated based on the bacterial negative rate of the clotrimazole cream formulation as 100, as in the stability test, and the larger the numerical value, the higher the effectiveness.
【表】
上記試験結果から明らかなように本発明の製剤
は、皮膚刺激が少なく自癬症に対する治療効果が
高い優れた製剤である。
次に実施例において本発明の実施態様を示す
が、これら実施例は何ら本発明を限定するもので
はない。
実施例 １−６
表２に示す組成々分および組成比の乳化製剤を
調製する。調製方法は下記のとおりである。
70〜80℃に加温した水あるいは水とプロピレン
グリコールまたは水とポリエチレングリコールの
混液に主薬を溶解または分散し、別に他の組成々
分を混合、70〜80℃に加温、混和したものに加
え、撹拌、乳化を行つた後、PH緩衝液を加えてPH
４〜７に調製し、撹拌しながら室温まで冷却し、
乳化製剤を得た。[Table] As is clear from the above test results, the preparation of the present invention is an excellent preparation that causes little skin irritation and is highly effective in treating japonicosis. Next, embodiments of the present invention will be shown in Examples, but these Examples are not intended to limit the present invention in any way. Example 1-6 An emulsified formulation having the composition and composition ratio shown in Table 2 is prepared. The preparation method is as follows. The active ingredient is dissolved or dispersed in water heated to 70 to 80°C, or a mixture of water and propylene glycol, or water and polyethylene glycol, and the other components are separately mixed, heated to 70 to 80°C, and mixed. After adding, stirring, and emulsifying, add PH buffer to adjust the PH.
4 to 7, cooled to room temperature while stirring,
An emulsified formulation was obtained.
【表】【table】
Claims (1)
シ］フエニル］ビニル］−1H−イミダゾールまた
はその製薬上許容される塩0.2〜2.0％、油性物質
〜50％、非イオン性界面活性剤0.5〜15％および
水を含有することを特徴とするイミダゾール系抗
真菌性外用乳化製剤。 ２ １−［１−［２−［（３−クロロベンジル）オキ
シ］フエニル］ビニル］−1H−イミダゾールまた
はその製薬上許容される塩0.2〜2.0％、油性物質
１〜50％、非イオン性界面活性剤0.5〜15％、カ
ルボキシビニルポリマー0.1〜2.5％、C2〜C6の一
乃至三価アルコール０〜30％、平均分子量200〜
4000のポリエチレングリコール０〜30％、適量の
安定剤および水を含有することを特徴とするイミ
ダゾール系抗真菌性外用乳化製剤。 ３ １−［１−［２−［（３−クロロベンジル）オキ
シ］フエニル］ビニル］−1H−イミダゾール塩酸
塩、セチルアルコール、ミリスチン酸、２−オク
チルドデシル、モノステアリン酸ソルビタン、ス
テアリン酸ポリオキシエチレンソルビタン、カル
ボキシビニルポリマー、エチレンジアミン四酢酸
ジナトリウム、ｐ―ヒドロキシ安息香酸メチル、
ｐ−ヒドロキシ安息香酸ブチルおよび水を含有す
る特許請求の範囲２の製剤。[Claims] 1 1-[1-[2-[(3-chlorobenzyl)oxy]phenyl]vinyl]-1H-imidazole or a pharmaceutically acceptable salt thereof 0.2-2.0%, oily substance ~50% , an imidazole-based antifungal emulsion preparation for external use, characterized by containing 0.5 to 15% of a nonionic surfactant and water. 2 1-[1-[2-[(3-chlorobenzyl)oxy]phenyl]vinyl]-1H-imidazole or its pharmaceutically acceptable salt 0.2-2.0%, oily substance 1-50%, nonionic interface Activator 0.5-15%, carboxyvinyl polymer 0.1-2.5%, C2 - C6 mono- to trihydric alcohol 0-30%, average molecular weight 200-
An imidazole-based antifungal emulsion preparation for external use, characterized by containing 0 to 30% of polyethylene glycol 4000, an appropriate amount of a stabilizer, and water. 3 1-[1-[2-[(3-chlorobenzyl)oxy]phenyl]vinyl]-1H-imidazole hydrochloride, cetyl alcohol, myristic acid, 2-octyldodecyl, sorbitan monostearate, polyoxyethylene stearate Sorbitan, carboxyvinyl polymer, disodium ethylenediaminetetraacetate, methyl p-hydroxybenzoate,
The formulation of claim 2 containing butyl p-hydroxybenzoate and water.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58196504A JPS6087222A (en) | 1983-10-19 | 1983-10-19 | Imidazole-type antimycotic emulsion for external use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58196504A JPS6087222A (en) | 1983-10-19 | 1983-10-19 | Imidazole-type antimycotic emulsion for external use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6087222A JPS6087222A (en) | 1985-05-16 |
| JPH0335288B2 true JPH0335288B2 (en) | 1991-05-27 |
Family
ID=16358851
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58196504A Granted JPS6087222A (en) | 1983-10-19 | 1983-10-19 | Imidazole-type antimycotic emulsion for external use |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6087222A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9705340D0 (en) * | 1997-03-14 | 1997-04-30 | Nycomed Imaging As | Compositions |
-
1983
- 1983-10-19 JP JP58196504A patent/JPS6087222A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6087222A (en) | 1985-05-16 |
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