CN1098074C - 外用酮康唑乳剂 - Google Patents
外用酮康唑乳剂 Download PDFInfo
- Publication number
- CN1098074C CN1098074C CN95194847A CN95194847A CN1098074C CN 1098074 C CN1098074 C CN 1098074C CN 95194847 A CN95194847 A CN 95194847A CN 95194847 A CN95194847 A CN 95194847A CN 1098074 C CN1098074 C CN 1098074C
- Authority
- CN
- China
- Prior art keywords
- emulsion
- acid
- ketoconazole
- polysorbate
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 239000000839 emulsion Substances 0.000 title claims abstract description 52
- 229960004125 ketoconazole Drugs 0.000 title claims abstract description 41
- 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 title claims abstract description 40
- 230000000699 topical effect Effects 0.000 title description 3
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 7
- 230000008569 process Effects 0.000 claims abstract description 6
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 5
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 5
- 235000010265 sodium sulphite Nutrition 0.000 claims abstract description 5
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical group CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 48
- 239000000203 mixture Substances 0.000 claims description 32
- -1 polyoxyethylene Polymers 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 21
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 20
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 17
- 239000003513 alkali Substances 0.000 claims description 15
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 13
- 229920000053 polysorbate 80 Polymers 0.000 claims description 13
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 claims description 13
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 12
- 239000000872 buffer Substances 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 12
- 229940068968 polysorbate 80 Drugs 0.000 claims description 12
- 229920002125 Sokalan® Polymers 0.000 claims description 11
- 239000004816 latex Substances 0.000 claims description 11
- 229920000126 latex Polymers 0.000 claims description 11
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 9
- 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 9
- 229960001631 carbomer Drugs 0.000 claims description 9
- 239000003921 oil Substances 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 8
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 8
- 230000002421 anti-septic effect Effects 0.000 claims description 8
- 229960000541 cetyl alcohol Drugs 0.000 claims description 8
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 7
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 7
- 230000000845 anti-microbial effect Effects 0.000 claims description 7
- ZCTXEAQXZGPWFG-UHFFFAOYSA-N imidurea Chemical compound O=C1NC(=O)N(CO)C1NC(=O)NCNC(=O)NC1C(=O)NC(=O)N1CO ZCTXEAQXZGPWFG-UHFFFAOYSA-N 0.000 claims description 7
- 239000003755 preservative agent Substances 0.000 claims description 7
- 239000001587 sorbitan monostearate Substances 0.000 claims description 7
- 235000011076 sorbitan monostearate Nutrition 0.000 claims description 7
- 229940035048 sorbitan monostearate Drugs 0.000 claims description 7
- 239000004599 antimicrobial Substances 0.000 claims description 6
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 claims description 6
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 claims description 6
- 229940113124 polysorbate 60 Drugs 0.000 claims description 6
- 230000002335 preservative effect Effects 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 5
- 239000003381 stabilizer Substances 0.000 claims description 4
- 239000006071 cream Substances 0.000 claims description 3
- 239000007764 o/w emulsion Substances 0.000 claims description 3
- 239000002085 irritant Substances 0.000 claims 1
- 231100000021 irritant Toxicity 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000012071 phase Substances 0.000 description 17
- 239000002562 thickening agent Substances 0.000 description 12
- 239000002674 ointment Substances 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 239000003995 emulsifying agent Substances 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- 239000000080 wetting agent Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000003925 fat Substances 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical class CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 206010070834 Sensitisation Diseases 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229920000136 polysorbate Polymers 0.000 description 3
- 230000008313 sensitization Effects 0.000 description 3
- DTOUUUZOYKYHEP-UHFFFAOYSA-N 1,3-bis(2-ethylhexyl)-5-methyl-1,3-diazinan-5-amine Chemical compound CCCCC(CC)CN1CN(CC(CC)CCCC)CC(C)(N)C1 DTOUUUZOYKYHEP-UHFFFAOYSA-N 0.000 description 2
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LVDKZNITIUWNER-UHFFFAOYSA-N Bronopol Chemical compound OCC(Br)(CO)[N+]([O-])=O LVDKZNITIUWNER-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 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 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000003796 beauty Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229960003168 bronopol Drugs 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 229960004867 hexetidine Drugs 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 229960000502 poloxamer Drugs 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 229950008882 polysorbate Drugs 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000002884 skin cream Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 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 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- JCIIKRHCWVHVFF-UHFFFAOYSA-N 1,2,4-thiadiazol-5-amine;hydrochloride Chemical compound Cl.NC1=NC=NS1 JCIIKRHCWVHVFF-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- CTTJWXVQRJUJQW-UHFFFAOYSA-N 2,2-dioctyl-3-sulfobutanedioic acid Chemical compound CCCCCCCCC(C(O)=O)(C(C(O)=O)S(O)(=O)=O)CCCCCCCC CTTJWXVQRJUJQW-UHFFFAOYSA-N 0.000 description 1
- DBHODFSFBXJZNY-UHFFFAOYSA-N 2,4-dichlorobenzyl alcohol Chemical compound OCC1=CC=C(Cl)C=C1Cl DBHODFSFBXJZNY-UHFFFAOYSA-N 0.000 description 1
- OFQCQIGMURIECL-UHFFFAOYSA-N 2-[2-(diethylamino)ethyl]-2',6'-dimethylspiro[isoquinoline-4,4'-oxane]-1,3-dione;phosphoric acid Chemical compound OP(O)(O)=O.O=C1N(CCN(CC)CC)C(=O)C2=CC=CC=C2C21CC(C)OC(C)C2 OFQCQIGMURIECL-UHFFFAOYSA-N 0.000 description 1
- TWJNQYPJQDRXPH-UHFFFAOYSA-N 2-cyanobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1C#N TWJNQYPJQDRXPH-UHFFFAOYSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- WRFYIYOXJWKONR-UHFFFAOYSA-N 4-bromo-2-methoxyaniline Chemical compound COC1=CC(Br)=CC=C1N WRFYIYOXJWKONR-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 1
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- 206010061218 Inflammation Diseases 0.000 description 1
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- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
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- 235000019445 benzyl alcohol Nutrition 0.000 description 1
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- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
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- 125000002091 cationic group Chemical group 0.000 description 1
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- 239000000919 ceramic Substances 0.000 description 1
- 229940085262 cetyl dimethicone Drugs 0.000 description 1
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- SOROIESOUPGGFO-UHFFFAOYSA-N diazolidinylurea Chemical compound OCNC(=O)N(CO)C1N(CO)C(=O)N(CO)C1=O SOROIESOUPGGFO-UHFFFAOYSA-N 0.000 description 1
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- 229960004698 dichlorobenzyl alcohol Drugs 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
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Abstract
本发明涉及含有酮康唑,pH为6-8的稳定的乳剂,其特征在于这些乳剂不含抗氧化剂亚硫酸钠;本发明还涉及制备所述乳剂的方法。
Description
本发明提供稳定的外用酮康唑(Ketoconazole)乳剂,其中不含亚硫酸钠,因而减少了这种乳剂对皮肤的刺激或致敏的可能。本发明的组合物与现有技术的乳膏剂相比,不仅具有不相上下的贮存期限,而且耐受性有明显的改善。
美国专利4,335,125叙述了作为杀真菌药物的酮康唑及其制剂和应用。多年来,2%的酮康唑皮肤乳膏剂在若干国家的市场上都可以买到,其中含有酮康唑、丙二醇、1-十八醇、1-十六醇、脱水山梨糖醇-硬脂酸酯、聚山梨酸酯60、聚山梨酸酯80、肉豆蔻酸异丙酯、亚硝酸钠和水。虽然这种乳膏剂治疗皮肤真菌感染是有效的,但还希望在保持基令人满意的贮存期限的同时,提高该组合物的耐受性。
酮康唑易发生氧化降解。现有技术的酮康唑皮肤乳膏剂是用亚硫酸钠稳定的,这是一种普通的抗氧化剂。意外地发现在省掉乳剂中的抗氧化剂之后,只要使配方的pH保持在严格的范围内,就观测不到酮康唑有明显的降解。
本发明具体地涉及含有酮康唑且pH为6-8的乳剂,其特征在于这些乳剂不含有用作抗氧化剂的亚硫酸钠。
应将本组合物敷在皮肤感染的部位上并立即包裹起来。这些乳剂的优点是可以采取每日一次的剂量方案。显然,剂量方案是可以改变的,这取决于被治患者的反应和/或取决于开出本发明组合物处方的医生的判断。
本文所用术语“稳定的”涉及在40℃低于40℃下贮存长达12个月之后,其中酮康唑含量的下降<10%的组合物,优选<5%和最优选<2%。
酮康唑是1-乙酰基-4-[4-[2-(2,4-二氯苯基)-2-咪唑-1-基甲基-1,3-二氧戊环-4-基甲氧基]苯基]哌嗪的通称。本文所用的术语“酮康唑”包括游离碱型的酮康唑、其药物学上可接受的加成盐、其立体化学上的异构体及其互变异构形式。优选的酮康唑化合物是(±)-(顺式)游离碱形式。
通过碱型的酮康唑与适宜的酸反应可以得到酸加成型。适宜的酸包括:例如无机酸,例如氢卤酸(例如氢氯酸或氢溴酸)、硫酸、硝酸和磷酸等;或有机酸,例如乙酸、丙酸、羟乙酸、乳酸、丙酮酸、草酸、丙二酸、丁二酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、环己烷氨基磺酸、水杨酸、对氨基水杨酸和双羟萘酸等。上文所用的术语加成盐也包括能够生成酮康唑及其盐类的溶剂化物。这样的溶剂化物是例如水物、醇化物等。
在下文中,组合物中每一种成分的量都以基于制剂总重的重量百分数表示。同样,也规定比例为重量与重量之比。
在根据本发明的乳剂中,酮康唑的浓度可以为0.1%-10%,优选为0.5%-5%,更优选为1%-3%和特别优选为约2%。高达99%或99%以上的酮康唑在乳剂中可处于悬浮状态,其余(如果有的话)是溶解的。
本发明的乳剂由水相和油相组成。该组合物可以为油包水型乳剂,或优选为水包油型乳剂。这些乳剂宜包含50-80%的水。乳剂的油相可以包含例如石蜡油、分馏的椰子油;肉豆蔻酸异丙酯;脂肪醇类,例如鲸蜡醇(十六醇)、硬脂醇(十八醇)等;脂肪酸酯类,例如脱水山梨糖醇一硬酯酸酯等。
这些乳剂可以以常规产品例如乳膏剂、乳胶和洗剂等形式使用。这些制剂可以用本领域书已知的适当容器,例如塑料、玻璃或陶瓷罐、管,例如有PVC盖的铝管或带有喷雾嘴的瓶包装。
第一类乳剂为乳膏剂的形式(I型)。这些乳膏剂中的油相优选包含肉豆蔻酸异丙酯,因为它的存在可得到粘性和敷展性良好的乳膏,这提高了产品在美容方面的可接受性。
然而有些类型的皮肤(例如油性皮肤)和皮肤病情需要脂肪材料含量低的制剂。油脂限量的制剂,还具有更便于应用在带毛发的皮肤上的优点。因此第二类乳剂为乳胶的形式(II型)。这些II型的乳剂只含少量的脂肪材料。本文所用的脂肪材料包含上文提到的油相物质以及例如脂肪酸类,例如硬脂酸、棕榈酸和肉豆蔻酸等。II型乳剂中脂肪材料的浓度优选为1-10%,更优选为约5%。II型乳剂适合包含用分馏法制取的椰子油作为油相。
本发明乳剂还可包含各种添加剂,例如乳化剂、缓冲剂体系、润湿剂、酸类或碱类、稳定剂、抗微生物防腐剂和增稠剂等。
适宜的乳化剂是例如阴离子、阳离子型乳化剂、或更优选非离子型乳化剂,例如蔗糖酯类、葡萄糖酯类、聚氧乙烯脂肪酸酯类、聚氧乙烯脂肪醇醚类、甘油酯类、例如甘油一硬脂酸酯、脱水山梨糖醇酯类,例如脱水山梨糖醇一棕榈酸酯(=Span 40)、脱水山梨糖醇一硬脂酸酯(=Span 60)、脱水山梨糖醇酯类的聚氧乙烯衍生物,例如聚山梨酸酯40(=Tween 40、聚山梨酸酯60(=Tween 60)、鲸蜡基二甲聚硅氧烷基共聚多醇等。
I型乳膏组合物优选包含作为乳化剂成分的脱水山梨糖醇一硬脂酸酯和聚山梨酸酯60,每一种的用量为0.5-10%,每一种的用量优选为1-2%。
适宜润湿剂的实例是脱水山梨糖醇酯的聚氧乙烯衍生物,例如聚山梨酸酯80(=Tween 80)、聚山梨酸酯20(=Tween 20)、月桂基硫酸钠、二辛基磺基丁二酸酯钠盐等。优选使用聚山梨酸酯80,其用量为0.01-1%,优选为0.1-0.2%。
缓冲剂体系包含适宜量的酸(例如磷酸、丁二酸、酒石酸、乳酸或柠檬酸)和碱,特别是氢氧化钠或磷酸氢二钠的混合物。或者,可加酸例如氢氯酸或碱例如氢氧化钠等固定组合物的pH。在乳剂中包含酸类和/或碱类是为了保持制剂的pH在6-8范围内,更优选pH为6.5-7.5,最优选为7左右。
提高组合物物理化学稳定性的适宜的稳定剂是例如无机盐类,例如氯化钠等;丙二醇,甘油等。在制剂中也可以含有丙二醇作为润湿剂。优选乳剂中包含10%或更少的丙二醇,以便进一步减少刺激和致敏的可能。乳剂宜含有0.5-10%的丙二醇,优选为5-10%。
在本发明的一个特殊方面,乳剂含有抗微生物防腐剂,特别是二种或多种抗微生物防腐剂。当采用复合防腐剂时,与采用单独一种防腐剂相比,在保持符合药典对微生物数所规定有要求有同时,可以降低这些防腐剂的用量。降低防腐剂的浓度可减少刺激和致敏的可能。适合本发明组合物的防腐剂是抗微生物的酸类及其盐类,例如苯甲酸及其盐;山梨酸及其盐;丙酸及其盐;甲醛和甲醛供体,例如溴硝丙二醇(bronopol)、戊二醛、羟甲基二甲基乙内酰脲(MDMH)、二羟甲基二甲基乙内酰脲(DMDMH)、季铵(quaternium)15(-Dowicil 200)、二唑烷基脲(GermalII)和咪唑烷基脲(=Germal 115);汞盐,例如乙酸苯汞、硼酸苯汞、硝酸苯基和硫汞撒(thiomersal);EDTA及其盐,例如EDTA钠;乙醇;甲酚及其衍生物,例如氯甲酚和异丙基甲酚;苄醇;二氯苄醇(=MyacidtSP);己脒羟乙基磺酸盐(hexamidine isethionate);海克替啶(hexetidine);季化合物,例如溴化十六烷基三甲铵、氯化苯甲烃铵等;对羟苯甲酸酯,例如对羟苯甲酸甲酯和对羟苯甲酸丙酯;双氯苯双胍己烷及其盐。在乳剂中适合使用咪唑烷基脲、溴化十六烷基三甲铵、EDTA钠和/或二唑烷基脲(diazolidinyl urea)。每一种防腐剂的浓度优选不超过0.5%,更优选不超过0.3%。
当加入增稠剂时,可增加本发明制剂的粘度,增稠剂有例如疏液性试剂,例如1-十八醇、1-十六醇、甘油-硬脂酸酯、巴西棕榈蜡、蜂蜡、三羟基硬脂酸酯等;或亲液性试剂,例如纤维素衍生物,例如羧甲基纤维素钠;聚氧气烯;甲壳素及其衍生物,例如脱乙酰壳多糖;泊洛沙姆(poloxamer s);粘土;天然树胶;淀粉衍生物;卡波姆(Carbomers)(聚丙烯酸衍生物),聚乙二醇等。适宜的I型乳剂含有作为增稠剂的1-十八醇和1-十六醇,每一种的含量为0.5-10%,其用量分别优选为约7.5%和2%。II型乳胶适合含卡波姆增稠剂,其含量为0.1-5%,优选为0.3-0.6%。含有卡波姆增稠剂的II型乳胶具有能很快滴下的粘度(速断现象),在擦抹时,在皮肤上呈现很好的敷展性。在用于有毛发或发炎的皮肤上或大面积体表时,II型的特性是特别适用的。当在本乳剂中使用卡波姆增稠剂时,制得稳定的制剂几乎不需要或根本不需要乳化物质。特定的II型乳剂还含有聚氧乙烯增稠剂,其含量为0.1-1%,优选含量为0.2%左右。优选聚氧乙烯增稠剂的平均分子量为200000。在乳胶中采用聚氧乙烯,其美容上的优点在于擦抹时有柔软感。
按基于组合物总重的重量百分数计,优选的乳剂含有:
(a)0.5-5%的酮康唑;
(b)缓冲剂、酸或碱,以使组合物的pH范围维持在6-8;
(c)足够的皮肤病学上可接受的抗微生物防腐剂,以防组合物降解;
(d)0.5-40%的在皮肤病学上可接受的油;和
(e)加水至100%。
更优选的乳剂是那些还含有增稠剂和润湿剂的优选乳剂。
按基于组合物总重的重量百分数计,优选的I型乳剂(乳膏剂配方)含有:
(a)0.5-5%的酮康唑;
(b)缓冲剂、酸或碱,以维持pH在6-8范围内;
(c)0.1-0.5%的二唑烷基脲和0.1%-0.5%的EDTA钠;
(d)0.5-5%的肉豆蔻酸异丙酯;
(e)5%-10%的1-十八醇和1%-5%的1-十六醇;
(f)0.5-5%的脱水山梨糖醇一硬脂酸酯和0.5-5%的缩聚山梨
醇油酸酯60;
(g)5%-10%的丙二醇;
(h)0.05%-0.2%的聚山梨酸酯80;和
(i)加水至00%。
按基于组合物总重的重量百分数计,最优选的I型乳剂(乳膏剂)约含有:
(a)2%的酮康唑;
(b)缓冲剂、酸或碱,以维持pH在6-8范围内;
(c)0.2%的二唑烷基脲和0.1%的EDTA钠;
(d)1%的肉豆蔻酸异丙酯;
(e)7.5%的1-十八醇和2%的1-十六醇;
(f)2%的脱水山梨糖醇一硬脂酸酯和1.5%的聚山梨酸酯
60;
(g)10%的丙二醇:
(h)0.1%的聚山梨酸酯80;和
(i)加水至100%。
按基于组合物总重的重量百分数计,优选的II型乳剂(乳胶配方)含有:
(a)0.5-5%的酮康唑;
(b)缓冲剂、酸或碱,以维持pH在6-8范围内;
(c)0.1%-0.5%的咪唑烷基脲、0.1%-0.5%的溴化十六烷基三
甲铵和0.1%-0.5%的EDTA钠;
(d)1%-10%的用分馏法制取的椰子油;
(e)0.1%-2%的卡波姆和0.1%-0.5%的聚氧乙烯;
(f)5%-10%的丙二醇;
(g)0.1%-0.5%的聚山梨酸酯80;和
(h)加水至100%。
按基于组合物总重的重量百分数计,最优选的II型乳剂(乳胶)约含有:
(a)2%的酮康唑;
(b)缓冲剂、酸或碱,以维持pH在6-8范围内;
(c)0.3%的咪唑烷基脲、0.1%的溴化十六烷基三甲铵和0.2%的
EDTA钠;
(d)5%的用分馏法制取的椰子油;
(e)0.45%卡波姆和0.2%聚氧乙烯;
(f)5%的丙二醇;
(g)0.2%的聚山梨酸酯80;和
(h)加水至100%。
为了制备本发明的药物组合物,按照本领域已知的方法将治疗有效量的酮康唑与皮肤病学上可接受的载体混合成紧密的混合物。优选先单独制备载体制剂,然后向其中加入活性成分。
制备I型乳膏剂宜包括下列步骤:
(1)将稳定剂和乳化剂溶解在水相中;
(2)将增稠剂和乳化剂溶解在油相中;
(3)将相(1)和相(2)均化;
(4)将润湿剂和防腐剂溶解在水中;
(5)使酮康唑悬浮在相(4)中;
(6)将相(3)和相(5)混合;
(7)加入缓冲剂、酸或碱,将pH调节至在6-8范围内;和
(8)用水将相(7)稀释到所需要的体积。
制备II型乳胶宜包括下列步骤:
(1)使增稠剂悬浮在油相中;
(2)将防腐剂溶解在水相中;
(3)将相(1)与相(2)混合;
(4)加入缓冲剂、酸或碱、将pH调节到在6-8范围内;和
(5)使酮康唑悬浮在(4)中。
任选在惰性气氛下例如在不含氧的氮气或氩气气氛下进行上述步骤。任选在真空下将酮康唑粉末加到装有载体制剂的容器中,使其可以加到载体制剂中。另外,采用微粉形式的酮康唑来增加药物与皮肤的接触面积可能是有利的。利用本领域已知的微粉化技术,例如通过在适宜的研磨机中研磨并经过适宜的筛进行筛分,可制备微粉化状态的酮康唑。
用下列实施例从各个方面说明本发明的范围。
实施例I:F1(乳胶)
成分 数量
超细酮康唑 20mg
Miglyol 812(用分馏法制取的 50mg
椰子油)
聚氧乙烯200000 2mg
丙二醇 50μl
咪唑烷基脲 3mg
溴化十六烷基三甲铵 1mg
EDTA钠 2mg
聚山梨酸酯80 2mg
卡波姆1382 4,5mg
氢氧化钠(分析纯) 适量加入,使pH=7
纯化水 适量加入,至1g
(1)使2mg聚氧乙烯200000悬浮在50μl的丙二醇中;
(2)使4.5mg卡波姆1382悬浮在50mg Miglyol 812中;
(3)将1mg溴化十六烷基三甲铵、2mg EDTA钠和2mg聚山梨酸酯80溶解于0.85g水中;
(4)将悬浮液(1)加入溶液(3)中;
(5)将悬浮液(2)加入溶液(4)中;
(6)加入氢氧化钠,直至pH=7;
(7)将水加入(6)中,直至1g;和
(8)使2mg酮康唑悬浮在(7)中。
实施例2:F2(乳膏)
成分 数量,mg/g乳膏
超细酮康唑 20mg
二唑烷基脲 2mg
EDTA钠 1mg
丙二醇 100μl
1-十八醇 75mg
1-十六醇 20mg
脱水山梨糖醇一硬脂酸酯 20mg
聚山梨酸酯60 15mg
肉豆蔻酸异丙酯 10mg
聚山梨酸酯80 1mg
氢氧化钠 适量,加至pH=7
纯化水 适量,加至1g
(1)在70-75℃下,利用搅拌使100μl丙二醇和15mg聚山梨酸酯60溶解于水中;
(2)在75-80℃下,使10mg肉豆蔻酸异丙酯、75mg 1-十八醇、20mg 1-十六醇和20mg脱水山梨糖醇一硬脂酸酯混合;
(3)利用搅拌使相(1)与相(2)混合均匀,并冷却到35-40℃;
(4)利用搅拌将1mg聚山梨酸酯80、2mg二唑烷基脲和1mg EDTA钠溶解于水中;
(5)利用搅拌使20mg超细酮康唑悬浮在相(4)中;
(6)利用搅拌使相(5)与相(3)混合;
(7)将氢氧化钠加入相(6),直至pH=7;和
(8)用水将相(7)稀释至1g。
实施例3
在4℃、25℃、30℃和40℃下将上文所述的乳剂F1贮存12个月。在这几种温度下贮存后,酮康唑的浓度均没有发生明显的变化。检测不出有任何降解产物。因而乳剂F1符合上文所述对稳定制剂的要求。
Claims (8)
1、稳定的,低刺激性的,局部施用于皮肤的水包油乳剂,它用基于乳剂总重量计,其中含有:
(a)0.5-5%的超细酮康唑;
(b)缓冲剂、酸或碱、以将组合物的pH维持在6-8范围内;
(c)足够的在皮肤病学上可接受的抗微生物防腐剂,以防组合物降解;
(d)0.5-10%的稳定剂,它是丙二醇,
(e)0.5-40%的皮肤病学上可接受的油;和
(f)加水至100%
其特征在于乳剂中不含抗氧化剂亚硫酸钠。
2、按照权利要求1的水包油型乳剂,其中含有50%-80%(重量)的水。
3、权利要求2的乳剂,该乳剂为乳膏型。
4、权利要求2的乳剂,该乳剂为乳胶型,且其中脂肪材料的浓度范围为1%-10%(重量)。
5、权利要求1的乳剂,其中含有两种或更多种抗微生物防腐剂,这些防腐剂选自咪唑烷基脲、溴化十六烷基三甲铵、EDTA钠和二唑烷基脲。
6、权利要求1的乳剂,该乳剂为乳膏型,且基于组合物总重量计,其中含有:
(a)0.5-5%的超细酮康唑;
(b)缓冲剂、酸或碱、以将pH维持在6-8范围内;
(c)0.1%-0.5%的二唑烷基脲和0.1%-0.5%的EDTA钠;
(d)0.5-5%的肉豆蔻酸异丙酯;
(e)5%-10%的1-十八醇和1%-5%的1-十六醇;
(f)0.5-5%的脱水山梨糖醇一硬脂酸酯和0.5-5%的聚山梨酸酯60;
(g)5%-10%的丙二醇;
(h)0.05%-0.2%聚山梨酸酯80;和
(i)加水至100%。
7、权利要求1的乳剂,该乳剂为乳胶型,且基于组合物总重量计,其中含有:
(a)0.5-5%的超细酮康唑;
(b)缓冲剂、酸或碱、以维持pH在6-8范围内;
(c)0.1%-0.5%的咪唑烷基脲、0.1%-0.5%的溴化十六烷基三甲铵和0.1%-0.5%的EDTA钠;
(d)1%-10%的用分馏法制取的椰子油;
(e)0.1%-2%的卡波姆和0.1%-0.5%的聚氧乙烯;
(f)5%-10%的丙二醇;
(g)0.1%-0.5%的聚山梨酸酯80;和
(h)加水至100%。
8、权利要求1-7中任一项乳剂的制备方法,其特征在于将治疗上有效量的超细酮康唑与皮肤学上可接受的载体紧密混合。
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EP (1) | EP0778771B1 (zh) |
JP (1) | JP3959110B2 (zh) |
KR (1) | KR100381701B1 (zh) |
CN (1) | CN1098074C (zh) |
AT (1) | ATE291917T1 (zh) |
AU (1) | AU698065B2 (zh) |
CA (1) | CA2198240C (zh) |
DE (1) | DE69534120T2 (zh) |
DK (1) | DK0778771T3 (zh) |
ES (1) | ES2240977T3 (zh) |
IL (1) | IL115105A (zh) |
MX (1) | MX9701397A (zh) |
MY (1) | MY115980A (zh) |
PT (1) | PT778771E (zh) |
SI (1) | SI0778771T1 (zh) |
TW (1) | TW460296B (zh) |
WO (1) | WO1996006613A1 (zh) |
ZA (1) | ZA957329B (zh) |
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KR20140057414A (ko) | 2011-06-22 | 2014-05-12 | 바이옴 바이오사이언스 피브이티. 엘티디. | 컨쥬게이트계 항진균 및 항세균 프로드러그 |
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- 1995-08-25 KR KR1019970701169A patent/KR100381701B1/ko not_active IP Right Cessation
- 1995-08-25 ES ES95931931T patent/ES2240977T3/es not_active Expired - Lifetime
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Publication number | Publication date |
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CA2198240A1 (en) | 1996-03-07 |
AU3518395A (en) | 1996-03-22 |
ATE291917T1 (de) | 2005-04-15 |
ZA957329B (en) | 1997-02-28 |
EP0778771A1 (en) | 1997-06-18 |
JPH10505346A (ja) | 1998-05-26 |
DK0778771T3 (da) | 2005-07-25 |
IL115105A (en) | 1999-12-22 |
DE69534120D1 (de) | 2005-05-04 |
IL115105A0 (en) | 1995-12-08 |
CN1156407A (zh) | 1997-08-06 |
PT778771E (pt) | 2005-08-31 |
AU698065B2 (en) | 1998-10-22 |
MY115980A (en) | 2003-10-31 |
ES2240977T3 (es) | 2005-10-16 |
JP3959110B2 (ja) | 2007-08-15 |
MX9701397A (es) | 1997-05-31 |
KR100381701B1 (ko) | 2003-09-26 |
WO1996006613A1 (en) | 1996-03-07 |
DE69534120T2 (de) | 2006-01-26 |
TW460296B (en) | 2001-10-21 |
SI0778771T1 (en) | 2005-10-31 |
EP0778771B1 (en) | 2005-03-30 |
CA2198240C (en) | 2007-04-10 |
US5854246A (en) | 1998-12-29 |
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