硝酸益康唑脂质体凝胶剂的研究
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摘要
考察了硝酸益康唑的基本理化性质，通过正交设计筛选硝酸益康唑脂
质体的处方；用微型柱离心法和超速离心法测定药物包封率，分析脂质体
中硝酸益康唑的分布状态。
建立了一种测定皮肤表皮和真皮中药物含量的高效液相色谱法，用立
式扩散池考察基质对脂质体释药性的影响和pH、脂质体的粒径、乙醇的含
量、磷脂类型、基质对用药24小时后硝酸益康唑在皮肤表皮和真皮中含量
的影响，并分别与市售软膏作了比较。结果表明，HPMC对脂质体的释药
性影响小，释药速度快；脂质体溶液的pH、乙醇的含量、磷脂和基质类型
对药物在表皮和真皮中的滞留量有显著性影响；以HPMC为基质的脂质体
凝胶剂比市售软膏的释药速度大，药物在表皮和真皮中滞留量高。
研究了硝酸益康唑脂质体凝胶剂在体皮肤用药3天后的表皮和真皮中药
物消除过程，求出消除过程中的AUC值，并与市售软膏作了比较。结果表
明脂质体凝胶剂表皮和真皮中最大药物浓度大大高于市售软膏的最大药物
浓度：表皮中AUC_(脂质体凝胶剂)/AUC_(市售软膏)为4.87，而真皮中AUC_(脂质体凝胶剂)/AUC_(市售软膏)为
1.30，脂质体凝胶剂能显著提高药物在表皮中的滞留时间，不能增加在真
皮中滞留时间，因此硝酸益康唑脂质体凝胶剂比较适合用于治疗病灶在表
皮的皮肤真菌感染。
考察了硝酸益康唑脂质体的理化性质、稳定性、皮肤刺激性和初步临
床疗效。电镜扫描观察、偏光显微镜观察、X衍射证明硝酸益康唑脂质体凝
胶剂中无药物结晶，市售软膏中有大量药物结晶。制备的硝酸益康唑脂质
体凝胶剂稳定性好，皮肤刺激性小，具有显著的临床疗效。
The basic physical-phemical properties of Econazole Nitrate
were studied and the formulation was optimized by orthogonal design.
The two different entrapment efficiencies were determined by
mincolumn centrifugation method and ultraceritrifugation method,
which demonstrated the distribution of Econazole Nitrate in
1 ipo some.
A high-performance liquid chromatographic method for the
quantitative determination of Econazole nitrate in epidermis and
dermis was developed. The effects of the additives on the drug release
from liposomal gel and the effects of pH, liposome size, ethanol
content, phospholipid sorts and the additives on the content of drug
in epidermis and dermis 24 hours after application were studied,
which were compared with the ointment on sale. The results showed
that pH, ethanol content, phospholipid sorts and the additives had
significant effects on the content of drug in epidermis and dermis
and HPMCiposome gel had a higher rate of drug release and a more
content of Econazole nitrate in epidermis and dermis than other
liposomal gels ,furthermore, much higher than the ointment on sale
The clearance procedures of Econazole nitrate in rat back
skin (epidermis and dermis) 3 days after application were studied and
AUC were calculated by trapezoidal rule, which were compared with
the marketed Econazole nitrate ointment. The results showed that the
C of Econazole nitrate from the prepared liposomal gel in epidermis
and dermis 3 days after application were significantly higher than
that from the ointment on sale. The ratios of AUCLP. to AUC0. in
epidermis and dermis were 4.87 and 1.30 respectively, which showed
that liposomal gel could prolong duration time of Econazole nitrate
in epidermis but not in dermis. It demonstrated Econazole nitrate
liposomal gel was adapted to fungal skin infections whose focus is
in epidermis.
The physical-phemical properties, stability, skin irritation
and preliminary clinical pharmacological action of prepared
liposomal gel were investigated. The results of polarizing
microscope observation scanning microscope observation and X-way
diffraction test showed a lot of crystal of Econazole nitrate in the
ointment on sale ,but no crystal in prepared liposomal gel. The
irritation test and preliminary clinical investigation showed the
prepared liposomal gel had no irritation for application and had
significant pharmacological action for fungal skin infections.
质体的处方；用微型柱离心法和超速离心法测定药物包封率，分析脂质体
中硝酸益康唑的分布状态。
建立了一种测定皮肤表皮和真皮中药物含量的高效液相色谱法，用立
式扩散池考察基质对脂质体释药性的影响和pH、脂质体的粒径、乙醇的含
量、磷脂类型、基质对用药24小时后硝酸益康唑在皮肤表皮和真皮中含量
的影响，并分别与市售软膏作了比较。结果表明，HPMC对脂质体的释药
性影响小，释药速度快；脂质体溶液的pH、乙醇的含量、磷脂和基质类型
对药物在表皮和真皮中的滞留量有显著性影响；以HPMC为基质的脂质体
凝胶剂比市售软膏的释药速度大，药物在表皮和真皮中滞留量高。
研究了硝酸益康唑脂质体凝胶剂在体皮肤用药3天后的表皮和真皮中药
物消除过程，求出消除过程中的AUC值，并与市售软膏作了比较。结果表
明脂质体凝胶剂表皮和真皮中最大药物浓度大大高于市售软膏的最大药物
浓度：表皮中AUC_(脂质体凝胶剂)/AUC_(市售软膏)为4.87，而真皮中AUC_(脂质体凝胶剂)/AUC_(市售软膏)为
1.30，脂质体凝胶剂能显著提高药物在表皮中的滞留时间，不能增加在真
皮中滞留时间，因此硝酸益康唑脂质体凝胶剂比较适合用于治疗病灶在表
皮的皮肤真菌感染。
考察了硝酸益康唑脂质体的理化性质、稳定性、皮肤刺激性和初步临
床疗效。电镜扫描观察、偏光显微镜观察、X衍射证明硝酸益康唑脂质体凝
胶剂中无药物结晶，市售软膏中有大量药物结晶。制备的硝酸益康唑脂质
体凝胶剂稳定性好，皮肤刺激性小，具有显著的临床疗效。
The basic physical-phemical properties of Econazole Nitrate
were studied and the formulation was optimized by orthogonal design.
The two different entrapment efficiencies were determined by
mincolumn centrifugation method and ultraceritrifugation method,
which demonstrated the distribution of Econazole Nitrate in
1 ipo some.
A high-performance liquid chromatographic method for the
quantitative determination of Econazole nitrate in epidermis and
dermis was developed. The effects of the additives on the drug release
from liposomal gel and the effects of pH, liposome size, ethanol
content, phospholipid sorts and the additives on the content of drug
in epidermis and dermis 24 hours after application were studied,
which were compared with the ointment on sale. The results showed
that pH, ethanol content, phospholipid sorts and the additives had
significant effects on the content of drug in epidermis and dermis
and HPMCiposome gel had a higher rate of drug release and a more
content of Econazole nitrate in epidermis and dermis than other
liposomal gels ,furthermore, much higher than the ointment on sale
The clearance procedures of Econazole nitrate in rat back
skin (epidermis and dermis) 3 days after application were studied and
AUC were calculated by trapezoidal rule, which were compared with
the marketed Econazole nitrate ointment. The results showed that the
C of Econazole nitrate from the prepared liposomal gel in epidermis
and dermis 3 days after application were significantly higher than
that from the ointment on sale. The ratios of AUCLP. to AUC0. in
epidermis and dermis were 4.87 and 1.30 respectively, which showed
that liposomal gel could prolong duration time of Econazole nitrate
in epidermis but not in dermis. It demonstrated Econazole nitrate
liposomal gel was adapted to fungal skin infections whose focus is
in epidermis.
The physical-phemical properties, stability, skin irritation
and preliminary clinical pharmacological action of prepared
liposomal gel were investigated. The results of polarizing
microscope observation scanning microscope observation and X-way
diffraction test showed a lot of crystal of Econazole nitrate in the
ointment on sale ,but no crystal in prepared liposomal gel. The
irritation test and preliminary clinical investigation showed the
prepared liposomal gel had no irritation for application and had
significant pharmacological action for fungal skin infections.
引文
[1] 国家级药物制剂新产品开发指南(第一辑)．1993：432-481
[2] 郑俊民主编．经皮给药新剂型．北京：人民卫生出版社1997：173-178
[3] 赵红，郑俊民．新型的皮肤给药系统——脂质体．沈阳药科大学学报．1997，14(2)：148
[4] 中华人民共和国药典(2000年版)。化学工业出版社
[5] Cartwright RY. Pharmacology of imidazole derivatives with antimycotic activity. Mykosen, Suppl. 1978,1(Med Mycol),298-303
[6] 胡文驿等．国家基本药物及新特药临床指南．天津科技翻译出版社(1996)：61
[7] Yoshiharu Y, Katsuhisa U, Hideyo Y et al. Studies on the antifungal activity of econazole。1 In vitro. Shinkin to Shinkinsho, 1977, 18(3),216-224
[8] Toshiaki F, Atsushi T, Kazashi. Physicochemical proporties and stability of 1-[2,4-dichloro-β-(R-chlorbenzyloxy) phenethyl] imidazole nitrate(econazole nitrate), Iyakuhin Kcukyu 1978,9(2)448-459(CA, 114, 65202Z)
[9] 毕殿洲主编．药剂学(第四版)．北京．人民卫生出版社．2000
[10] 吴翠栓等．皮肤局部用药物的近期研究进展．中国药学杂志．
[11] 章育正．微生物与寄生虫学．上海科学技术出版社．1994：140
[12] Shreier H, Bouwstra J. Liposomes and niosomes DGSs topical drug carriers: dermal and transdermal drug delivery. J. Control. Release, 1994, 30:1-15
[13] Touitou E, Junginger E, Weiner N. Liposomes as carriers for topical and transdermal delivery. J. Pharm. Sci. 1994, 83:1189-1203
[14] 平其能．现代药剂学．中国科技出版社．1998
[15] Mezei. Administration of drugs with multiphase liposomal delivery system. U.S.Patent,212, 012. 1988-06-27
[16] Naeff. R. Feasibility of topical liposome drugs produced on an industrial scale. Advanced drug delivery Reviews 18(1996)343-347
[17] 柳正良，主浩，杨武等．动态改性高效液相色谱法测定益康唑及其制剂的含量．药学分析杂志，1995，15(1)：21-23
[18] 曾经泽．生物药物分析．北京医科大学中国协和医科大学联合出版社．北京．1998：214
[19] 陆彬．药物新剂型与新技术．人民卫生出版社．1998
[20] 胡佳惠等．阿霉素脂质体中磷脂含量的测定．西北药学杂志，1996，11(5)：195-196
[21] Foldvari M, Jarvis B, Oguejiofor CJN. Topical dosage form of liposomal tetracaine: effect of additives on the in vitro release and in vivo efficacy. J Contro. Release. 1993, 27:193-20
[22] Yerushalmi N, Arad A and Margalit R. Molecular and cellular studies of hyaluronic aicd-modified liposomes as bioadhesive carriers for topical drug delivery in wound healing. Arch biochem biophys, 1994, 313(2):267-276
[23] Yerushalmi N, Margalit R. Bioadhesive collagen-modified liposome: molecular and cellular lever studies on the kinetics of drug release and binding to cell monolayers. Biochem Biophys Acta, 1994, 1189:13-20
[24] 朱盛山主编．药物新剂型．北京：人民卫生出版社，1993：68
[25] Touitou E, Meidan VM, Horwitz E. Method for quantitative determination of drug localized in the skin .J Controlled Release. 1998,56:7-21
[26] Volpato NM, Nicoli S,Laureri C. et al. In vitro acyclovir distrbution in human skin layers after transdermal iontophoresis. J. Control. Rel. 1998,50:291-296
[27] Touitou E, Levi-Schaffer F, Dayan N et al. Modulation of caffeine skin delivery by carrier design: liposomes versus permeation enhancers, Int J Pharm. 1994(103)131-136
[28] Patel VB, Misra AN, Marfatia. YS. A topical dosage form of liposomal clofazimine: research and clinical implications. Pharmazie, 1999, 54(6):448-452
[29] Rougier A, Lotte C, Maibach HI., In vivo percutaneous penetration of some organic compounds related to anatomic site in humans: predictive assessment by the stripping method, J. Pharm. Sci. 1987,76:451-454
[30] Pellet MA, Roverts MS, Hadgraft J. Supersaturated solutions evaluated with an in vitro drug from charged multilamellar liposomes. J Drug Targeting, 1999, 6(6):4
stratum corneum tape stripping technique. Int.J.Pharm.1997,l57:9l-98
[30] Kammerau B.Zesch A,Shaefer H. Abosolute concentrations of dithranol and triacetyl-ditranol in the skin layers after local treatment: in vivo investigations with four different types of pharmaceutical vehicles, J. Invest. Dermatol. 1975,64:145-149
[31] Schaefer H, Stuttgen G, Absolute concentrations of an antimvcotic agent,econazole. in the human skin after local application,Drug Res. 1976(26) 432-435
[32] Kligman AM, Christophers E. Preparation of isolated sheets of human skin, Arch.Dermatol. 1963,88:702-705
[33] Mak VHW, Potts RO. Guy RH. Percutaneous penetration enhancement in vivo measured by attenuated total reflectance infrared spectroscopy, Pharm. .Res,1990,7:835-841
[34] Kolmel K, Sennhen B, Giese K. Evaluation of drug penetration into the skin by photoacoustic measurement. J. Soc.Cosmet. 1986． 37:375-385
[35] Fabin B,Touitou E. Localization of lipophilic molecules penetrating rat skin in vivo by quantitative autoradiography Int. J. Pharm, 1991,74:59-65
[36] Hofland. HEJ. Bouwstra. JA. Spies.F et al. Interactions between liposomes and human stratum corneum in vitro: Freeze fracture election microscopical visualization and small angle X-ray scattering studies. Br J Dermatoi 132:853-856
[37] Piret J. Goutde P. Cormier H. Efficacy of gel formulations containing free and liposomal Foscarnet in a murine model of cutaneous HSV-1 infection J.Liposome.Res. 1999:181-198
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[2] 郑俊民主编．经皮给药新剂型．北京：人民卫生出版社1997：173-178
[3] 赵红，郑俊民．新型的皮肤给药系统——脂质体．沈阳药科大学学报．1997，14(2)：148
[4] 中华人民共和国药典(2000年版)。化学工业出版社
[5] Cartwright RY. Pharmacology of imidazole derivatives with antimycotic activity. Mykosen, Suppl. 1978,1(Med Mycol),298-303
[6] 胡文驿等．国家基本药物及新特药临床指南．天津科技翻译出版社(1996)：61
[7] Yoshiharu Y, Katsuhisa U, Hideyo Y et al. Studies on the antifungal activity of econazole。1 In vitro. Shinkin to Shinkinsho, 1977, 18(3),216-224
[8] Toshiaki F, Atsushi T, Kazashi. Physicochemical proporties and stability of 1-[2,4-dichloro-β-(R-chlorbenzyloxy) phenethyl] imidazole nitrate(econazole nitrate), Iyakuhin Kcukyu 1978,9(2)448-459(CA, 114, 65202Z)
[9] 毕殿洲主编．药剂学(第四版)．北京．人民卫生出版社．2000
[10] 吴翠栓等．皮肤局部用药物的近期研究进展．中国药学杂志．
[11] 章育正．微生物与寄生虫学．上海科学技术出版社．1994：140
[12] Shreier H, Bouwstra J. Liposomes and niosomes DGSs topical drug carriers: dermal and transdermal drug delivery. J. Control. Release, 1994, 30:1-15
[13] Touitou E, Junginger E, Weiner N. Liposomes as carriers for topical and transdermal delivery. J. Pharm. Sci. 1994, 83:1189-1203
[14] 平其能．现代药剂学．中国科技出版社．1998
[15] Mezei. Administration of drugs with multiphase liposomal delivery system. U.S.Patent,212, 012. 1988-06-27
[16] Naeff. R. Feasibility of topical liposome drugs produced on an industrial scale. Advanced drug delivery Reviews 18(1996)343-347
[17] 柳正良，主浩，杨武等．动态改性高效液相色谱法测定益康唑及其制剂的含量．药学分析杂志，1995，15(1)：21-23
[18] 曾经泽．生物药物分析．北京医科大学中国协和医科大学联合出版社．北京．1998：214
[19] 陆彬．药物新剂型与新技术．人民卫生出版社．1998
[20] 胡佳惠等．阿霉素脂质体中磷脂含量的测定．西北药学杂志，1996，11(5)：195-196
[21] Foldvari M, Jarvis B, Oguejiofor CJN. Topical dosage form of liposomal tetracaine: effect of additives on the in vitro release and in vivo efficacy. J Contro. Release. 1993, 27:193-20
[22] Yerushalmi N, Arad A and Margalit R. Molecular and cellular studies of hyaluronic aicd-modified liposomes as bioadhesive carriers for topical drug delivery in wound healing. Arch biochem biophys, 1994, 313(2):267-276
[23] Yerushalmi N, Margalit R. Bioadhesive collagen-modified liposome: molecular and cellular lever studies on the kinetics of drug release and binding to cell monolayers. Biochem Biophys Acta, 1994, 1189:13-20
[24] 朱盛山主编．药物新剂型．北京：人民卫生出版社，1993：68
[25] Touitou E, Meidan VM, Horwitz E. Method for quantitative determination of drug localized in the skin .J Controlled Release. 1998,56:7-21
[26] Volpato NM, Nicoli S,Laureri C. et al. In vitro acyclovir distrbution in human skin layers after transdermal iontophoresis. J. Control. Rel. 1998,50:291-296
[27] Touitou E, Levi-Schaffer F, Dayan N et al. Modulation of caffeine skin delivery by carrier design: liposomes versus permeation enhancers, Int J Pharm. 1994(103)131-136
[28] Patel VB, Misra AN, Marfatia. YS. A topical dosage form of liposomal clofazimine: research and clinical implications. Pharmazie, 1999, 54(6):448-452
[29] Rougier A, Lotte C, Maibach HI., In vivo percutaneous penetration of some organic compounds related to anatomic site in humans: predictive assessment by the stripping method, J. Pharm. Sci. 1987,76:451-454
[30] Pellet MA, Roverts MS, Hadgraft J. Supersaturated solutions evaluated with an in vitro drug from charged multilamellar liposomes. J Drug Targeting, 1999, 6(6):4
stratum corneum tape stripping technique. Int.J.Pharm.1997,l57:9l-98
[30] Kammerau B.Zesch A,Shaefer H. Abosolute concentrations of dithranol and triacetyl-ditranol in the skin layers after local treatment: in vivo investigations with four different types of pharmaceutical vehicles, J. Invest. Dermatol. 1975,64:145-149
[31] Schaefer H, Stuttgen G, Absolute concentrations of an antimvcotic agent,econazole. in the human skin after local application,Drug Res. 1976(26) 432-435
[32] Kligman AM, Christophers E. Preparation of isolated sheets of human skin, Arch.Dermatol. 1963,88:702-705
[33] Mak VHW, Potts RO. Guy RH. Percutaneous penetration enhancement in vivo measured by attenuated total reflectance infrared spectroscopy, Pharm. .Res,1990,7:835-841
[34] Kolmel K, Sennhen B, Giese K. Evaluation of drug penetration into the skin by photoacoustic measurement. J. Soc.Cosmet. 1986． 37:375-385
[35] Fabin B,Touitou E. Localization of lipophilic molecules penetrating rat skin in vivo by quantitative autoradiography Int. J. Pharm, 1991,74:59-65
[36] Hofland. HEJ. Bouwstra. JA. Spies.F et al. Interactions between liposomes and human stratum corneum in vitro: Freeze fracture election microscopical visualization and small angle X-ray scattering studies. Br J Dermatoi 132:853-856
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