LBH复方软膏的研制与分析
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摘要
外阴瘙痒是一种非常常见的妇科疾病,发病率较高。目前国内治疗该类药物主要是中成药,起效慢。而西药也只有单方制剂,不能同时起到止痒、消炎、杀菌、保护皮肤的作用。本文根据国内外用药情况,以利多卡因、盐酸苯海拉明,EX和麝香草酚为模型药物,研制了阴道用复方软膏剂,具有起效全面快速,使用方便等优势。
通过乳化剂的考察和基质用量的正交试验,确定了复方软膏剂的最佳处方。即以平平加O为乳化剂,以白凡士林、液体石蜡、山嵛醇、单硬脂酸甘油酯为油相,甘油为水相,肉豆蔻酸异丙酯为透皮吸收促进剂。单因素考察了制备工艺参数,最终确定其理想工艺过程为:乳化温度80℃,将油相缓缓加入水相中,保温搅拌5min,再以1500rpm的速度搅拌至冷。
建立了HPLC法同时测定利多卡因,盐酸苯海拉明和麝香草酚三组分含量的方法。采用C18色谱柱(46×250mm,5μm),以甲醇-pH8.0磷酸盐缓冲液-乙腈(60:25:15)为流动相,流速1.0ml/min,柱温35℃,255nm检测。经过方法学验证,该方法简便快速,结果准确可靠。同时还建立并方法学验证了HPLC法测定EX含量及利多卡因和盐酸苯海拉明的有关物质。
对复方软膏的理化性质及稳定性进行了考察。结果本软膏外观,pH值,熔点,稠度均符合药典规定,通过染色法验证了本软膏为o/w型乳膏。影响因素和留样实验表明本软膏中EX及麝香草酚均对光和热敏感,应室温避光保存。
Pruritus vulvae with a high attack rate is most common Gynecological disease. There are many medicine to treat this disease internal at present,most of which are chinese traditional medicine.Western medicine is only single preparation,which do not have the function of curing itch,dephlogistication and bacteriostasis simultaneously.On the basis of the requirement,lidocaine,benadryl hydrochloride, EX and thymol are taken as the model drugs to prepare the compound ointment which has rapid curative effect.
After the investigation of emulsifier and basis material,we selected and optimized the formula by orthogonal design.The compound ointment was composed of peregal, liquid paraffin, docosyl alcohol, glyceryl monostearate, glycerin, isopropyl myristate and water.The study also includes praeparatum technology of the formula.
An HPLC method was established to determine three constituent content in the same chromatographic condition. The drugs were eluted with the mobile phase of methanol-buffer phosphate(pH8.0)-acetonitrile(60:25:15) at the flow rate of 1.0mL·min~(-1) on a C18 column at 35℃. The drugs were detected at the wavelength of 255nm. After validating,the method is convenient,rapid,accurate and reliable.We also established HPLC methods to determine the content of vitamin E and related substances of lidocaine and benadryl hydrochloride respectively.
The physicochemical properties and stability of compound ointment were studied.The appearance,pH value, fusing point and consistance of the ointment all conformed to the pharmacopoeia stipulation. The ointment style was qualified by staining method as oil-in-water .From influential factors experiments, accelerated tests and room temperature trials, it could be concluded that EX and thymol were unstable,so the ointment should be preserved away from light in room temperature.
通过乳化剂的考察和基质用量的正交试验,确定了复方软膏剂的最佳处方。即以平平加O为乳化剂,以白凡士林、液体石蜡、山嵛醇、单硬脂酸甘油酯为油相,甘油为水相,肉豆蔻酸异丙酯为透皮吸收促进剂。单因素考察了制备工艺参数,最终确定其理想工艺过程为:乳化温度80℃,将油相缓缓加入水相中,保温搅拌5min,再以1500rpm的速度搅拌至冷。
建立了HPLC法同时测定利多卡因,盐酸苯海拉明和麝香草酚三组分含量的方法。采用C18色谱柱(46×250mm,5μm),以甲醇-pH8.0磷酸盐缓冲液-乙腈(60:25:15)为流动相,流速1.0ml/min,柱温35℃,255nm检测。经过方法学验证,该方法简便快速,结果准确可靠。同时还建立并方法学验证了HPLC法测定EX含量及利多卡因和盐酸苯海拉明的有关物质。
对复方软膏的理化性质及稳定性进行了考察。结果本软膏外观,pH值,熔点,稠度均符合药典规定,通过染色法验证了本软膏为o/w型乳膏。影响因素和留样实验表明本软膏中EX及麝香草酚均对光和热敏感,应室温避光保存。
Pruritus vulvae with a high attack rate is most common Gynecological disease. There are many medicine to treat this disease internal at present,most of which are chinese traditional medicine.Western medicine is only single preparation,which do not have the function of curing itch,dephlogistication and bacteriostasis simultaneously.On the basis of the requirement,lidocaine,benadryl hydrochloride, EX and thymol are taken as the model drugs to prepare the compound ointment which has rapid curative effect.
After the investigation of emulsifier and basis material,we selected and optimized the formula by orthogonal design.The compound ointment was composed of peregal, liquid paraffin, docosyl alcohol, glyceryl monostearate, glycerin, isopropyl myristate and water.The study also includes praeparatum technology of the formula.
An HPLC method was established to determine three constituent content in the same chromatographic condition. The drugs were eluted with the mobile phase of methanol-buffer phosphate(pH8.0)-acetonitrile(60:25:15) at the flow rate of 1.0mL·min~(-1) on a C18 column at 35℃. The drugs were detected at the wavelength of 255nm. After validating,the method is convenient,rapid,accurate and reliable.We also established HPLC methods to determine the content of vitamin E and related substances of lidocaine and benadryl hydrochloride respectively.
The physicochemical properties and stability of compound ointment were studied.The appearance,pH value, fusing point and consistance of the ointment all conformed to the pharmacopoeia stipulation. The ointment style was qualified by staining method as oil-in-water .From influential factors experiments, accelerated tests and room temperature trials, it could be concluded that EX and thymol were unstable,so the ointment should be preserved away from light in room temperature.
引文
[1] Isohanni MH, Ahonen J, Neuvonen PJ, et al. Effect of ciprofloxin on the phar- -macokinetics of intravenous lidocaine. Eur J Anaesthesiol, 2005; 22(10): 795～799.
[2] Miller RD. Local anethesthetics. Miller's Anesthesia. 2006;6th edition: 594～595
[3]胡胜,路志宏,郑玉等.钠离子通道在异氟醚预处理诱导的脑保护中的作用.第四军医大学学报.2002,23(15):1366～1368
[4]翟海云,高建华,刘栓富,盐酸苯海拉明的二级散射法测定,郑州大学学报,2002,34(1):59～61
[5] Reisli R, Celik J, Tuncer S,et al.The effects of adding diphenhydramine hydrochloride to lidocaine in intravenous regional anaesthesia.The Pain Clinic.2003,15(4):441～446
[6]黄磊.促进药物透皮吸收的方法及应用前景.综述报告.2006,15(21):62～63
[7]徐立斌,张慧,粘膜给药,黑龙江医药,2006,19(5):384～285.
[8]刘可春,刘昌衡.辣椒碱软膏及制剂其配方的优选试验研究.山东科学, 2004, 17(2): 3336～3336.
[9]龚盛昭,王宗锐.水杨酸软膏用乳化剂筛选研究.广东药学院学报. 2004, 20(5):466～468
[10]张苏,高永良.透皮吸收促进剂的研究进展.科学与技术工程,2004,4 (8):732～735
[11]冯小龙,王晖,朱慧明.不同透皮吸收促进剂对环吡酮胺和水杨酸体外经皮渗透性的影响.中国新医药,2003,2(6):27～28
[12]许卫铭,王晖,王宗锐等.不同浓度薄荷醇对甲硝唑透皮吸收的影响.中药药理与临床.2001,17(3):10～12
[13]许卫铭,王晖,郑丽燕.薄荷醇及其二组分系统对双氯酚酸钠的促透作用.中国医院药学杂志.2002,22(3):160～162
[14]赵怀军,王晖,冯建青.薄荷醇对环丙沙星粘膜吸收的影响.中国临床药理学与治疗学.2002,7(4):314～316
[15]王晖,许卫铭.薄荷醇及其二组分系统对5-氟尿嘧啶经皮渗透和贮库效应的影响.中国临床药理学与治疗学.2003,8(4):422～423
[16]郑俊民.经皮给药新剂型.北京:人民卫生出版社,1997:49～50
[17]李国风,刘立捷,神山文男.肉豆蔻酸异丙酯对酮基布洛芬经皮渗透的影响.中国药学杂志,2002,37(10):755～758
[18]王刚,王鉴,王立娟等.抗氧剂作用机理及研究进展.合成材料老化与应用.2006,35(2):38～42
[19]冯士清,赵华.从使用频率看化妆品防腐剂走势.日用化学品科学.2006,29(11):30～33
[20]宋彦,董银卯,王友升.化妆品防腐剂,表面活性剂与功效添加剂的相互效应.日用化学品科学.2006,29(8):25～27
[21]冯秀娟,李忠生,李冰.皮特芬溶液对家兔皮肤刺激性试验.中国动物检疫。2007,24(1):41～42)
[22]栾海云,董圣军,张树平.聚维酮碘贴剂的制备与应用.齐鲁药事.2006,25(12):753～754)
[23]张顺国,李芳,唐跃年.阿昔洛韦软膏的稳定性研究.中国药房.2003,14(3):175～176
[24]张荣,费燕.正交试验优先银锌霜的配方及生产工艺条件.华西药学杂志,2004,199(3):241～242
[25]沈鸿,张继明.乳膏基质不同处方的筛选.中国医院药学杂志.2005,25(9):877～878
[26]于西全,晏明.多效胃镜乳的处方改进及稳定性考察.中国药业.2006,15(18):35～36
[27]王海学,王庆利,彭键.美国食品药品监督管理局复方制剂非临床安全性评价指导原则介绍.中国心要与临床杂志.2005,24(11):896～898
[28]严群芳.非离子表面活性剂的性质及应用.贵州化工.2005,30(5):4～7
[29]柳正青,胡晋红,朱全刚等.盐酸格拉司琼巴布剂基质处方设计.中国新药杂志.2006,15(17):1467～1469
[30]沈美意.鞣酸软膏的配制工艺改进.中国药师.2005,8(3):260～260.
[31]翟凌,任海霞,张文利.益肤霜的制备工艺研究.山东中医杂志.2001 20(6):369～370
[32]顾孝红,靳祖英,罗小荣.复方硝酸益康唑软膏制备工艺与质量标准研究.江西中医学院学报.2003,15(4):60～61
[33]孙淑娟,谷大建,杨久丽等.高效液相色谱法测定复方利多卡因乳膏中丙胺卡因与利多卡因的含量.中国医院药学杂志.2002,22(11):675～677
[34]郭建鹏,全哲山,黄海善.反相高效液相色谱法测定复方盐酸苯海拉明搽剂中两组分的含量.延边大学医学学报,2004,27(3):179～182
[35]廖小玲,黎海英,曹仲文.紫外分光广度法测定止痒搽剂中麝香草酚含量.广东药学学报,2OO2,18(4):287～288.
[36]张伯,赵彤英,王秀琴.紫外分光光度法测定麝香草粉醇溶液的含量.中国医院药学杂志.2002,22(3):143～145
[37]陈振霆.气相色谱法测定无极膏中樟脑、薄荷脑、水杨酸甲酯、麝香草酚的含量.海峡药学.2005,17(3):65～67
[38]霍保方,徐英宏,杨君等.HPLC测定复方麝香草酚醑中2组分的含量.中国药学杂志2005,40(11):859～861
[39]郭社民,HPLC法测定薄荷麝香草酚搽剂中3种主药的含量.中国药事.2006,20(1):51～53
[40]张玉琥.化学药物复方制剂杂志研究的特点及基本思路.中国新药杂志.2006,15(6):1327～1329
[41]江燕.高效液相色谱法测定盐酸苯海拉名片的有关物质和溶出度.中国现代应用药学杂志.2006,8(23):331～333
[42]成海平高建青霍秀敏,影响因素试验在药物研发中的作用及其关注点,新药在线,2006-11-30
[2] Miller RD. Local anethesthetics. Miller's Anesthesia. 2006;6th edition: 594～595
[3]胡胜,路志宏,郑玉等.钠离子通道在异氟醚预处理诱导的脑保护中的作用.第四军医大学学报.2002,23(15):1366～1368
[4]翟海云,高建华,刘栓富,盐酸苯海拉明的二级散射法测定,郑州大学学报,2002,34(1):59～61
[5] Reisli R, Celik J, Tuncer S,et al.The effects of adding diphenhydramine hydrochloride to lidocaine in intravenous regional anaesthesia.The Pain Clinic.2003,15(4):441～446
[6]黄磊.促进药物透皮吸收的方法及应用前景.综述报告.2006,15(21):62～63
[7]徐立斌,张慧,粘膜给药,黑龙江医药,2006,19(5):384～285.
[8]刘可春,刘昌衡.辣椒碱软膏及制剂其配方的优选试验研究.山东科学, 2004, 17(2): 3336～3336.
[9]龚盛昭,王宗锐.水杨酸软膏用乳化剂筛选研究.广东药学院学报. 2004, 20(5):466～468
[10]张苏,高永良.透皮吸收促进剂的研究进展.科学与技术工程,2004,4 (8):732～735
[11]冯小龙,王晖,朱慧明.不同透皮吸收促进剂对环吡酮胺和水杨酸体外经皮渗透性的影响.中国新医药,2003,2(6):27～28
[12]许卫铭,王晖,王宗锐等.不同浓度薄荷醇对甲硝唑透皮吸收的影响.中药药理与临床.2001,17(3):10～12
[13]许卫铭,王晖,郑丽燕.薄荷醇及其二组分系统对双氯酚酸钠的促透作用.中国医院药学杂志.2002,22(3):160～162
[14]赵怀军,王晖,冯建青.薄荷醇对环丙沙星粘膜吸收的影响.中国临床药理学与治疗学.2002,7(4):314～316
[15]王晖,许卫铭.薄荷醇及其二组分系统对5-氟尿嘧啶经皮渗透和贮库效应的影响.中国临床药理学与治疗学.2003,8(4):422～423
[16]郑俊民.经皮给药新剂型.北京:人民卫生出版社,1997:49～50
[17]李国风,刘立捷,神山文男.肉豆蔻酸异丙酯对酮基布洛芬经皮渗透的影响.中国药学杂志,2002,37(10):755～758
[18]王刚,王鉴,王立娟等.抗氧剂作用机理及研究进展.合成材料老化与应用.2006,35(2):38～42
[19]冯士清,赵华.从使用频率看化妆品防腐剂走势.日用化学品科学.2006,29(11):30～33
[20]宋彦,董银卯,王友升.化妆品防腐剂,表面活性剂与功效添加剂的相互效应.日用化学品科学.2006,29(8):25～27
[21]冯秀娟,李忠生,李冰.皮特芬溶液对家兔皮肤刺激性试验.中国动物检疫。2007,24(1):41～42)
[22]栾海云,董圣军,张树平.聚维酮碘贴剂的制备与应用.齐鲁药事.2006,25(12):753～754)
[23]张顺国,李芳,唐跃年.阿昔洛韦软膏的稳定性研究.中国药房.2003,14(3):175～176
[24]张荣,费燕.正交试验优先银锌霜的配方及生产工艺条件.华西药学杂志,2004,199(3):241～242
[25]沈鸿,张继明.乳膏基质不同处方的筛选.中国医院药学杂志.2005,25(9):877～878
[26]于西全,晏明.多效胃镜乳的处方改进及稳定性考察.中国药业.2006,15(18):35～36
[27]王海学,王庆利,彭键.美国食品药品监督管理局复方制剂非临床安全性评价指导原则介绍.中国心要与临床杂志.2005,24(11):896～898
[28]严群芳.非离子表面活性剂的性质及应用.贵州化工.2005,30(5):4～7
[29]柳正青,胡晋红,朱全刚等.盐酸格拉司琼巴布剂基质处方设计.中国新药杂志.2006,15(17):1467～1469
[30]沈美意.鞣酸软膏的配制工艺改进.中国药师.2005,8(3):260～260.
[31]翟凌,任海霞,张文利.益肤霜的制备工艺研究.山东中医杂志.2001 20(6):369～370
[32]顾孝红,靳祖英,罗小荣.复方硝酸益康唑软膏制备工艺与质量标准研究.江西中医学院学报.2003,15(4):60～61
[33]孙淑娟,谷大建,杨久丽等.高效液相色谱法测定复方利多卡因乳膏中丙胺卡因与利多卡因的含量.中国医院药学杂志.2002,22(11):675～677
[34]郭建鹏,全哲山,黄海善.反相高效液相色谱法测定复方盐酸苯海拉明搽剂中两组分的含量.延边大学医学学报,2004,27(3):179～182
[35]廖小玲,黎海英,曹仲文.紫外分光广度法测定止痒搽剂中麝香草酚含量.广东药学学报,2OO2,18(4):287～288.
[36]张伯,赵彤英,王秀琴.紫外分光光度法测定麝香草粉醇溶液的含量.中国医院药学杂志.2002,22(3):143～145
[37]陈振霆.气相色谱法测定无极膏中樟脑、薄荷脑、水杨酸甲酯、麝香草酚的含量.海峡药学.2005,17(3):65～67
[38]霍保方,徐英宏,杨君等.HPLC测定复方麝香草酚醑中2组分的含量.中国药学杂志2005,40(11):859～861
[39]郭社民,HPLC法测定薄荷麝香草酚搽剂中3种主药的含量.中国药事.2006,20(1):51～53
[40]张玉琥.化学药物复方制剂杂志研究的特点及基本思路.中国新药杂志.2006,15(6):1327～1329
[41]江燕.高效液相色谱法测定盐酸苯海拉名片的有关物质和溶出度.中国现代应用药学杂志.2006,8(23):331～333
[42]成海平高建青霍秀敏,影响因素试验在药物研发中的作用及其关注点,新药在线,2006-11-30