复方结合雌激素黄体酮阴道用乳膏的乳化剂筛选与体外释放研究  

Study on emulsifier screening and in vitro release of a compoundconjugated estrogens progesterone cream for vaginal use

作　　者：李盼盼 崔海洋 肖岑宇 黄群群 高晓黎[1,3] LI Panpan;CUI Haiyang;XIAO Cenyu;HUANG Qunqun;GAOXiaoli(College of Pharmacy,Xinjiang Medical University,Urumqi 830017,China;Xinjiang Xinziyuan Biological Pharmaceutical Co.,Urumqi 830017,China;Engineering Research Center of Xinjiang and Central Asian Medicine Resources,Urumqi 830017,China)

机构地区：[1]新疆医科大学药学院 [2]新疆新姿源生物制药有限责任公司 [3]新疆及中亚特色医药资源教育部工程研究中心,乌鲁木齐830017

出　　处：《新疆医科大学学报》2024年第9期1274-1280,共7页Journal of Xinjiang Medical University

基　　金：新疆维吾尔自治区重大科技专项资助(2022A02013-3)。

摘　　要：目的筛选复方结合雌激素黄体酮阴道用乳膏的乳化剂,并测定乳膏体外释放特性。方法以十六醇、单硬脂酸甘油酯、白蜂蜡、硬脂酸甲酯、液体石蜡、鲸蜡醇硬脂酸酯、丙二醇硬脂酸酯、黄体酮为油相,苯甲醇、甘油、结合雌激素、纯化水为水相。分别加入0.24%十二烷基硫酸钠(Sodium dodecyl sulfate,SDS)或8%聚二乙醇-7-硬脂酸酯(Tefose■63)为乳化剂,采用乳化法制备2种O/W型复方结合雌激素(Conjugated estrogens,CE)黄体酮(Progesterone,P4)阴道用乳膏,并采用综合评分法进行质量评价。2种乳膏均含有结合雌激素0.625 mg/g和黄体酮80 mg/g。选取16只新西兰大耳兔,随机分为4组,SDS组(使用含SDS乳膏进行给药)、Tefose■63组(使用含Tefose■63乳膏进行给药)、空白基质组(不含乳化剂的空白基质)以及生理盐水组(以生理盐水代替乳膏进行给药),4组均皮肤给药0.5 mL,阴道给药1 mL,每天1次,连续给药7 d后取皮肤、阴道组织进行HE染色,评价2种乳膏刺激性。筛选出较优的复方乳膏,采用LOGAN体外透皮仪测定该复方乳膏中CE和P4的单位面积累计释放量与累计释放率。结果含SDS乳膏综合评分为(95.83±0.03)分,含Tefose■63乳膏综合评分为(95.80±0.05)分。空白基质组与生理盐水组兔阴道黏膜完整,SDS组出现明显阴道黏膜复层扁平上皮损伤,Tefose■63组阴道黏膜轻微损伤。两种含不同乳化剂乳膏对皮肤均无明显刺激性。筛选出最优复方阴道用乳膏中CE释放速率为(13.15±0.37)μg·cm^(-2)·h^(-1/2),P4的释放速率为(297.73±12.48)μg·cm^(-2)·h^(-1/2),两者单位面积累积释放量与时间的平方根呈线性关系,符合Higuchi方程。结论采用Tefose■63为乳化剂的复方结合雌激素黄体酮阴道用乳膏外观洁白细腻、性质稳定、阴道黏膜的刺激性较小,并具有良好的体外释放特性。Objective To screen the emulsifiers of compounded conjugated estrogens progesterone cream for vaginal use and to determine the in vitro release characteristics of the cream.Methods Cetyl alcohol,glyceryl monostearate,white beeswax,methyl stearate,liquid paraffin,cetearyl stearate,propylene glycol stearate and progesterone were used as oil phase and benzyl alcohol,glycerol,conjugated estrogens and purified water as aqueous phase.2 O/W complexes of conjugated estrogens(CE)progesterone(P4)vaginal creams were prepared by emulsification method,and the quality was evaluated by a composite scoring method.16 New Zealand lop-eared rabbits were randomly divided into 4 groups:SDS group(SDS-containing cream was administered),Tefose■63 group(Tefose■63-containing cream was administered),blank substrate group(blank substrate without emulsifier)and saline group(saline was administered instead of cream).All 4 groups were administered 0.5 mL of the cream on the skin,and 1 mL of the cream was administered vaginally once a day,and the irritation properties of the creams were evaluated by taking the skin and vagina tissues after 7 consecutive days and conducting HE staining.The superior compounded cream was selected,and the cumulative release per unit area and cumulative release rate of CE and P4 from the compounded cream were determined using LOGAN in vitro transdermal instrument.Result The composite score of SDS-containing cream was(95.83±0.03)points and the composite score of Tefose■63-containing cream was(95.80±0.05)points.The vaginal mucosa was intact in rabbits in the blank matrix and saline groups,significant flat epithelial damage to the vaginal mucosal complex was seen in SDS group,and slight damage to the vaginal mucosa was seen in the Tefose■63 group.Neither of the 2 creams with different emulsifiers showed significant skin irritation.The release rate of CE in the optimal compounded cream for vaginal use was screened to be(13.15±0.37)μg·cm^(-2)·h^(-1/2),and that of P4 was(297.73±12.48)μg·cm^(-2)·h^(-1/2),

关 键 词：结合雌激素 黄体酮 阴道给药 皮肤黏膜刺激性 体外释放 

分 类 号：R944[医药卫生—药剂学]