CN116159018A - 一种新型外用溴莫尼定凝胶剂 - Google Patents
一种新型外用溴莫尼定凝胶剂 Download PDFInfo
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- CN116159018A CN116159018A CN202310188180.XA CN202310188180A CN116159018A CN 116159018 A CN116159018 A CN 116159018A CN 202310188180 A CN202310188180 A CN 202310188180A CN 116159018 A CN116159018 A CN 116159018A
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- brimonidine
- oil
- carbomer
- tea tree
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Abstract
本发明属于医药技术领域，提供了一种新型外用的溴莫尼定凝胶剂以及在治疗轻、中度红斑血管扩张型及丘疹脓疱型玫瑰痤疮中的应用，该新型溴莫尼定凝胶剂用挥发油代替传统羟苯酯类防腐剂，不仅避免固体羟苯酯类防腐剂在凝胶剂中的析晶问题和规避羟苯酯类化合物对人体的潜在风险；而且加入挥发油能显著增加酒石酸溴莫尼定在减少玫瑰痤疮患者的红斑面积和缓解症状方面的疗效。该新型溴莫尼定凝胶剂制备工艺简单，易于工业化生产，具有较好的应用潜力。
Description
技术领域
本发明涉及医药技术领域，具体涉及一种含有挥发油的新型外用溴莫尼定凝胶剂和制备方法以及治疗轻、中度红斑血管扩张型及丘疹脓疱型玫瑰痤疮中的应用。
背景技术
酒石酸溴莫尼定(Brimonidine tartrate)，为5-溴-6-(2-咪唑双烯氨)喹噁啉L-酒石酸盐，结构式如下：
作为一种肾上腺素α2-受体激动剂，其作用于虹膜-睫状体α2-肾上腺素能受体，通过减少房水生成，达到降低眼压的作用，且副作用较小。临床上使用0.2％
及0.15％/>
酒石酸溴莫尼定滴眼液治疗开角型青光眼及高眼压症。近年来有研究发现溴莫尼定具有收缩血管的生理作用，2013年，FDA批准了Galderma公司的新产品
为浓度0.33％溴莫尼定(相当于5％酒石酸溴莫尼定)外用凝胶，通过作用于面部血管周围平滑肌，收缩血管，从而减轻患者面部红斑与水肿等症状。主要适用于红斑血管扩张型玫瑰痤疮。玫瑰痤疮是一种常发于面中部，主要累及面部皮下血管与毛囊皮脂腺的慢性炎症型皮肤病，以面部红色斑块，毛细血管扩张、丘疹、水肿等症状为主，通常伴有灼热，刺痛，瘙痒等症状。目前其病因及发病机制尚未明确，主要认为与免疫系统缺陷、神经血管舒缩功能异常及局部微生物感染等因素有关，同时，受紫外线、温度刺激、饮食、情绪等外部因素影响。玫瑰痤疮治愈困难，目前临床治疗的主要目的是减轻临床症状，减缓病情进展过程。对于玫瑰痤疮中轻症患者，常使用外用药物治疗，溴莫尼定凝胶具有见效快、副作用较低、使用方便等优点，但对丘疹、脓疱及其带来的皮肤损伤无明显作用(AnzengruberF，Czernielewski J，Conrad C，et al.Swiss S1 guideline for the treatment ofrosacea.J Eur Acad Dermatol Venereol.2017；31(11)：1775-91)。
凝胶剂(gels)系指药物与能形成凝胶的辅料制成溶液、混悬或乳状液型的稠厚液体或半固体制剂。上市的
凝胶剂处方组成主要包括药物，卡波姆，丙二醇和丙三醇、尼泊金甲酯或羟苯甲脂、二氧化钛、pH调节剂、水。目前已公开的溴莫尼定外用凝胶专利主要是Galderma公司的CN2011800508992，该专利公开了一种以羟苯甲酯作为主要防腐剂溴莫尼定凝胶剂，用以治疗轻、中度红斑型玫瑰痤疮。该专利主要解决凝胶剂存在的羟苯甲酯结晶防止微生物污染问题，但固体羟苯甲酯水溶性较低且结晶性受卡波姆浓度影响，在凝胶剂开封使用后，仍存在析晶的风险。此外，尽管羟苯甲酯已广泛用于口服和外用制剂的防腐剂，但近年来的研究表明羟苯酯类防腐剂长期反复使用仍具有许多潜在风险，在CTFA进行的一项皮肤毒性研究中，一种含有0.2％羟苯甲酯的产品配方被局部应用于白化家兔3个月，接受每日5.5mg/cm2的剂量，涂布于8.4％的体表面积，结果发现与对照组相比，含有羟苯甲酯的产品可引起持续性明显至中度红斑、轻度水肿和间歇性轻度脱屑(CTFA，1981b.Subchronic(three-month)dermal toxicity study inrabbit with product CN0028 containing methyl paraben.)。尤其值得注意的是，Darbre，P等人的研究还发现羟苯甲酯对MCF7乳腺癌细胞具有极强的雌激素活性，可能达到17-β-雌二醇的几千倍，说明大量使用添加有羟苯甲酯的制剂会提高女性乳腺癌风险。William H等人研究也发现羟苯甲酯的添加还会提高乳腺癌细胞的抗药性，阻碍患者化疗过程，更进一步加剧了大众对于羟苯甲酯大范围使用的担忧(Goodson W.H.et al.(2011)Activation of the mTOR pathwayby low levels of xenoestrogens in breast epithelial cells from high-riskwomen.Carcinogenesis，32，1724-1733)。
挥发油(Essential Oils)是指从香料植物中加工提取所得到的挥发性油状芳香物质的总称。天然植物挥发油安全无毒，对皮肤具有杀菌、抗炎、愈合、除臭、镇静、驱虫、柔润细腻皮肤等作用，挥发油在外用药品和化妆品中，不仅使用广泛，而且历史悠久。常用的抗菌活性较好的挥发油有茶树油、薰衣草油、艾草油、橙花油、柠檬油、天竺葵油等，茶树油为一种从澳大利亚本土植物互叶白千层叶中蒸馏提取而出的一种天然植物精油，为一种带有特征香气的无色至淡黄色液体。主要组成为1.8-桉叶素、α-松油烯及γ-松油烯等。γ-松油烯已被证明可以影响细菌细胞壁的生成，破坏细胞质膜，并抑制葡萄糖依赖性呼吸，故其在抗菌消炎方面起有独特的作用。Carson CF等人的研究发现其对金黄葡萄球菌的MIC90为0.5％(Carson CF，Hammer KA，Riley TV.Broth micro-dilution method fordetermining the susceptibility of Escherichia coli and Staphylococcusaureusto the essential oil of Melaleucaalternifolia(tea tree oil).Microbios 1995；82：181-5)，Banes-Marshall L等人的研究发现其对铜绿假单胞菌的MIC90小于2％(Banes-Marshall L，Cawley P，Phillips CA.In vitro activity of Melaleuca alternifolia(tea tree)oil against bacterial and Candida spp.isolates from clinicalspecimens.Br J Biomed Sci 2001；58：139-45.)，均表明其对常见致病微生物具有良好的抑制作用，具有作为天然防腐剂的潜质。同时，其在促进伤口愈合方面亦有相关研究，KerrJ等在一项针对100名患有慢性伤口的患者研究表明，外用茶树油混合制剂作为辅助治疗，伤口愈合速度超出预期，同时，炎症、疼痛及伤口不良气味也迅速减少(Kerr J.usingessential oils in wound care for the elderly.Aromatherapy Today 2002；23：14-9.)。此外，关于茶树油的相关药物毒理性研究表明，其安全性良好，作为外用制剂对皮肤无刺激与副作用，Saller R，Berger T，Reichling J等人的研究表明，使用白化兔模型作为对象研究其急性真皮LD50数据时，将5.0g/kg.BW100％茶树油涂抹于白化兔皮肤，并保持2g/kg.BW 24h，实验对象无毒性迹象；在普通家兔皮肤上使用25％石蜡茶树油擦剂进行30天的皮肤刺激性试验，没有产生明显的刺激(Saller R，Berger T，Reichling J，etal.Pharmaceutical and medicinal aspects of Australian tea treeoil.Phytomedicine 1998；5：489-95.)。而羟苯甲酯大鼠真皮LD50约为500-1200mg/kg.EW，毒性远大于茶树油。薰衣草油、艾草油、橙花油、柠檬油、天竺葵油等对金黄色葡萄球菌、绿脓杆菌、白色念珠菌也都有显著的抑制作用。
针对溴莫尼定凝胶剂中羟苯甲酯防腐剂带来的上述风险问题，本专利提供一种含有抗菌作用挥发油的、无羟苯甲酯的外用酒石酸溴莫尼定凝胶剂以及在治疗轻、中度红斑血管扩张型及丘疹脓疱型玫瑰痤疮中的应用。研究结果令人高兴的是发现挥发油能显著增加酒石酸溴莫尼定在缓解玫瑰痤疮患者的红斑、丘疹的面积和症状方面的疗效，具有良好的应用前景。
发明内容
本发明的目的是能够提供一种含有抗菌作用挥发油的、无羟苯甲酯的外用酒石酸溴莫尼定凝胶剂以及在治疗轻、中度红斑血管扩张型及丘疹脓疱型玫瑰痤疮中的应用。
所述外用溴莫尼定凝胶剂由以下重量份的物质组成：酒石酸溴莫尼定，0.03-6.6％(w/w)，挥发油1-30％(w/w)，胶凝剂0.5-2％(w/w)，保湿剂4.5-15％(w/w)，物理遮光剂0.05-0.5％(w/w)，pH调节剂0.5-2.5％，纯化水46-90％。作为本发明的一种优选，包含以下重量比的物质：酒石酸溴莫尼定∶挥发油∶胶凝剂∶保湿剂∶物理遮盖剂∶pH调节剂∶纯化水＝(0.2-0.8％)∶(5-20％)∶(0.8-1.5％)∶(7-12％)∶(0.05-0.1％)∶(0.5-1％)∶(65-86％)。
所述外用溴莫尼定凝胶剂的pH为5.5-8.0；pH优选为6.5-7.5。pH检测方法为：取样品0.5g，加入蒸馏水及无水甲醇各25ml，搅拌使其充分溶解后用pH剂测定。
所述的外用溴莫尼定凝胶剂中，挥发油为天然植物经过提取纯化得到的且具有抗菌活性的提取物。挥发油选自薰衣草油、茶树油、艾草油、橙花油、柠檬油、天竺葵油中的一种或多种；作为本发明的优选，挥发油优选茶树油。本发明的进一步优选，茶树油添加量为10％。
所述的外用溴莫尼定凝胶剂中，胶凝剂选自卡波姆934P、卡波姆940、卡波姆941、卡波姆974P、甲基纤维素、羟丙基纤维素、羟丙甲基纤维素、羧甲基纤维素钠中的一种或多神，优选卡波姆974P；保湿剂选自丙二醇、丙三醇、丁二醇、聚乙二醇、聚丙二醇和山梨醇口的一种或几种；物理遮光剂选自二氧化钛、纳米二氧化钛、氧化锌和纳米氧化锌中的一种或几种；pH调节剂选自氢氧化钠、氢氧化钾、三乙醇胺中的一种或几种，优选氢氧化钠。
所述的外用溴莫尼定凝胶剂，具体制备方法如下：精密称取处方量胶凝剂加入适量纯水，溶胀12h备用。精密称取处方量酒石酸溴莫尼定、挥发油、保湿剂、物理遮盖剂，加入到溶胀完成的卡波姆溶液中，500r/min搅拌15min至混合完全，再将转速增加至800r/min，用1.5M氢氧化钠溶液调节混合物至适宜pH，最后加入适量纯水至足量，恃续搅拌至成品呈淡黄绿色质地均一凝胶，即得。
所述的外用溴莫尼定凝胶剂，其特征在于：适用局部给药，治疗包括但不限于轻、中度红斑血管扩张型及丘疹脓疱型玫瑰痤疮。
新型外用溴莫尼定凝胶剂的有益效果：(1)以挥发油代替羟苯甲酯作为制剂抑菌剂，避免了羟苯酯类防腐剂相关副作用及储存、使用过程中的析晶风险。(2)挥发油能显著增加溴莫尼定在缓解玫瑰痤疮患者的红斑、丘疹的症状方面的疗效(3)挥发油对皮肤具有杀菌、抗炎作用，有利于弥补了溴莫尼定凝胶制剂在应对细菌、毛囊虫感染导致的玫瑰痤疮效果不佳的缺点；挥发油能促进伤口愈合，有利于对玫瑰痤疮导致的脓疱，丘疹等症状的治疗。(4)茶树油等挥发油为植物天然提取成分，可进一步降低制剂对皮肤的刺激性，安全性高。(5)处方工艺简单，成本较低，适宜工业化生产。
附图说明
图1是胶凝剂浓度对溴莫尼定凝胶剂体外释放的影响。
图2是组合保湿剂浓度对溴莫尼定凝胶剂体外释放的影响。
图3是含与不含茶树油的溴莫尼定凝胶剂的体外释放曲线的比较。
图4含茶树油的溴莫尼定凝胶剂治疗后红斑面积减少量的比较(*P＜0.05，**P＜0.01)
图5含茶树油的溴莫尼定凝胶剂的药效评分(*P＜0.05，**P＜0.01)
具体实施方式
下面结合具体实例对本申请做出详细说明。实施例中提及药物、试剂、动物等均为市售产品。
实施例1制备不同浓度胶凝剂的溴莫尼定凝胶剂。
分别精密称取卡波姆974P 0.5g、1.0g、1.5g，加入约60ml纯水，溶胀12h备用；各组再加入酒石酸溴莫尼定0.5g，二氧化钛0.05g，甘油5g，丙二醇5g，500r/min搅拌15min至混合完全，再将转速增加至800r/min，用1.5M氢氧化钠溶液滴加至pH＝7，最后加入适量纯水将样品总重补至100g即得。
实施例2制备不同浓度保湿剂组合(甘油、丙二醇)的溴莫尼定凝胶剂。
精密称取1.0g卡波姆974P，加入约60ml纯水，溶胀12h备用；精密称取酒石酸溴莫尼定0.5g，二氧化钛0.05g，分别加入低浓度保湿剂组合(甘油3.5g，丙二醇3.5g)、中浓度保湿剂组合(甘油5.0g，丙二醇5.0g)及高浓度保湿剂组合(甘油6.5g，丙二醇6.5g)于溶胀完成的卡波姆溶液中，500r/min搅拌15min至混合完全，再将转速增加至800r/min，缓慢滴入1.5M氢氧化钠溶液至pH＝7，最后加入适量纯水将样品总重补至100g即得。
实施例3制备溴莫尼定凝胶剂。
精密称取1.0g卡波姆974P，加入约60ml纯水，溶胀12h备用；精密称取酒石酸溴莫尼定0.5g，二氧化钛0.05g，甘油5g，丙二醇5g，加入到溶胀完成的卡波姆溶液中，500r/min搅拌15min至混合完全，再将转速增加至800r/min，缓慢滴入1.5M氢氧化钠溶液至pH＝7，最后加入适量纯水将样品总重补至100g即得。
实施例4制备不同浓度茶树油的溴莫尼定凝胶剂
精密称取1.0g卡波姆974P，加入约60ml纯水，溶胀12h备用；加入酒石酸溴莫尼定0.5g，二氧化钛0.05g，甘油5g，丙二醇5g，分别称取茶树油1g，5g，10g，20g，30g，加入到卡波姆溶液中，500r/min搅拌15min至混合完全，再将转速增加至800r/min，缓慢滴入1.5M氢氧化钠溶液至pH＝7，最后加入适量纯水将样品总重补至100g即得。
实施例5制备不同浓度茶树油的凝胶剂.
精密称取1.0g卡波姆974P，加入约60ml纯水，溶胀12h备用；加入二氧化钛0.05g，甘油5g，丙二醇5g，分别称取茶树油5g、10g、20g，加入到卡波姆溶液中，500r/min搅拌15min至混合完全，再将转速增加至800r/min，缓慢滴入1.5M氢氧化钠溶液至pH＝7，最后加入适量纯水将样品总重补至100g，即得。
实施例6制备含艾草油的酒石酸溴莫尼定凝胶剂。
精密称取1.0g卡波姆940，加入约60ml纯水，溶胀12h备用；精密称取酒石酸溴莫尼定0.6g，艾草油10g，二氧化钛0.08g，甘油5g，丙二醇5g，加入到溶胀完成的卡波姆溶液中，500r/min搅拌15min至混合完全，再将转速增加至800r/min，缓慢滴入1.5M氢氧化钠溶液至pH＝6.90，最后加入适量纯水将样品总重补至100g。即得。
实施例7制备含薰衣草油的酒石酸溴莫尼定凝胶剂。
精密称取1.0g卡波姆940，加入约60ml纯水，溶胀12h备用；精密称取酒石酸溴莫尼定0.7g薰衣草油15g，二氧化钛0.1g，甘油5g，丙二醇5g，加入到溶胀完成的卡波姆溶液中，500r/min搅拌15min至混合完全，再将转速增加至800r/min，缓慢滴入1.5M氢氧化钠溶液至pH＝7.18，最后加入适量纯水将样品总重补至100g，即得。
实施例8药物凝胶剂体外释放试验
以Franz立体扩散池作为凝胶释药装置，有效扩散面积约为0.786cm2。选择0.45μm的PVDF微孔滤膜作为透过膜，安装好扩散池后，接收池中注满PBS缓冲溶液(pH＝7.4)，在给药池中加入1ml凝胶样品，保证接收池与给药池间无气泡滞留。将装置置于磁力搅拌器上，接通32℃恒温循环水，分别于30min，1h，2h，4h，6h，12h，24h取出1ml接受液(同时补充1ml等温PBS缓冲液)，过滤后滤液HPLC分析，测定溴莫尼定浓度，计算累积释放量。
(1)考察胶凝剂用量对溴莫尼定凝胶剂影响。
取实施例1的不同浓度胶凝剂的溴莫尼定凝胶剂，进行上述的体外释放试验，结果见图1。图1表明低浓度胶凝剂释放度最好，但在0.5％浓度下配制样品呈粘稠液体，测得其粘度仅72cP，达不到凝胶要求，故凝胶剂选用浓度即1.0％胶凝剂，其样品粘度为1200cP，符合凝胶要求。
(2)考察保湿剂用量对溴莫尼定凝胶剂影响。
实施例2中所配制样品作为实验对象，进行上述的体外释放试验，结果图2，图2可看出，中浓度保湿剂组合(甘油5g、丙二醇5g)配制的凝胶释放性能最好，故凝胶中保湿剂组合选为甘油5g、丙二醇5g。
(3)比较含与不含茶树油的溴莫尼定凝胶的体外释放度。
以实施例3和实施例4中茶树油浓度为10％的溴莫尼定凝胶剂进行释放度试验，结果见图3，图3表明添加茶树油有利于凝胶中溴莫尼定的释放。
实施例9含茶树油的溴莫尼定凝胶剂的相容性初步研究
取实施例4中茶树油浓度为10％的酒石酸溴莫尼定凝胶剂10g置于铝塑管包装中，密时置于40℃恒温稳定箱中，分别于第0、5、10天取样测定溴莫尼定浓度，观察外观。结果见表1.
表1含茶树油(10％)的酒石酸溴莫尼定凝胶剂相容性实验结果(n＝3)
| 时间/d | 外观 | 重量/g | pH | 含量％ | 外观 |
| 0 | 黄绿色均匀凝胶 | 10.03±0.02 | 6.99±0.04 | 0.491±0.21 | 均匀，无结晶 |
| 5 | 黄绿色均匀凝胶 | 9.81±0.04 | 7.03±0.08 | 0.494±0.14 | 均匀，无结晶 |
| 10 | 黄绿色均匀凝胶 | 9.79±0.06 | 7.01±0.13 | 0.503±0.41 | 均匀，无结晶 |
上述结果表明，添加10％茶树油对凝胶剂中溴莫尼定含量、pH和外观无明显影响，说明凝胶剂中茶树油与溴莫尼定具有较好的相容性。
实施例10凝胶剂的药效学评价
(1)LL-37抗菌肽诱导小鼠玫瑰痤疮模型的建立与治疗
小鼠先在独立通气笼中饲养48h，降低应激反应。在实验前24h用剃毛刀剃除小鼠背部毛发。将小鼠随机分为A(空白对照组)、B(造模组)、C(实施例5低浓度茶树油凝胶组)、D(实施例5中浓度茶树油凝胶组)、E(实施例6高浓度茶树油凝胶组)、F(实施例3溴莫尼定凝胶组)、G(实施例4低浓度茶树油的溴莫尼定凝胶组)、H(实施例1中浓度茶树油的溴莫尼定凝胶组)、I(实施例1高浓度茶树油的溴莫尼定凝胶组)，每组6只。
小鼠背部中央位置选出直径1cm的圆形区域作为受试部位。每12h对B、C、D、E、F、G、H、I组小鼠背部受试区域进行50μl LL-37溶液皮下注射，至形成真皮泡和红斑。共进行6次，A组在相同位置以相同频率皮下注射配置LL-37溶液用的注射用水。C、D、E、F、G、H、I组在第三次注射LL-37后，分别外用凝胶样品各0.5g进行治疗，每日两次，连续3天。
(2)结果
使用相机对第一次凝胶治疗前和凝胶最后一次给药后24h的患处进行拍照，并使用imageJ软件量取各实验小鼠患处红斑总面积，并计算红斑面积减少量，结果见表1和图4。
同时在最后一次给药治疗后24h对小鼠受试区域玫瑰痤疮红斑进行皮肤损伤评分，参照皮肤科疾病临床评分表，按照1-5分(5分为最高)对皮损程度，红斑扩散程度、水肿脓疱情况等指标对各实验对象玫瑰痤疮症状进行量化分析。并按照药效评分＝红斑面积减少量/(0.2*红斑扩散评分+0.4*皮损评分+0.4*水肿脓疱评分)，计算药效分数，评分数值越大代表治疗效果越好。结果见表1及图5。
表1凝胶治疗前、后红斑面积的比较
#与B组数据比较P＜0.05，##与B组数据比较P＜0.01；*与F组数据比较P＜0.05，**与F组数据比较P＜0.01；☆与G组数据比较P＜0.05，☆☆与G组数据比较P＜0.01.
表1和图4表明：治疗前除对照组(A组)外各组都形成明显的玫瑰痤疮样红斑，表明造模成功。治疗最后一次给药后24时各给药组(C至I组)小鼠患处玫瑰痤疮样红斑面积均有所减轻，从红斑面积减少量Δ值来看，与B组(造模组)Δ值相比各给药组(C-I组)的Δ值均有大幅度增加(P＜0.01)，表明茶树油凝胶、酒石酸溴莫尼定凝胶和含茶树油的酒石酸溴莫尼定凝胶均可显著减少小鼠受试部位红斑面积。与F组(溴莫尼定凝胶组)的Δ值比较，尽管三组茶树油凝胶(C、D、E组)的Δ值有一定增加，且呈现剂量-效应依赖性，但仅高剂量茶树油凝胶组(E组)Δ值与F组Δ值的差异具有统计学显著性(P＜0.05)；令人感兴趣的是，三组含茶树油的溴莫尼定凝胶组(G、H、I组)Δ值较F组Δ值有较大增加，其中H组和I组的Δ值与F组Δ值相比均具有极显著性差异(P＜0.01)，但H组和I组的Δ值相似，两者之间无显著性差异(P＞0.05)，表明茶树油添加量达到10％及以上时，茶树油-酒石酸溴莫尼定凝胶对红斑面积的减低效果最好。
从药效评分数据来看(见表1和图5)，给药各组(C-I组)药效分数与B组(造模组)相比均有较大提高(P＜0.01)，说明茶树油凝胶、溴莫尼定凝胶和含茶树油的溴莫尼定凝胶均可有效减轻小鼠受试部位总体症状。D组、E组的药效评分优于F组(P＜0.01)，说明茶树油单独治疗皮损、水肿、脓疱等症状的效果好于溴莫尼定。H组、I组药效数据最大，治疗效果最好，且与F组比较差异极显著(P＜0.01)，H组和I组不仅红斑面积大幅缩小，而且症状减轻更为明显，皮损部位基本愈合，疗效明显优于溴莫尼定凝胶，表明添加茶树油后能显著提高溴莫尼定对红斑、皮损、水肿、脓疱等玫瑰痤疮常见症状的疗效。
以上对本发明的具体实施例进行了详细描述，但只是作为范例，本发明并不限制于以上描述的具体实施例。因此，在不脱离本发明的精神和范围下所作的均等变换和修改，都应涵盖在本发明的范围内。
Claims (5)
1.一种新型外用溴莫尼定凝胶剂，其特征在于包含以下重量比的物质：酒石酸溴莫尼定0.03-6.6％(w/w)，挥发油1-30％(w/w)，胶凝剂0.5-2％(w/w)，保湿剂4.5-15％(w/w)，物理遮光剂0.05-0.5％(w/w)，pH调节剂0.5-2.5％(w/w)，纯水46-90％(w/w)；凝胶剂的pH为5.5-8.0。
2.根据权利要求1中所述的新型外用溴莫尼定凝胶剂，其特征在于所述挥发油为天然植物经过提取纯化得到的且具有抗菌活性的提取物。
3.根据权利要求1所述的新型外用溴莫尼定凝胶剂，其特征在于，挥发油选自薰衣草油、茶树油、艾草油、橙花油、柠檬油、天竺葵油中的一种或多种；胶凝剂选自卡波姆934P、卡波姆940、卡波姆941、卡波姆974P、甲基纤维素、羟丙基纤维素、羟丙甲基纤维素、羧甲基纤维素钠中的一种或多种；保湿剂选自丙二醇、丙三醇、丁二醇、聚乙二醇、聚丙二醇、山梨醇中的一种或几种；物理遮光剂选自二氧化钛、纳米二氧化钛、氧化锌和纳米氧化锌中的一种或几种；pH调节剂选自氢氧化钠、氢氧化钾、三乙醇胺中的一种或几种。
4.根据权利要求1中所述的新型外用溴莫尼定凝胶剂，其特征在于通过以下方法制备得到：精密称取处方量胶凝剂加入适量纯水，溶胀12h备用。精密称取处方量酒石酸溴莫尼定、挥发油、保湿剂、物理遮光剂，加入到溶胀完成的卡波姆溶液中，500r/min搅拌15min至混合完全，再将转速增加至800r/min，用1.5M氢氧化钠溶液调节pH，最后加入适量纯水至足量，持续搅拌至成品呈淡黄绿色质地均一凝胶，即得。
5.权利要求1-3中任一项所述的新型外用溴莫尼定凝胶剂，在制备治疗轻、中度红斑血管扩张型及丘疹脓疱型玫瑰痤疮的药物中的应用。
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