CN117860670A - 一种千层纸素外用制剂及其在银屑病治疗上的应用 - Google Patents
一种千层纸素外用制剂及其在银屑病治疗上的应用 Download PDFInfo
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Abstract
本发明公开了一种千层纸素外用制剂及其在银屑病治疗上的应用,所述的千层纸素外用制剂为皮肤给药制剂,选自溶液剂、乳膏剂和凝胶剂。本发明针对千层纸素难以水溶的缺陷,利用合适的溶剂(PEG300和丙二醇)提高了千层纸素的水溶解度,从而拓展了千层纸素的应用方式,并特别提高了它在银屑病上的治疗效果。
Description
技术领域
本发明属于医药技术领域,具体涉及一种千层纸素外用制剂及其在银屑病治疗上的应用。
背景技术
千层纸素是一种极具药用潜力的天然化合物,但由于其水溶性差的问题限制了它的使用。千层纸素几乎不溶于水,因此其给药途径大多局限于口服,于此同时,也产生了生物利用度低的问题。将千层纸素研磨成为极细粉末并利用羧甲基纤维素钠配成混悬液,虽然在短时间内(2周左右)能够满足其作为口服液的需求,但依然无法避免以下几个问题:①药物沉降;②使用前必须充分摇匀;③低温保存;④在超过一定时间后,羧甲基纤维素钠的悬浮能力下降,千层纸素悬浮效果变差;⑤水溶液中的千层纸素稳定性降低。
银屑病是个体与环境相互影响诱发的免疫介导的慢性、复发性、炎症性、系统性疾病,典型临床表现以红色丘疹或斑块覆盖有多层银白色鳞屑的皮损为特征。皮肤损害可泛发全身,并累计皮肤附属器和黏膜。少数患者发生脓疱和红皮病,严重的银屑病中发生关节炎比例较高。外用药物治疗的一线用药为外用糖皮质激素,但长期大面积使用糖皮质激素会导致皮肤和系统的不良反应。外用药物治疗的维持疗法为外用抗炎药物,如中弱效糖皮质激素或钙调神经磷酸酶抑制剂减小复发,其不良反应主要为局部灼烧感和刺激感。系统药物治疗主要用于银屑病的辅助治疗,为口服抗组胺药物、免疫抑制剂、糖皮质激素。基于此,一种可用于银屑病治疗,安全且有效的药物制剂为社会亟需。
由于千层纸素具有抗炎,抗菌,抗病毒,抗过敏,免疫调节等多种药理作用。将千层纸素制备为可用于银屑病治疗的外用制剂,其抗炎、抗菌的药理作用有利于银屑病皮肤损伤的恢复。外用制剂因其方便的使用方法、患者接受度高而在皮肤疾病上广泛采用。已有研究证明千层纸素口服能治疗银屑病,因此,改良千层纸素的水溶性问题,并将其制备成皮肤外用制剂对银屑病的治疗具有极大的意义。
发明内容
本发明的目的之一是提供一种千层纸素外用制剂,所述外用制剂为皮肤给药制剂,选自溶液剂、乳膏剂和凝胶剂;
所述溶液剂由千层纸素、PEG300、丙二醇、无水乙醇和/或水制成;
所述乳膏剂由千层纸素、溶剂、油相、乳化剂、增稠剂和水相制成;
所述凝胶剂由千层纸素、溶剂、增溶剂、防腐剂和凝胶相制成。
进一步地,所述乳膏剂中,溶剂选自聚乙二醇300、聚乙二醇400、丙二醇和无水乙醇,油相选自液体石蜡、凡士林、硬脂酸、单硬脂酸甘油酯和白蜂蜡,乳化剂选自吐温80和聚氧乙烯氢化蓖麻油RH40,增稠剂选自羧甲基纤维素钠、黄原胶和羟丙甲纤维素。
进一步地,所述凝胶剂中,溶剂选自聚乙二醇300、聚乙二醇400和丙二醇,防腐剂选自苯甲醇、苯扎氯铵、尼泊金甲酯和尼泊金乙酯,凝胶选自卡波姆、壳聚糖、海藻酸钠、羧甲基纤维素钠和羟丙甲纤维素。
在本发明的一个实施例中,所述溶液剂的处方为:千层纸素3g、200mL PEG300、200mL丙二醇、150mL无水乙醇。
本发明的目的之二是提供上述千层纸素外用制剂在制备银屑病治疗药物中的应用。
本发明针对千层纸素难以水溶的缺陷,利用合适的溶剂(PEG300和丙二醇)提高了千层纸素的水溶解度,从而拓展了千层纸素的应用方式,并特别提高了它在银屑病上的治疗效果。所得千层纸素外用制剂稳定性高,能够获得较好的粒径,进一步添加其他辅料拓展为乳膏剂或凝胶剂后均匀度佳、延展性好,对千层纸素的皮肤外用体验和药效起到了良好的提升作用。
具体实施方式
下面将结合实施例对本发明的优选实施方式进行详细说明。需要理解的是以下实施例的给出仅是为了起到说明的目的,并不是用于对本发明的范围进行限制。本领域的技术人员在不背离本发明的宗旨和精神的情况下,可以对本发明进行各种修改和替换。
下述实施例中所使用的实验方法如无特殊说明,均为常规方法。
下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
以下实施例所制备的千层纸素制剂处方如下:
表1实施例1~3及对比例1~2的组方
实施例1
本实施例中可用于皮肤给药的澄清透明千层纸素溶液的制备方法如下:将千层纸素3g加入到处方量的200mL PEG300、200mL丙二醇、150mL无水乙醇的混合溶液中,搅拌均匀并超声溶解可获得澄清溶液,继续加入处方量的50mL纯化水继续超声溶解可获得澄清溶液。
一、稳定性考察:上述千层纸素水溶液处方放置于长期条件:25℃±2℃,60%±5%RH;加速试验:40℃±2℃,75%±5%RH,于1天、5天、30天采用HPLC测定含量,纯度。其含量稳定性结果见如表2所示。
表2外用制剂的稳定性测试结果
以上结果表明千层纸素外用制剂在长期条件25℃±2℃,60%±5%RH,加速条件40℃±2℃,75%±5%RH放置30天内溶液的含量和纯度稳定。
二、千层纸素制剂的溶解度差异
表3千层纸素制剂在水中的溶解度差异
千层纸素几乎不溶于水,在没有合适溶剂的条件下,口服给药是千层纸素的唯一方式。对比例1中,将相应质量的千层纸素粉末制备为胶囊剂,用于口服给药;对比例2中,将千层纸素研磨后,利用羧甲基纤维素钠溶液制备为混悬液做口服液,用于口服给药。
在本发明中,PEG300和丙二醇的加入极大地提高了千层纸素的溶解度,得到澄清透明溶液,从而方便了千层纸素的使用并拓展了千层纸素的使用方式。
三、千层纸素制剂在应用于银屑病治疗的差异
1.实验材料
(1)药物
实施例1的外用溶液及对比例2的口服液。
(2)实验动物
C57BL/6J小鼠,雌性,8周龄,购自杭州子源实验动物科技有限公司(实验动物生产许可证:SCXK(浙)2019-0004,使用许可证:SYXK(苏)2018-0019)。饲养于SPF环境,温度20~25℃,相对湿度30~70%,12:12h光暗照明;自由饮水及采食。
(3)试剂
IMQ软膏:5%咪喹莫特乳膏(Imiquimod,IMQ)购自四川明欣药业;IL-17A、IL-23和IL-6细胞因子检测Elisa试剂盒(达优)。
2、银屑病小鼠建模及实验方法
(1)IMQ诱导的银屑病样小鼠模型构建及给药
将C57BL/6小鼠随机分组后,剔除小鼠背部毛发,使小鼠背部暴露约2cm×3cm的皮肤,将IMQ软膏(62.5mg)连续涂抹于小鼠背部皮肤7d诱导银屑病。实施例1采用皮肤外用给药,对比例2采用口服给药。
(2)小鼠银屑病样症状的皮肤炎症面积和严重程度指数
在造模过程中,每天监测小鼠生理指标(体重,皮肤变化)。临床症状采用PASI评分标准,从红斑、鳞屑、皮肤厚度3项指标进行评价,以0-4分进行记分,将3者积分相加得到总积分。PASI评分标准如下:0,无症状;1,轻度;2,中度;3,重度;4,极重度。造模第7天处死小鼠,取下小鼠的背部皮肤,进行后续评价。
(3)酶联免疫吸附实验
收集血清,根据ELISA试剂盒说明书,检测细胞因子表达水平。大致流程如下:样品孔中加入100μL样品,50μL/well加入稀释后的Biotinylated antibody,混匀后盖上封板膜,37℃温育90min。洗板,100μL/well加入稀释后的Streptavidin-HRP。37℃温育30min,100μL/well加入TMB,37℃避光孵育5-30min,根据孔内蓝色深浅来判定终止反应。100μL/well加入Stop solution终止反应,10min之内检测450nm处吸光值。
(4)小鼠表皮厚度检测
经过甲醛固定、石蜡包埋、切片,并进行了HE染色的小鼠皮肤样本,利用光学显微镜拍摄皮肤切片的照片。确保图像清晰且焦点准确。并通过校准尺和测量线测量小鼠表皮的表皮厚度。在不同的区域重复上述步骤以进行多次测量,以确保结果的准确性和可重复性。记录所有测量值,可以计算平均厚度和进行统计分析。将测量结果导出到一个表格(如Excel)中进行进一步的分析。
(5)小鼠皮肤组织中免疫细胞浸润检测
利用免疫荧光法检测特定细胞在组织内的浸润。组织按常规方法预处理,福尔马林溶液固定后进行石蜡包埋。石蜡组织样本脱蜡后进行常规免疫荧光染色:脱蜡后的切片进行抗原修复、打孔后封闭1h,再孵育一抗(1:200)过夜(4℃),二抗(1:500)孵育1h(室温)。PBS清洗后,染DAPI(1:1000),PBS再次清洗,滴加抗荧光猝灭剂,封片拍照分析。
表4千层纸素外用制剂相较口服给药在银屑病上的治疗效果差异
*P<0.05,**P<0.01,***P<0.001,****P<0.0001与模型对照组比较。
在利用实施例1获得溶解良好的千层纸素水溶液后,将其用于皮肤外用的银屑病治疗中,并以对比例2中的千层纸素口服液进行对比。结果显示,实施例1中的皮肤外用制剂可以显著性降低小鼠银屑病样症状,包括显著性下降促炎因子的表达,表皮细胞的增殖以及炎性免疫细胞的浸润程度。其治疗效果,与比口服制剂相比基本一致。
实施例2
千层纸素乳膏剂制备方法和性状考察
在实施例1能够获得溶解良好且稳定的千层纸素水溶液剂的基础上,进一步加入合适的制剂辅料,能够获得千层纸素乳膏剂,可用于皮肤外用。
千层纸素原料药颜色较深,喷雾剂涂抹后易沾染衣物,不便清洗,粘附性低。考虑到临床病人使用的顺应性、涂抹便利性,相比千层纸素喷雾剂,本实施例尝试将千层纸素制备为乳膏剂,增加药物的粘附性。
表5千层纸素乳膏剂处方
按表5加样量,千层纸素乳膏剂制备方法如下:
1、油相制备:称定处方量油相加入烧杯中混合在一起,75℃加热融化备用;
2、含药溶液制备:称定处方量API、PEG300、丙二醇、乙醇,混合均匀,75℃加热溶清,作为含药溶液备用;
3、水相制备:称定处方量纯化水加入羧甲基纤维素钠,加热搅拌至75℃后溶解成粘稠液体后,而后降温加入聚氧乙烯氢化蓖麻油RH40,备用;
4、乳膏剂制备:保持温度75℃,缓慢将油相加入至水相中,边加边高剪切3000rpm~6000rpm,时间5~30min。得均匀乳剂后,将含药溶液缓慢加入,继续高剪切,3000rpm~6000rpm,时间5~30min。降温即得乳膏剂。
表6千层纸素乳膏剂外观性状
以上结果(表6)表明,乳膏剂1~3均可制备出冷却后粘度适中,均匀不分层的软膏剂。
实施例3
千层纸素凝胶剂制备方法和性状考察
由于水性凝胶剂具有易涂展、舒适感、无油腻、易洗除、不妨碍皮肤的正常生理功能的优势,基于此,本实施例提供一种千层纸素水性凝胶剂的制备方法。
表7千层纸素凝胶剂处方
按表7加样量,千层纸素凝胶剂制备方法:
1、凝胶相制备:称定处方量卡波姆980NF加入至处方量水中,放置过夜,待自然溶胀开后,加入处方量三乙醇胺,边加边搅拌后,形成透明凝胶;
2、含药溶液制备:称定处方量千层纸素、PEG300、丙二醇,搅拌均匀后,超声5~30min,溶清后;
3、将含药溶液加入至凝胶相中,边加边搅拌,混合均匀,成浅褐色透明凝胶或混悬溶液;
4、将处方量的TPGS1000加入到透明凝胶并60℃加热搅拌使混合均匀,并降温后加入处方量的苯甲醇。
表8千层纸素凝胶剂涂抹感
对比千层纸素凝胶剂不同处方的外观性状和涂抹感受(表8),结果表明,千层纸素凝胶剂1,2可获得较好的外观性状和较舒适的涂抹感受。
Claims (5)
1.一种千层纸素外用制剂,其特征在于,所述外用制剂选自溶液剂、乳膏剂和凝胶剂;
所述溶液剂由千层纸素、PEG300、丙二醇、无水乙醇和/或水制成;
所述乳膏剂由千层纸素、溶剂、油相、乳化剂、增稠剂和水相制成;
所述凝胶剂由千层纸素、溶剂、增溶剂、防腐剂和凝胶相制成。
2.根据权利要求1所述的千层纸素外用制剂,其特征在于,所述乳膏剂中,溶剂选自聚乙二醇300、聚乙二醇400、丙二醇和无水乙醇,油相选自液体石蜡、凡士林、硬脂酸、单硬脂酸甘油酯和白蜂蜡,乳化剂选自吐温80和聚氧乙烯氢化蓖麻油RH40,增稠剂选自羧甲基纤维素钠、黄原胶和羟丙甲纤维素。
3.根据权利要求1所述的千层纸素外用制剂,其特征在于,所述凝胶剂中,溶剂选自聚乙二醇300、聚乙二醇400和丙二醇,防腐剂选自苯甲醇、苯扎氯铵、尼泊金甲酯和尼泊金乙酯,凝胶选自卡波姆、壳聚糖、海藻酸钠、羧甲基纤维素钠和羟丙甲纤维素。
4. 根据权利要求1所述的千层纸素外用制剂,其特征在于,所述溶液剂的处方为:千层纸素3 g、200 mL PEG300、200 mL丙二醇、150 mL无水乙醇。
5.权利要求1至4任一项所述的千层纸素外用制剂在制备银屑病治疗药物中的应用。
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