CN117017954A - 用于治疗轻中度银屑病的凝胶贴膏及制备方法 - Google Patents
用于治疗轻中度银屑病的凝胶贴膏及制备方法 Download PDFInfo
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- CN117017954A CN117017954A CN202311175202.5A CN202311175202A CN117017954A CN 117017954 A CN117017954 A CN 117017954A CN 202311175202 A CN202311175202 A CN 202311175202A CN 117017954 A CN117017954 A CN 117017954A
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Abstract
本发明提出一种用于治疗轻中度银屑病的凝胶贴膏及制备方法,凝胶贴膏包括依次设置的背衬层、防水层、含药凝胶层和保护层,含药凝胶层由JAK抑制剂、维A酸、凝胶基质材料、保湿剂及其他药学可接受的外用制剂辅料组成。本发明提供的贴膏,其药物基质层为含JAK抑制剂和维A酸。其中,JAK抑制剂和维A酸为治疗银屑病的治疗用药,而将含有JAK抑制剂和维A酸凝胶药物涂布于背衬层表面制成贴膏剂型,相对于传统的JAK抑制剂和维A酸应用,可避免两种药物全身应用和高剂量维A酸局部长期应用造成的副作用给患者带来的危害,同时可降低成本,使用方便、安全、可靠。
Description
技术领域
本发明属于医药技术领域,尤其涉及一种用于治疗轻中度银屑病的凝胶贴膏及制备方法。
背景技术
银屑病,俗称牛皮癣,是一种常见的皮肤病,其主要的表现是丘疹鳞屑性的皮肤损害。其主要的病理机制是由于炎症造成的皮肤损伤,主要的病理变化包括,基底层角质形成细胞角化过度伴角化不全,真皮层毛细血管增生、扩张,炎性细胞浸润。(Griffiths andothers,2021)银屑病在全球的发病率各有差异。据统计,欧洲银屑病患病率为0.75%~2.9%,平均2%左右,美国超过2%,亚洲大多国家<1%,(Boehncke and 2015)。由于银屑病是一种慢性炎症性皮肤病,除其皮损外,对患者的心身心理也有很大的影响,据统计银屑病患者的抑郁症发病率明显增高,因此,控制其病情的发展对患者的身心均具有重要意义。
近年来,随着对银屑病发病机制认识的深入,多种靶向药物相继问世,包括靶向IL-7和IL-23以及TNFa的生物制剂以及靶向Janus激酶的小分子抑制剂(JAKi)如托法替布。给银屑病患者带来了希望,但由于生物制剂成本高,经济负担重。虽然JAK抑制剂相对成本较低,疗效肯定,但长期全身应用所带来免疫抑制导致的感染,尤其是带状疱疹感染,和突发的血栓事件给患者带来巨大的风险。鉴于银屑病患者中多数患者为轻中度银屑病患者,其主要的病变在皮肤,这给皮肤外用药药物提供了可能,将JAK抑制剂局部外用,对轻中度银屑病患者来说可达到既能控制患者病情又避免全身用药的副作用,更大程度的造福患者和减少经济负担。因此,我们提出本发明。
维A酸类药物中的阿维A及他扎罗汀均被批准用于银屑病的治疗。其中,阿维A对于脓疱型银屑病疗效最佳,其次为红皮病型银屑病,而关节病型银屑病及寻常性银屑病的疗效欠佳,常需要联合用药。而他扎罗汀主要用于治疗寻常性银屑病,疗效良好。外用维A酸类药物的不良反应以皮肤黏膜刺激反应为主,临床表现包括干燥、脱屑、瘙痒、刺痛感、灼烧感、红斑等。本发明在维A酸类药物的基础上,同时加入JAK抑制剂。由于JAK抑制剂的抗炎靶点较多,使该组合能够尽可能降低的浓度,减少维A酸类药物的副作用,另一方面,利用JAK抑制剂的抗炎作用,并可避免JAK抑制剂全身应用造成的免疫功能低下而导致的感染,肿瘤,以及血栓等副作用。同时可以避免软膏类药物易挥发,弄脏衣服等问题。为轻中度银屑病提供安全,有效,便捷且成本低廉的治疗凝胶贴膏。
发明内容
为了解决现有技术中目前缺乏轻中度银屑病治疗中缺少疗效可靠,副作用小且成本低,使用方便的治疗轻中度银屑病药物剂型的问题。本发明提出的一种用于治疗轻中度银屑病的凝胶贴膏及制备方法,改变目前轻中度银屑病和重度银屑病一样采用全身治疗从而导致较多严重副作用的现状。
为实现上述目的,本发明提供如下技术方案:
一方面,本发明提供了一种用于治疗轻中度银屑病的凝胶贴膏,所述缺陷诊断方法具体包括以下步骤:
所述凝胶贴膏包括依次设置的背衬层、防水层、含药凝胶层和保护层,其特征在于,
所述含药凝胶层含药凝胶层的处方组成包含:
JAK抑制剂0.1%~10%
维A酸类药物0.025%~0.1%
凝胶基质材料5.0%~40.0%
保湿剂10.0%~40.0%
透皮促进剂0%~5.0%
防腐剂0%~5.0%
填充剂0%~10.0%
pH调节剂0%~1.0%
交联剂0%~8.0%
抗氧化剂0%~5.0%
纯化水40.0%~70.0%。
优选的,所述JAK抑制剂选自托法替尼、鲁索利替尼、奥拉替尼或巴瑞替尼中的至少一种。
优选的,所述维A酸类药物全反式维A酸、异维A酸、阿利维A酸、维胺酯、芳香维A酸乙酯、他扎罗汀、贝扎罗汀、阿达帕林中的至少一种。
优选的,所述含药凝胶层的凝胶基质材料选自聚丙烯酸部分中和物、聚丙烯酸及其盐(聚丙烯酸、聚丙烯酸钠、聚丙烯酸钾、聚丙烯酸二乙醇胺等)、羧甲基纤维素钠、聚乙烯醇、聚乙烯吡咯烷酮、明胶、阿拉伯胶、卡波姆中的一种或多种;
所述保湿剂选自甘油、山梨醇、尿囊素、聚乙二醇中的一种或多种;
所述透皮促进剂选自丙二醇、肉豆蔻酸异丙酯、克罗米通、己二酸二异丙酯、棕榈酸异丙酯、L-薄荷醇中的一种或多种;
所述防腐剂选自对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、苯甲酸、苯甲酸钠中的一种或多种;
所述抗氧化剂选自二丁基羟基甲苯、生育酚、抗坏血酸及其盐中的一种或多种;
所述填充剂选自高岭土、二氧化钛、滑石粉、碳酸钙、氧化锌中的一种或多种;
所述交联剂选自氢氧化铝、二羟基氨基乙酸铝、三氯化铝、柠檬酸铝中的一种或多种。
所述pH调节剂选自L-酒石酸、DL-酒石酸、枸橼酸、磷酸、盐酸、硫酸中的一种或多种。
优选的,所述背衬层包括但不限于无纺布、聚酯无纺布、聚乙烯膜、铝箔中的一种;
所述保护层包括但不限于涂有石蜡或二甲基硅油的PET聚酯膜、聚丙烯膜、聚乙烯膜、纸-聚酯复合膜中的一种。
优选的,所述凝胶贴膏的形状为方形、圆形,椭圆形、长方形;所述凝胶贴膏的颜色包括黄色、棕色、白色、或橘色;所述凝胶贴膏的尺寸为1cm2~30cm2。
另一方面,本发明提供了用于治疗轻中度银屑病的凝胶贴膏制备方法,包括以下步骤:
步骤1:将处方量的聚丙烯酸钠、甘羟铝、EDTA-2Na、高岭土、对羟基苯甲酸甲酯、肉豆蔻酸异丙酯混匀,加入处方量的甘油,搅拌均匀,放至室温作为A相,取处方量的酒石酸及羧甲基;
步骤2:纤维素钠加至纯化水中,搅拌使其溶解,作为B相;
步骤3:另取适量纯化水,加入处方量的jak抑制剂和异维A酸使其溶解,作为C相;
步骤4:将B相与C相混合均匀后缓慢加至A相中,继续搅拌直至得到均匀的含药凝胶基质;
步骤5:以无纺布作为背衬层,涂二甲基硅油的PET聚酯膜作为防粘层,将以上基质进行涂布、裁切、包装,得治疗轻中度银屑病治疗的凝胶贴膏。
与现有技术相比,本发明具备以下有益效果:
本发明提供的贴膏,其药物基质层为含JAK抑制剂和维A酸类药物。其中,JAK抑制剂和维A酸类药物为治疗银屑病的治疗用药,而将含有AK抑制剂和维A酸类药物凝胶药物涂布于背衬层表面制成凝胶贴膏剂型,相对于传统的AK抑制剂和维A酸类药物应用,可避免两种药物全身应用和高剂量维A酸类药物局部长期应用造成的副作用给患者带来的危害,同时可降低成本,使用方便、安全、可靠。
附图说明
图1为本发明一种实施方式的贴膏的结构示意图。
图2A:不同药物处理组小鼠的疾病活动度评分。
图2B:不同药物处理组小鼠第六天疾病活动度评分较咪喹莫特处理组降低值。
图2C:不同药物处理组小鼠第六天皮肤厚度变化。
图2D:不同药物处理组小鼠第六天皮肤厚度较咪喹莫特处理组降低的厚度值。
图3:不同药物处理组小鼠的大体表现以及组织学H&E染色结果。其中对照是阴性对照。
图4:使用凝胶贴膏前后效果对比图。
图中:10-背衬层;11-防水层;12-药物基质层;13-保护层。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。
实施例1:
本实施例提供一种用于治疗轻中度银屑病的凝胶贴膏,包括依次设置的背衬层10、防水层11、含药凝胶层12和保护层13,含药凝胶层12的处方组成如表1所示:
表1
制备工艺:将处方量的聚丙烯酸钠、二羟基氨基乙酸铝、EDTA-2Na、对羟基苯甲酸甲酯、肉豆蔻酸异丙酯、高岭土混匀,加入处方量的甘油,搅拌均匀,放至室温作为A相。取处方量的酒石酸及羧甲基纤维素钠加至纯化水中,搅拌使其溶解,作为B相。另取适量纯化水,加入处方量的托法替尼和异维A酸使其溶解,作为C相。将B相与C相混合均匀后缓慢加至A相中,
实施例2:
本实施例的凝胶贴膏,与实施例1相同,其中含药凝胶层12的处方组成如表2所示:
表2
制备工艺:将处方量的聚丙烯酸钠、二羟基氨基乙酸铝、EDTA-2Na、对羟基苯甲酸甲酯、肉豆蔻酸异丙酯混匀,加入处方量的甘油,搅拌均匀,放至室温作为A相。取处方量的酒石酸及羧甲基纤维素钠加至纯化水中,搅拌使其溶解,作为B相。另取适量纯化水,加入处方量的托法替尼和异维A酸使其溶解,作为C相。将B相与C相混合均匀后缓慢加至A相中,继续搅拌直至得到均匀的含药凝胶基质。以无纺布作为背衬层,涂二甲基硅油的PET聚酯膜作为防粘层,将以上基质进行涂布、裁切、包装等工序,做成凝胶贴膏。
药效学试验
本实验通过咪喹莫特制备银屑病动物模型,并在炎症发生时,给予制备乳膏进行干预,观察炎症缓解的情况验证制备的乳膏的效果。
具体方法如下:
1.实验样品
2%托法替尼凝胶贴膏,0.5mg/g异维A酸凝胶贴膏,2%托法替尼+0.5mg/g异维A酸凝胶贴膏,不含药物成分凝胶贴膏。
2.分组和给药
(1)采用10-12周雌性C57/B6J小鼠做为实验动物。正式实验前2天,剪去小鼠背部皮肤,并用脱毛膏进行脱毛,清水洗净脱毛膏,防止脱毛膏损伤皮肤。
(2)脱毛后两天,小鼠称重,按照35μl/10g计量,腹腔注射10%水合氯醛进行麻醉。
(3)小鼠麻醉后,每只小鼠背部皮肤2.5cm×2.5cm大小的区域抹25mg咪喹莫特乳膏。此为第0天。
(4)实验第1天起,根据小鼠背部皮肤状态进行疾病评分。评分的标准为:0分,皮肤无明显表现;1分,皮肤轻度泛红;2分,皮肤泛红,角质层轻微增厚;3分,皮肤红肿,角质层增厚明显,体重减轻;4分,皮肤红肿,角质层增厚,有明显破溃,状态萎靡。
(5)实验第三天,根据疾病评分及动物体重进行实验分组(每组6只),保证在干预前,每组之间小鼠疾病评分较为一致,分为:
2%托法替尼凝胶贴膏治疗组、
2%托法替尼+0.5mg/g异维A酸凝胶贴膏治疗组、
0.5mg/g异维A酸凝胶贴膏治疗组、
阳性实验组、以及
阴性对照组。
(6)按照实验分组,第三天起干预组小鼠在咪喹莫特乳膏吸收后(约抹药后2小时)在小鼠背部皮肤贴上相应的凝胶贴膏治疗。阳性实验组及阴性对照组分别给予不含药物的凝胶贴膏;其中,阳性实验组给予咪喹莫特诱导模型后给予不含药物的凝胶贴膏治疗,阴性对照组同样剃毛和麻醉后,只给予不含药物的凝胶贴膏,不使用咪喹莫特。
(7)实验第7天,颈椎脱臼小鼠,取小鼠背部皮肤,浸入4%中性甲醛即福尔马林固定24小时后进行组织HE染色。
3.实验结果
结果如图2A至图2D以及图3所示。结果显示:
①咪喹莫特诱导的PSO小鼠动物模型,可见皮肤出现红肿,增厚等现象,根据PASI评分,各组小鼠评分后可见,单独使用托法替尼以及低塞米松的小鼠,PASI评分均可见显著下降,而联合使用托法替尼与异维A酸联合的乳膏,PASI评分降低最为显著(图2A);
②在模型诱导的第6天,计算最后各治疗组评分的均值与咪喹莫特诱导组评分均值相减,可见,托法替尼可降低PASI评分1.8分,异维A酸治疗可降低PASI评分1.2分,而使用托法替尼以及异维A酸联合治疗组可降低PASI评分3.4分(图2B),降低炎症评分最为显著;
③根据小鼠皮肤组织切片H&E染色结果(图3),测量得到的皮肤厚度的变化结果可见,咪喹莫特治疗组小鼠皮肤表皮层厚度显著增加,而托法替尼以及异维A酸治疗组,均可显著降低小鼠皮肤厚度,联合治疗组的降低程度最为显著,与单独治疗组相比具有显著差异(图2C);
④根据各组小鼠厚度的均值与咪喹莫特组小鼠厚度差值可见,托法替尼治疗组可使皮肤厚度降低1.4mm,异维A酸治疗组可使皮肤厚度降低1.3mm。而联合两者的药物治疗组可降低皮肤厚度2.8mm,其效果最佳(图2D)。
临床实验
1.实验样品
2%托法替尼凝胶贴膏,
2%托法替尼+0.5mg/g异维A酸凝胶贴膏。
2.实验方法
临床招募银屑病初诊患者,实验总共招募10位临床诊断为银屑病的患者,其中PASI评分小于5分的共4位,PASI评分大于5分的共6位。
用药前,根据患者皮损程度,5位PASI初始评分小于5分的患者,使用2%托法替尼凝胶贴膏治疗。5位PASI初始评分大于5分的患者,使用2%托法替尼+0.5mg/g异维A酸凝胶贴膏治疗。根据实验方法进行分组治疗。
用药治疗1个月后,分局皮损程度,再次评分,观察2%托法替尼凝胶贴膏治疗以及2%托法替尼+0.5mg/g异维A酸凝胶贴膏治疗对银屑病患者皮损的改变情况。
3.实验结果
实验结果如图4以及表5所示。
表5
结果显示,使用托法替尼单组分凝胶贴膏治疗患者,在用药前平均评分为2.86分,用药1个月后,降低为1.15分,平均降低1.71分。使用托法替尼+异维A酸联合的凝胶贴膏治疗患者,用药前平均评分为6.45分,用药1个月后,降低为2.65分,平均降低3.8分。
结果表明,PASI评分较低,疾病较轻患者使用单独托法替尼凝胶贴膏可达到有效患者的作用。而PAS I评分较高,疾病较重患者使用托法替尼+异维A酸联合的凝胶贴膏治疗也可达到较好的疗效,对于疾病程度较高的患者具有很好的治疗效果。
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,根据本发明的技术方案及其发明构思加以等同替换或改变,都应涵盖在本发明的保护范围之内。
Claims (7)
1.一种用于治疗轻中度银屑病的凝胶贴膏,所述凝胶贴膏包括依次设置的背衬层、防水层、含药凝胶层和保护层,其特征在于,
所述含药凝胶层含药凝胶层的处方组成包含:
JAK抑制剂0.1%~10%
维A酸类药物0.025%~0.1%
凝胶基质材料5.0%~40.0%
保湿剂10.0%~40.0%
透皮促进剂0%~5.0%
防腐剂0%~5.0%
填充剂0%~10.0%
pH调节剂0%~1.0%
交联剂0%~8.0%
抗氧化剂0%~5.0%
纯化水40.0%~70.0%。
2.根据权利要求1所述的一种用于治疗轻中度银屑病的凝胶贴膏,其特征在于,所述JAK抑制剂选自托法替尼、鲁索利替尼、奥拉替尼或巴瑞替尼中的至少一种。
3.根据权利要求1所述的一种用于治疗轻中度银屑病的凝胶贴膏,其特征在于,所述维A酸类药物选自全反式维A酸、异维A酸、阿利维A酸、维胺酯、芳香维A酸乙酯、他扎罗汀、贝扎罗汀、阿达帕林中的至少一种。
4.根据权利要求1所述的一种用于治疗轻中度银屑病的凝胶贴膏,其特征在于,所述含药凝胶层的凝胶基质材料选自聚丙烯酸部分中和物、聚丙烯酸及其盐(聚丙烯酸、聚丙烯酸钠、聚丙烯酸钾、聚丙烯酸二乙醇胺等)、羧甲基纤维素钠、聚乙烯醇、聚乙烯吡咯烷酮、明胶、阿拉伯胶、卡波姆中的一种或多种;
所述保湿剂选自甘油、山梨醇、尿囊素、聚乙二醇中的一种或多种;
所述透皮促进剂选自丙二醇、肉豆蔻酸异丙酯、克罗米通、己二酸二异丙酯、棕榈酸异丙酯、L-薄荷醇中的一种或多种;
所述防腐剂选自对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、苯甲酸、苯甲酸钠中的一种或多种;
所述抗氧化剂选自二丁基羟基甲苯、生育酚、抗坏血酸及其盐中的一种或多种;
所述填充剂选自高岭土、二氧化钛、滑石粉、碳酸钙、氧化锌中的一种或多种;
所述交联剂选自氢氧化铝、二羟基氨基乙酸铝、三氯化铝、柠檬酸铝中的一种或多种。
所述pH调节剂选自L-酒石酸、DL-酒石酸、枸橼酸、磷酸、盐酸、硫酸中的一种或多种。
5.根据权利要求1所述的一种用于治疗轻中度银屑病的凝胶贴膏,其特征在于,所述背衬层包括但不限于无纺布、聚酯无纺布、聚乙烯膜、铝箔中的一种;
所述保护层包括但不限于涂有石蜡或二甲基硅油的PET聚酯膜、聚丙烯膜、聚乙烯膜、纸-聚酯复合膜中的一种。
6.根据权利要求1-5任一所述的一种用于治疗轻中度银屑病的凝胶贴膏,其特征在于,所述凝胶贴膏的形状为方形、圆形,椭圆形、长方形;所述凝胶贴膏的颜色包括黄色、棕色、白色、或橘色;所述凝胶贴膏的尺寸为1cm2~30cm2。
7.一种用于治疗轻中度银屑病的凝胶贴膏制备方法,其特征在于,包括以下步骤:
步骤1:将处方量的聚丙烯酸钠、甘羟铝、EDTA-2Na、高岭土、对羟基苯甲酸甲酯、肉豆蔻酸异丙酯混匀,加入处方量的甘油,搅拌均匀,放至室温作为A相,取处方量的酒石酸及羧甲基;
步骤2:纤维素钠加至纯化水中,搅拌使其溶解,作为B相;
步骤3:另取适量纯化水,加入处方量的jak抑制剂和异维A酸使其溶解,作为C相;
步骤4:将B相与C相混合均匀后缓慢加至A相中,继续搅拌直至得到均匀的含药凝胶基质;
步骤5:以无纺布作为背衬层,涂二甲基硅油的PET聚酯膜作为防粘层,将以上基质进行涂布、裁切、包装,得治疗轻中度银屑病治疗的凝胶贴膏。
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