CN112933096B - 丁酰噻吗洛尔在制备治疗浅表型、混合型或深部血管瘤的药物中的用途 - Google Patents
丁酰噻吗洛尔在制备治疗浅表型、混合型或深部血管瘤的药物中的用途 Download PDFInfo
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Abstract
本申请涉及一种丁酰噻吗洛尔在制备治疗浅表型、混合型或深部婴幼儿血管瘤的药物中的用途。
Description
技术领域
本申请涉及药物化学领域，具体而言涉及丁酰噻吗洛尔在制备治疗浅表型、混合型或深部血管瘤的药物中的用途。
背景技术
婴幼儿血管瘤是婴幼儿中最常见的良性肿瘤之一，在高加索人种中的发生率高达10-12％，在我国新生儿中的发生率也达到1％，国内的患病人群多达二千万。约有10％的患儿会在病程中出现溃疡、感染、疼痛，甚至失明、窒息等严重并发症，而即使没有这些并发症，较大的瘤体消退后仍会残存脂肪纤维组织或(及)表面皮肤质地改变，导致继发畸形，再加之其易好发于头面部的特点，这不得不需要后期整形手术修复，因此早期干预血管瘤治疗变得尤为重要。传统的口服激素、放射疗法、激光、冷冻治疗婴幼儿血管瘤等因其副作用已被逐渐淘汰，随着2008年口服普萘洛尔治疗血管瘤的意外发现，目前国内外一系列临床研究已确立了口服普萘洛尔在难治性婴幼儿血管瘤治疗中的一线地位，使得一些难治性的婴幼儿血管瘤都得到了有效的治疗，然而随着时间的推移，对口服普萘洛尔在婴幼儿中的治疗也慢慢产生了质疑，除众所知晓的心率减慢、血压下降、低血糖、诱发支气管哮喘等系统性不良反应外，有学者提出其可能会通过患儿血脑屏障而影响与学习、记忆所相关的神经系统通路，呼吁需要更长时间的随访来证明其安全性。外用马来酸噻吗洛尔制剂或普萘洛尔制剂有着安全、无系统性吸收的优势，对绝大部分浅表型婴幼儿血管瘤有良好的疗效，但对于混合型或深部血管瘤效果欠佳，主要的原因就在于药物无法深入渗透皮肤，到达深部瘤体，因此这类血管瘤不得不使用口服心得安治疗。为了避免口服心得安所带来的系统性不良反应和其远期对学习、记忆所可能产生的影响，目前急需一种可以通过局部给药、高效渗透皮肤，有效作用混合或深部血管瘤，而避免全身用药带来不良反应的新型噻吗洛尔制剂。
对于混合型或深部婴幼儿血管瘤病灶，血管瘤中的皮下成分在初始进行噻吗洛尔外用制剂治疗后仍进展，虽然如此，这些血管瘤的浅表成分在局部治疗期间仍然出现了退化指征，如颜色的淡化和病灶的软化，并且随着局部治疗时间的延长，血管瘤消退的反应性逐步提高。对于深部病灶，则变化不明显，这一现象的主要原因是噻吗洛尔外用制剂的在透皮上的局限性。尽管软膏可以促进皮肤的水合作用，增强了一部分透皮功能，但是如果病灶部位厚度较大，药物可能无法渗透到一定的深度。药物难以渗入瘤体所有部位，故对于特殊部位或深部血管瘤难以彻底治愈。
既能油溶又能水溶的药物(即油/水分配系数值适中者)具有较高的穿透性；如果药物在油、水中都难溶，则很难透皮吸收。角质层犹如类脂膜，脂溶性大的药物易通过角质层。药物穿过角质层后，需继续分配进入活性表皮。因此，油水分配系数接近1者具有较好的经皮渗透系数。离子型药物不易通过皮肤吸收，这是因为其强亲水性质难以在脂性细胞间隙扩散所决定的。
对于类脂性的、非极性强的皮肤细胞膜来说，脂溶性更强的药物更易穿透皮肤。
在本发明的发明人通过相关研究发现，化学结构较噻吗洛尔更为优化的丁酰噻吗洛尔可促进对婴幼儿血管瘤，特别是混合型或深部病灶的外用药物治疗。
发明内容
本发明的目的是针对现有噻吗洛尔无法深入渗透皮肤，提供一种丁酰噻吗洛尔在制备治疗浅表型、混合型或深部婴幼儿血管瘤的药物中的用途。
优选地，在本申请所述的用途中，所述药物为经皮给药。
更优选地，所述药物的经皮给药的剂量浓度为1-10mg/ml(即，0.1％-1.0％)。次数为每日2-4次，根据个人不同的血管瘤体表面积，每人每天用量为1-5mg/平方厘米血管瘤。
本发明的优点在于所述丁酰噻吗洛尔可用于治疗所有类型的婴幼儿血管瘤，特别是传统噻吗洛尔外用制剂疗效不佳的混合型或深部的婴幼儿血管瘤，其皮肤渗透量高；在皮肤中的药物浓度高；较强的成脂能力，促进血管瘤的消退。
附图说明
图1显示了马来酸噻吗洛尔、丁酰噻吗洛尔的体外透皮试验药物累积释放量图。其中，从左下到右上依次为马来酸噻吗洛尔(完整皮肤)，丁酰噻吗洛尔(完整皮肤)，马来酸噻吗洛尔(去角质皮肤)，丁酰噻吗洛尔(去角质皮肤)。
图2显示了马来酸噻吗洛尔、丁酰噻吗洛尔的血浆药物浓度时间曲线
图3显示了马来酸噻吗洛尔、丁酰噻吗洛尔的血浆药物浓度质谱检测结果
图4显示了马来酸噻吗洛尔、丁酰噻吗洛尔的皮肤药物浓度质谱检测结果
图5显示了马来酸噻吗洛尔和丁酰噻吗洛尔对血管瘤内皮细胞的凋亡实验结果。其中，从左到右依次为空白对照，马来酸噻吗洛尔(100uM)，丁酰噻吗洛尔(100uM)。
图6显示了马来酸噻吗洛尔和丁酰噻吗洛尔油红染色结果。其中，从左上到右下依次为HUVEC细胞成脂诱导，10uM马来酸噻吗洛尔诱导HemSC，100uM马来酸噻吗洛尔诱导HemSC，10uM丁酰噻吗洛尔诱导HemSC。
具体实施方式
实验原料药来源：
马来酸噻吗洛尔购自USP Catalog#1667406；
丁酰噻吗洛尔购自MCE,Cat.No.:HY-102032A。
实验实施例
实验实施例一、丁酰噻吗洛尔体外透皮试验
本实验实施例中，采用8周龄的雌性裸鼠，处死后取其皮肤进行体外透皮试验。
(1)试验用小鼠以断颈法处死，将小鼠背部的毛发用剪刀剪除，剪取一块小鼠背部的皮肤；
(2)用剪刀将皮下脂肪组织去除干净，以蒸馏水和生理盐水依次冲洗皮肤；
(3)用滤纸将皮肤表面的水渍擦干，用胶带粘贴在皮肤表面，轻轻按压后撕去胶带，重复20次以去除皮肤角质层；
(4)将处理好的皮肤置于双室渗透扩散装置中，包含扩散池、接收池及恒温水浴系统。接收池的溶液为75％磷酸缓冲液/乙醇，接收池的体积为1ml，温度控制在37℃，扩散面积为0.785cm2；
(5)试验设计如表1共分为4组，定时取样，更换新鲜接收液，过滤样品后用紫外分光光度计在294nm处测量吸收值，计算药物在一定时间内的累积释放量。
表1体外试验设计分组
利用双扩散池渗透系统进行体外透皮试验，每隔一定时间计算一次药物的累积释放量(见图1)。从图上我们可以看到，不论是去角质的皮肤，还是没有去除角质的完整皮肤，丁酰噻吗洛尔渗透量都远高于马来酸噻吗洛尔，这说明丁酰噻吗洛尔有更强的透皮性能。
实验实施例三、马来酸噻吗洛尔和丁酰噻吗洛尔在血管瘤内皮细胞及干细胞的成脂和凋亡功能比较
本实验实施例使用婴幼儿血管瘤内皮细胞(Hemangioma derived endothelialcells,HemECs)及干细胞(Hemangioma derived stem cells,HemSCs)。HemECs和HemSCs从组织的分离分别通过CD31和CD133标记的磁珠进行。婴幼儿血管瘤标本来自上海市交通大学医学院附属第九人民医院整复外科手术切除的增生期血管瘤。标本放进50ml离心管中用PBS摇晃冲洗两次后以5％BSA常温下保存，运输至实验室。在培养皿中盛5ml含3mM CaCl2的HBSS(无CaCl2及MgSO4)溶液，放入标本，用组织剪刀去除表皮及皮下脂肪，將标本剪成1mm3块状后，置于15ml离心管中，加入0.2％I型胶原酶，37℃震荡消化1小时，1300rpm离心3分钟，弃去上清，反复清洗(PBS重悬、离心)2次，进行CD31及CD133免疫磁珠分选血管瘤内皮细胞及干细胞。最后分选出的细胞用含10％FBS及1％双抗的EGM-2重悬，接种于I型胶原蛋白(1:100)铺底的6cm2培养皿中，37℃，5％CO2培养箱内静置培养。
1、马来酸噻吗洛尔及丁酰噻吗洛尔在血管瘤内皮细胞凋亡实验结果
在六孔板中每孔接种10万个HemEC，孵育24小时后，分别用DMSO、100uM马来酸噻吗洛尔、100uM丁酰噻吗洛尔1:1000稀释的去血清的EGM-2培养液孵育48小时。给药48小时后，用0.25％的胰酶消化收集，用FITC Annexin V(BD Pharmingen Cat.559763)流式凋亡试剂盒处理并上机测试。
Annexin V凋亡流式细胞实验(图5)结果提示，在相同浓度(100uM)下，马来酸噻吗洛尔及丁酰噻吗洛尔促HemEC凋亡的效果不显著。
2、马来酸噻吗洛尔及丁酰噻吗洛尔诱导血管瘤干细胞成脂分化实验结果
在六孔板中每孔接种10万HemSC，孵育48小时或直到长满盘，在成人脂肪间充质干细胞成脂诱导分化培养基(Cyagen,产品货号：HUXMD-90031)加入DMSO、100uM马来酸噻吗洛尔、10uM马来酸噻吗洛尔、10uM丁酰噻吗洛尔成脂诱导培养14天后，进行油红染色。以人脐静脉内皮细胞(HUVEC，Promocell，Cat.No.:C-12203)作为阴性对照，以同样条件培养及检测。婴幼儿血管瘤干细胞(HemSC)加药诱导成脂后油红染色实验(图6)提示，HUVEC无成脂作用，而低浓度的丁酰噻吗洛尔诱导HemSC成脂能力与较高浓度的马来酸噻吗洛尔相当。因此，在细胞学层面上，丁酰噻吗洛尔与马来酸噻吗洛尔作用于婴幼儿血管瘤干细胞相比，具有较强的成脂能力，促进血管瘤的消退。
综上，丁酰噻吗洛尔可作为一个新的局部外用药物，用于治疗婴幼儿血管瘤位于皮下深部的病灶。
Claims (4)
1.一种丁酰噻吗洛尔在制备治疗浅表型、混合型或深部婴幼儿血管瘤的药物中的用途，
2.根据权利要求1所述的用途，其中，所述药物为经皮给药。
3.根据权利要求1或2所述的用途，所述药物的经皮给药的浓度为1-10mg/ml。
4.根据权利要求1或2所述的用途，所述药物每人每天用量为1-5mg/平方厘米血管瘤。
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