CN110613892A - 一种经皮给药*** - Google Patents
一种经皮给药*** Download PDFInfo
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Abstract
本发明公开了一种经皮给药***，包括海绵骨针和低频超声装置，所述的经皮给药***先对皮肤进行低频超声处理，再利用海绵骨针按摩皮肤表面。本发明***可以显著增强皮肤对于亲水药物分子的透过率。
Description
技术领域
本发明涉及一种经皮给药***。
背景技术
皮肤给药(Skin Drug Delivery)相比其他给药途径有很多独特的优势，主要体现在：避免肝脏首过效应；药物吸收不受消化道环境和胃肠道功能的影响；可缓释或控释给药；病人治疗的顺应性好；等等。然而，皮肤的本质是一种生物膜屏障，除了极少数的药物分子(分子量小于500Da且油水分配系数适中)可以通过皮肤角质层屏障，绝大部分的药物分子很难通过皮肤渗透吸收，因此，如何克服皮肤屏障，安全有效地将各种理化性质不同的生物大分子药物或活性物质经皮输送至病灶部位，是一项极具挑战性的工作，同时也是皮肤给药领域的研究难点和热点。
在所有的皮肤给药的促渗技术中，微针技术最具发展前景。微针技术自从1998年面世以来，已经逐渐发展出五大类别，包括实心微针、空心微针、可溶微针、涂层微针及相转化微针，主要用于疫苗接种，胰岛素给药和皮肤疾病的治疗等方面。然而，微针技术在皮肤疾病治疗上依然面临着一系列挑战及瓶颈问题，包括：实心微针的微孔维持时间太短，微通道通常会在微针离开皮肤后的20min内自动闭合，这极大地限制了药物的经皮渗透量和生物利用度。微针贴片(包括可溶微针、涂层微针、空心微针等)的给药面积固定且相对较小(通常 1cm2)，限制了其用于大面积皮肤病变的治疗。微针通常为阵列排布，在鼻翼等异面和非平坦区域难以发挥作用。
申请人从人工养殖的蜂海绵(Sponge Haliclona sp.)中分离纯化获得的蜂海绵骨针 (Sponge Haliclona sp.spicules)，其末端尖锐，性质稳定且机械强度高(SiO2含量95％)，形态单一且尺寸均匀(长度约120μm，直径约7μm)，可作为一种微针技术应用于皮肤给药，有效促进模型药物(S.Zhang,et al.,2017)和纳米载体的经皮吸收(C.Zhang,etal., 2019)。SHS在小鼠活体皮肤上递送模型药物(葡聚糖，分子量10KDa)的效率是商业化实心微针200μm的大约15倍。然而，SHS用于皮肤给药仍然存在多个不足之处：1)SHS的促渗效果随着药物的分子量的增加而急剧减小；2)SHS的皮肤刺激性和其使用剂量有相关性，使用剂量越大，按摩强度越大，皮肤刺激性越大。
发明内容
本发明的主要目的，在于提供一种经皮给药***。
本发明解决其技术问题的所采用的技术方案是：
一种经皮给药***，包括海绵骨针和低频超声装置，所述的经皮给药***先对皮肤进行低频超声处理，再利用海绵骨针按摩皮肤表面，之后再在皮肤表面敷药；或是对皮肤进行低频超声处理之后，在皮肤表面敷药的同时，利用海绵骨针按摩按摩皮肤表面。
优选地，所述的海绵骨针为蜂海绵骨针。
在本发明中，所述的超声频率为10-30KHZ。
在本发明中，优选的超声频率为15-28KHZ。
本技术方案与背景技术相比，它具有如下优点：
1.海绵骨针与低频超声协同促渗***可以显著增强皮肤对于亲水药物分子的透过率：相对于单独使用低频超声促渗技术或是单独使用海绵骨针促渗技术，两者的协同作用显著增强，对经超声作用后的皮肤再用海绵骨针进行按摩，骨针刺入皮肤角质层后，不仅可以新形成一些孔道，也会对原先形成的孔道起扩大增强的作用，从而使得皮肤对亲水性药物分子的转运效率增强；
2、蜂海绵骨针可刺入角质层打开皮肤屏障，并长时间滞留于皮肤角质层形成大量持续存在的微通道(至少72h)，远高于传统微针作用皮肤后微通道停留的时间(20min)；
3.蜂海绵骨针与低频超声协同促渗***能够降低蜂海绵骨针的使用剂量和按摩强度，减小蜂海绵骨针的皮肤刺激性，有效增加了使用安全性。
附图说明
下面结合附图和实施例对本发明作进一步说明。
图1为不同经皮递送方式促进FITC-Dextran(FD)-4K皮肤吸收的效果。
图2为不同经皮递送方式促进FD-4K在皮肤各层累积分布情况。
其中，SC1-10：分别为角质层由外向内1-10层(采用胶带剥离法分离)；
Epi：活性表皮层
Der:真皮层
Rec：接收池
图3为药物荧光在不同皮层内分布情况。
图4为使用安全性实验结果。
a-c为蜂海绵骨针协同低频超声实验组；
d-f为对照组
具体实施方式
1、蜂海绵骨针：制备方法见CN201610267764.6“高纯度海绵骨针的制备方法”。
2、超声装置：宁波新芝生物科技公司JY-92IIN超声波细胞粉碎机。
在以下实施例和对比例中，超声装置都使用如下的参数：
a.超声频率：20KHZ
b.超声总时间：90s(占空比50％,超声开时间2s；超声关时间2s)
c.超声输出功率：130W
d.超声耦合介质：2ml 1％SLS(溶于0.2mol/LPBS缓冲液)
e.变幅杆与皮肤距离：3mm。
3、模型药物：荧光标记的葡聚糖(分子量为4000，FD-4K，浓度为1mg/ml)
取直径2cm的圆形离体角质层无损伤去脂肪层猪皮，将其固定在Franz透皮池上，接收池中加12ml 0.2mol/L的PBS缓冲液，用夹子夹紧分别进行a-e组局部给药方式。
a.超声+骨针组：将Franz透皮池中的猪皮经低频超声处理90s(见前述超声装置的参数部分)后吸出给药池中的耦合剂溶液，用0.2mol/l的PBS缓冲液冲洗三遍，给药池中加入100ul浓度为20mg/ml的蜂海绵骨针溶液，然后手动按摩2min(转速为120r/min)后冲掉残余蜂海绵骨针溶液，加入150ul模型药物后开始进行体外透皮
b.骨针+超声组：在Franz透皮池的给药池中加入100ul浓度为20mg/ml的蜂海绵骨针溶液，然后手动按摩2min(转速为120r/min)后冲掉残余蜂海绵骨针溶液，将猪皮经低频超声作用90s(同a组相同)后吸出给药池中的耦合剂溶液，用0.2mol/L的PBS缓冲液冲洗三遍后，加入150ul模型药物开始体外透皮
c.不同剂量蜂海绵骨针按摩组：在Franz透皮池的给药池中分别加入100ul浓度为20mg/ml，100mg/ml，10mg/ml的蜂海绵骨针溶液，然后手动按摩2min(转速为120r/min) 后冲掉残余蜂海绵骨针溶液，加入150ul模型药物开始体外透皮
d:超声组：将Franz透皮池中的猪皮经低频超声作用90s(同技术方案中的步骤)后吸出给药池中的耦合剂溶液，用0.2mol/L的PBS缓冲液冲洗三遍后，加入150ul模型药物开始体外透皮
e.对照组：不做任何处理，在给药池中加入150ul模型药物开始体外透皮
微针预处理：取直径2cm的圆形离体角质层无损伤的猪皮，去处真皮层之下的脂肪层，用德国dermaroller滚轮微针(微针长度0.2mm，微针数量162根)在皮肤表面按照“米”字型滚动一次，将微针预处理后的皮肤固定在Franz透皮池上
f.微针组：在经微针预处理的猪皮上加入150ul模型药物开始体外透皮
g.微针+超声组：将Franz透皮池中经微针预处理的猪皮经低频超声作用90s(同技术方案中的步骤)，吸出给药池中的耦合剂溶液，用0.2mol/L的PBS缓冲液冲洗三遍后，加入150ul模型药物开始体外透皮。
结果：
1、采用以上a-g组不同的局部给药方式体外透皮16h后，采用胶带剥离法分离检测各皮层药物含量，对比其经皮吸收效果，其结果见图1，以及FD-4K在皮肤各层的分布情况，其结果见图2和图3。
2、采用不同的局部给药方式体外透皮16h后，利用冷冻切片机将皮肤组织纵切成20um 厚的切片，经树脂固定装片后，在激光共聚焦显微镜(激发波长490nm，发射波长530nm) 下观察药物荧光在不同皮层内分布情况，结果见图3A-I。
由定量以及定性结果分析可得，
1).低频超声和蜂海绵协同作用可以显著增强FD-4K葡聚糖的经皮递送，远大于单独利用蜂海绵骨针或是单独利用低频超声的经皮递送效率，也显著高于滚轮微针或是滚轮微针协同低频超声的经皮递送效率；
2).低频超声和蜂海绵协同处理皮肤后，药物分子大多集中在表皮层以下的皮肤深层部位，完全跨过了角质层屏障，而其它经皮给药方式药物大多难以穿过角质层屏障，大部分集中在表皮层之上，被角质层所阻碍
3).经超声处理过的皮肤相对海绵骨针，药物较容易被递送到活性表皮层，说明低频超声在皮肤表面的作用深度较海绵骨针深
4)要先对皮肤进行低频超声处理再利用蜂海绵骨针按摩皮肤表面才能发挥两者的协同功效，反之，先利用蜂海绵骨针按摩皮肤表面再对皮肤进行低频超声处理的协同效果不明显，药物经皮递送率不高，原因可能是骨针按摩后刺入皮肤后阻碍了低频超声的空化作用的进行，同时低频超声作用于骨针表面会影响骨针在皮肤表面形成微通道，导致该局部给药方式的经皮递送效率较低。
蜂海绵骨针协同低频超声技术的使用安全性：
1)实验操作：选取8-10周龄的普通级雌性豚鼠，剃去豚鼠背部平坦皮肤表面的毛发，不破坏豚鼠皮肤完整性，圈定一个直径为1cm的实验区，先在低频超声下处理20s(因为豚鼠皮肤比猪皮薄很多，所以超声时间适当缩短)，其它超声条件不变，接着用2mg蜂海绵骨针手动按摩2min(转速120r/min)，观察豚鼠皮肤表面情况如图4：
2)实验结果：
a.蜂海绵骨针协同低频超声实验组：见图4a-c。
b.对照组，见图4d-f。
根据国际通行的Draize皮肤刺激性评价标准，对比分析实验后皮肤的红斑生成情况以及水肿形成情况：可见实验组较对照组皮肤表面没有显著红斑，没有显著水肿，皮肤屏障完好，证明蜂海绵骨针与低频超声协同***对皮肤刺激性较小，具有使用安全性
以上所述，仅为本发明较佳实施例而已，故不能依此限定本发明实施的范围，即依本发明专利范围及说明书内容所作的等效变化与修饰，皆应仍属本发明涵盖的范围内。
Claims (7)
1.一种经皮给药***，其特征在于：包括海绵骨针和低频超声装置，所述的经皮给药***先对皮肤进行低频超声处理，再利用海绵骨针按摩皮肤表面，之后再在皮肤表面敷药；或是对皮肤进行低频超声处理之后，在皮肤表面敷药的同时，利用海绵骨针按摩按摩皮肤表面。
2.如权利要求1所述的一种经皮给药***，其特征在于：所述的海绵骨针为蜂海绵骨针。
3.根据权利要求1所述的一种经皮给药***，其特征在于：所述的低频超声频率为10-30KHZ。
4.根据权利要求3所述的一种经皮给药***，其特征在于：所述的低频超声频率为15-28KHZ。
5.一种经皮给药***，其特征在于：所述的经皮为药物经过角质层；所述的***包括海绵骨针和低频超声装置，所述的经皮给药***先对皮肤进行低频超声处理，再利用海绵骨针按摩皮肤表面，之后再在皮肤表面敷药；或是对皮肤进行低频超声处理之后，在皮肤表面敷药的同时，利用海绵骨针按摩按摩皮肤表面。
6.如权利要求5所述的一种经皮给药***，其特征在于：所述的海绵骨针为蜂海绵骨针。
7.根据权利要求1至6任一项所述的一种经皮给药***，其特征在于：所述的药物为亲水性药物。
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| WO2021004500A1 (zh) * | 2019-07-10 | 2021-01-14 | 厦门大学 | 一种经皮给药*** |
| CN113368386A (zh) * | 2021-06-21 | 2021-09-10 | 温州医科大学慈溪生物医药研究院 | 一种结合电刺激和超声的大分子药物入脑递送*** |
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