CN1430526A - 具有涂敷有欲施加到皮肤上的物质的研磨表面的投注器 - Google Patents
具有涂敷有欲施加到皮肤上的物质的研磨表面的投注器 Download PDFInfo
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Abstract
本发明提供了一种改进的将物质运送入皮肤的方法。该方法是在对皮肤进行研磨的同时将核酸,氨基酸,氨基酸衍生物,肽和多肽等物质运送入皮肤,本发明中所述方法与在运送物质前对皮肤进行预先研磨的方法相比,其物质运送效果及生物反应都得到了很大改善。
Description
技术领域
本发明涉及一种将物质局部送入皮下的装置,尤其是通过角质层将物质送入表皮层的装置。
背景技术
将物质送入体内的典型方法往往都具有侵入性,如使用针体或注射器进行表皮(ID)、肌肉(IM)或皮下(SC)注射。这些方法会给接受者带来痛苦,而且需要经过训练的人员进行操作并常常会引起出血。近来,为了避免这些缺点人们更多的使用一些仪器将角质层切开而将所需的物质送到露出的表皮层上。角质层是由角质细胞组成的大约10-20um厚的薄层,它是皮肤的外部屏障。物质通过表皮层到达真皮层,然后通过血管和淋巴吸收并运送到全身。在疫苗局部运送中,表皮层自身也是用于运送物质的理想目标,因其含有丰富的抗原细胞。角质层和表皮层不含有神经和血管,因此在将物质送入皮层并使抗原产生反应的过程中不会产生痛苦或是流血。
现有技术中公开过很多破坏角质层从而将物质送入人体的装置和方法。例如,在授予Carson等人的第US5,679,647号美国专利中就公开了一种将角质层切开的穿刺方法。该专利中公开了在例如用于结核菌素皮肤测试和敏感性皮肤测试的小直径杆(tynes)上涂敷一层聚核苷酸并利用其来将这种涂敷物质送入皮肤的技术。使用这项技术的方法是用杆(tynes)穿刺皮肤并将其上涂敷的物质物质注射到皮下。本发明中所述方法与该方法的不同之处在于:本发明中是将物质涂在小直径的微凸物上,该微凸物是横向研磨皮肤而不是对皮肤进行穿刺,相比而言本发明中所述这种方法更加有效。专利US5,003,987、US5,879,326和US3,964,482虽然公开了通过研磨撕开角质层的方法,但并没有提到利用此方法进行局部送药的最有效方式。本发明中所述优选方法主要用来核酸的局部运送,尤其是应用在核酸的疫苗和基因的治疗中。在这一点上,最易想到的局部运送方法是在施用疫苗之前先对皮肤磨损。但是,在研磨皮肤的同时进行核酸、例如变态反应原等肽或多肽物质的运送,会产生出人意料且更加有效的结果。
发明内容
本发明提供了一种优选的局部运送物质的方法,所述方法尤其适合于运送核酸、氨基酸、氨基酸衍生物、肽或多肽。已经发现,在研磨皮肤的同时运送上述物质,可以使得核酸表现出更强的基因表达水平并对压缩蛋白质产生出更强的免疫反应。同样的,与传统的变态反应测试方法相比,本发明中所述的这种在磨损皮肤的同时运送变态反应原的方法可以产生出更强的反应。
附图说明
附图1表示的是实施例1中采用所述不同核酸运送方案所得到的基因表达水平的试验结果。
附图2表示的是实施例2中采用不同研磨次数所得到的基因表达水平的试验结果。
附图3表示的是实施例3中采用所述不同核酸的形态及运送方案所得的基因表达水平的试验结果。
附图4表示的是实施例4中所述局部投送质体DNA所得的抗体反应的试验结果。
具体实施方式
用在这里的术语“磨损”的含义是将皮肤的外层分裂,例如通过刮或磨使角质层破裂。而不同于“穿刺”,“穿刺”是在角质层上穿数个分离的洞,但各个洞之间的部分并不分裂。根据本发明所述方法,如核酸疫苗和肽或多肽等物质的运送是与对皮肤的研磨过程同时进行的,而不是预先对皮肤进行处理。也就是说,物质是在对皮肤进行研磨的同时送入皮肤而不是将其送入经预先处理好的皮肤。本发明中所述这种方法与在对皮肤进行研磨之后再施加物质的方法相比可改善运送和反应的效果。
物质可以任何能够接受的形态运送到皮肤内,但最佳的形态是液体和凝胶体。在一个实施例中,物质被涂敷在皮肤上后,用一个研磨装置对物质和皮肤进行相对移动和摩擦。为取得理想效果所需进行研磨的程度要尽可能的小。本领域中对已确定的物质量进行研磨的程度的判断并不需要特殊的技巧。在另一项实施例中,物质可以在应用之前被制成干燥形态放置到运送装置的研磨表面上。在此实施例中,一溶解液体被涂在皮肤上欲运送物质的位置,一涂有物质的研磨装置放置在涂有该溶解液的位置。然后移动该装置并使之摩擦皮肤使得物质在皮肤表面溶解于所述溶解液并在研磨的同时被运送到皮肤内。也可将溶解液放置在研磨装置中,在该装置对皮肤进行研磨时释放出来以溶解物质。也可以将核酸制剂以凝胶状涂于研磨装置进行操作,但是利用这种方式所取得的基因表达的改善效果不如本发明中其它 优选
实施例中所述方式好。
本领域中任何一种用来研磨角质层的研磨装置都可以用于本发明所述方法中。其中包括:例如使用带有多列显微针和微突起的微机电(MEMS)装置,砂纸状装置,刮刀或类似装置。如果研磨装置不包括储存和排放液体的贮存器,那么就必须在研磨前利用例如独立的分配器或泵等装置将承载物质的液体或溶解液涂抹在皮肤上。但是,也可将贮存器做成是研磨装置的一个组成部分。典型的情况是利用下述方式使贮存器与装置的研磨表面相接通以允许液体流动:例如通过针头或突起的内部通道,或是通过位于针头和突起之间的贮存器的出口,或是通过贮存器与研磨表面之间的多孔材料。在这个实施例中,物质和溶解液置于研磨装置的贮存器中,并在进行研磨前或在研磨的同时涂抹在皮肤表面上。该研磨装置还可以包括用来控制物质和溶解液的运送速度和数量的控制装置。
本发明所述方法中使用的核酸可以是RNA或DNA。它们可以是任何适合局部投药和细胞吸收或渗出的物理形态。它可以包含病毒媒介或微脂粒,或是作为例如质体等自由多核苷酸的形式被运送,这些在本领域中均是公知的。核酸可以制成例如液体或是凝胶体等任何利于发挥药效的形态,前述这两种形态比较适合核酸。在本发明中使用的肽和多肽,还有变态反应原化合物所采用的形态都是本领域中所公知的可以发挥药效的形态。
已经发现的最小研磨量(仅对皮肤进行一次研磨)对于满足改善将核酸传递到皮肤细胞效果的要求已经是足够的了。核酸的运送量和渗出量(expression)随着在皮肤上研磨次数的增多而持续增加。在我们的试验体系中,六次和更多的研磨可以使核酸的运送效果得到最大的改善。虽然多次研磨可以在同一块皮肤上进行,但优选的情况是在研磨时选取不同的位置。当今最普遍的运送核酸疫苗的做法是IM注射,这种方法在药剂量小时通常要使用额外的反应增强器。利用本发明中所述方法来运送核酸疫苗的合适剂量的确定属于本领域中的公知技术。与IM注射方法相比,本发明的优点在于:即使不使用反应增强器其运送核酸疫苗的方法也将更有效率,这一点可以通过基因表达水平和免疫反应的刺激加以证实。
也可以根据本发明中所述方法对氨基酸、氨基酸衍生物、肽和多肽,尤其是变态反应原等物质进行局部运送。将变态反应原送入皮肤的传统方法是使用与结核菌素测试类似的杆(tyne)装置进行穿刺。但是,在进行研磨的同时运送物质可以获得更强的过敏反应,这一发现是出人意料的。采用此种方法使得试验更加灵敏,可以很容易探测到使用传统方法无法探测到的较小或微小的反应,在这一点上本发明中所述方法也优于传统方法。
实施例1
使用固体微型针阵列运送质体
将混有发光的荧光霉素的质体DNA(35微克)用标准的30克针头和1cc注射器对麻醉过的BALB/c老鼠进行IM注射或ID注射,或使用200毫克硅微状针体阵列进行局部投药。使用微型针头阵列来进行DNA投放可以采用两个方案:
研磨的同时运送物质(ABRdel):用电剪对老鼠尾巴背部的皮肤刮削,然后使用10号解剖刀去除剩余的毛发。将DNA溶液涂于皮肤表面1平方厘米的区域上并将微型针头阵列与此区域接触,然后在皮肤表面不同的方向横向移动六次(每个方向三次)。DNA剩余溶液在空气中蒸发干,处理过的皮肤待其自行复原。
预先研磨(preABR):如前所述刮削老鼠的皮肤,再对1平方厘米大小的皮肤进行研磨,使用微型针头在皮肤表面的不同方向作六次横向移动(每个方向三次)。然后将DNA溶液涂在研磨后的皮肤表面直至蒸发干。
作为对照,仅对动物进行如上述的刮削而不用微型针头进行研磨(noABR)使得DNA溶液只能通过毛囊或经刮削产生的裂隙进入皮肤。将DNA溶液涂在1平方厘米大小刮削后的皮肤区域上,直至蒸发干。
每一组试验中,DNA投放后24小时采集组织样本。通过发光化验分析组织匀浆中的荧光素酶。经过标准BCA蛋白质化验测定,所有的样本中的总蛋白质含量都是符合规范的。数据用单位毫克蛋白质中的相应的光单位(RLU)表示,试验结果如附图1所示。每个圆点代表一只老鼠的对应结果。图中说明两个单独试验的累积数据(每一组n=6)。通过ABRdel获得的基因表达的荧光素酶含量与使用针头的IM和ID注射所得的结果相近,而远远高于(p=0.02)预先研磨和不研磨皮肤局部运送的结果。
实施例2
运送物质与研磨次数之间的关系
采用实施例1中所述的ABRdel方式来运送含有荧光素酶的质体DNA(35微克),但是研磨装置在皮肤表面的横向移动次数各不相同(12次,10次,6次,4次和2次)。另外,将DNA溶液涂抹在刮削后但没有研磨的皮肤表面,然后用微型针头阵列分别压向皮肤(六次)以模拟穿刺方式送药方法。不使用研磨(noABR)而通过毛囊和划痕而进行局部投送DNA溶液的方式用来作为对照。投药后24小时取皮肤活体组织按实施例1中的方法检查其中荧光素酶的活性。
结果显示在图2中。每一个圆点表示一只老鼠反应的结果,除了“X12”和“X6”以外其他组的n=3,“X12”和“X6”这两组的n=5。随着微型针头研磨皮肤表面次数的增多,基因表达的水平随之增高。进行六次或六次以上研磨的组所达到的平均表达水平是noABR对照组的1000至2800倍。进行4次,2次和1次研磨的组所达到的平均表达水平分别是底数的300,200和30倍。“穿刺”组所达到的平均表达水平仅仅是底数的2倍,和noABR对照组差别不大。
这些数据表明在向皮肤局部运送DNA中研磨过程起着决定性的作用。仅经过一次研磨就可以观察到基因表达,且随着研磨次数的增多,所获得的基因表达水平也会随之增高。另外,横向摩擦和研磨皮肤所达到的核酸运送和基因表达效果大大优于仅仅用微型针头按压皮肤而不横向研磨的效果。
实施例3
核酸疫苗的形态
含有荧光素酶的质体(35微克)以液体形式通过ID注射或通过实施例1中所述的用微型针头装置在皮肤表面进行同步研磨运送(“ABRdel液体”)的方式来进行运送,其中对皮肤进行六次研磨。另外,将DNA冷冻成粉状并涂抹在微型针头阵列的表面,然后在研磨的同时进行运送物质(“ABRdel粉”)或是在应用物质时在PBS缓冲剂中溶解(ABRdel粉/溶解)。溶解的方式是在皮肤表面滴一小滴PBS,然后将涂有粉状物质的微型针头阵列与之接触,进行研磨和运送物质。微型针头上涂有的DNA在0.5%的琼脂糖凝胶中溶解,如上述方式进行研磨及运送(“ABRdel凝胶”)。作为对照,不研磨而仅在皮肤局部涂抹液体(noABR)。投药后24小时取活体组织按照实施例1中的方法进行检验。
试验结果如附图3所示,每一个圆点代表一只老鼠的反应结果。图中说明两个单独试验的数据累积,每一组的n=6。ID注射、ABRdel液体和ABRdel粉/溶解各组所得的荧光素酶的含量相近(差不多是noABR的20到30倍)。虽然使用凝胶状或是粉状DNA直接投送而不溶解所得的基因表达数据并不高于noBAR对照组,但直接投送凝胶状物质所得的结果还是平均值的2至10倍。这些结果显示了在研磨和运送时使用溶解的干燥形式的疫苗和使用液体形式的疫苗的结果是相似。这在商业应用上具有优势,带有液体贮存器的研磨装置可以在研磨前预先涂上粉状疫苗。
实施例4
局部运送质体DNA的抗体反应
将含有肝炎B表面抗原(HbsAg)的质体DNA用标准的30克针头和1cc注射器对麻醉过的BALB/c老鼠进行IM注射或ID注射,或使用200毫克硅微型针头阵列按例1的ABRdel方式进行局部投药。对老鼠总共施加三应次免疫物质,每次施加的剂量均为100微克物质。施加免疫物质2-3星期后,用ELISA分析血浆样本中的HbsAg抗体(总Ig)。作为对照,在只刮削而不研磨(noABR)的皮肤上局部投放DNA使其通过毛囊和划痕被吸收。最高浓度血浆样本吸收值代表HbsAg抗体的值,该值至少是底线(没有免疫过的幼鼠的血浆)的三倍。
每组总共分析十只老鼠。平均值在图4上以条形示出,每个空心圆点代表一只老鼠的反应结果。该图表明ABRdel方案所得的血浆抗体反应最强。该反应值(第二次和第三次免疫后p<0.05)强于由IM注射(现在采用的运送DNA疫苗的标准方法)和ID注射所得的值。另外,应用ABRdel所得的反应值的变异性远小于使用针头注射方式所得的反应值。ABRdel组三次免疫后的平均值是12,160,而IM注射和ID注射分别只有820和4800。值得注意的是,在经过两次免疫后ABRdel组所得的反应值相当接近即效率相当高;通过ABRdel治疗的老鼠100%(10/10)在两次免疫后都发生了血清转化,而通过IM注射和ID注射的分别只有40%(4/10)和50%(5/10)。没有一只经无研磨方式局部投放质体DNA的老鼠可以探测到抗体反应。该图显示通过ABRdel方式和IM注射、ID注射方式所得的抗体图有相同的图形趋势,都包含IgG1和IgG2a。这些结果和前面所述的应用基因枪进行皮下疫苗接种不同,该方法所得的抗体反应只有IgG1而没有IgG2a(可参见MolecularMedicine 5:187,1999上刊登的McCluskie,MJ等的论文)。
实施例5
变态反应原的局部运送
使用200微克硅微型针头阵列按实施例1中所述的ABRdel对皮肤进行研磨的同时运送物质的方式(ABRdel;在皮肤表面进行4次研磨)对猪局部投放二盐酸组胺(2.5毫克)。该组胺可以是液体的,或是制成干粉状涂于微型针头阵列的表面,在投放到皮肤上时进行溶解。作为对比,将一滴组胺溶液滴于皮肤上后立即用杆(tyne)状装置与之接触并对皮肤进行穿刺。该杆状装置由七支重34克长1毫米的金属针头组成,这与市场上可以买到的常用于反应原测试中的装置相似。用微型针头阵列和杆状穿刺装置在经测试的皮肤相邻接的皮肤上进行上述操作但不加组胺,来观察没有物质而只有装置作用时皮肤的反应。另外的对照试验是对皮肤进行无研磨和穿刺的组胺局部投药。组胺可以引起皮肤的炎症反应,如红、肿、出现水疱。
使用固体微型针头阵列进行组胺投放的皮肤上可以看到剧烈的炎症反应。经过组胺投放的皮肤上全部出现明显的红斑和肿胀(高于皮肤2毫米),而在仅用装置而没有组胺作用的皮肤上只在沿着研磨的方向上有轻微的红点,没有丝毫肿胀。无论是液体还是将粉状组胺溶解所得到的反应都是相当的强烈。使用杆状装置对组胺溶液进行穿刺的皮肤也表现出严重的红斑和肿胀,但是反应只局限在被穿刺的地方及其周围很小范围的部位。仅用组胺溶液进行局部投药而不使用研磨或穿刺的皮肤没有出现炎症,与未经试验的皮肤几乎没有什么不同。
在本领域中二盐酸组胺是用来检测肽和多肽变态反应原的常用物质。上面的结果表明,所述的同步研磨运送技术可以有效的用于氨基酸和氨基酸衍生物的变态反应原的局部投药中,并且可以得出和上述肽和多肽变态反应原相似的效果。通过微研磨进行变态反应原运送比对皮肤进行穿刺的好处在于,可以使物质在更大的皮肤范围中起作用,因此其反应效果好于使用杆状装置进行穿刺而使物质集中在局部难以分散。物质分散的范围增大,提高了免疫刺激的程度,表皮对变态反应原的敏感度也比采用已有的杆状皮肤穿刺测试方法时的敏感度要高。另外,本发明中所述方法针对的目标是位于毛细血管床和神经网之上的浅表皮层,因而与现今的测试方法相比本发明中所述方法具有更小的侵入性从而也更加安全。
Claims (25)
1.一种将物质运送入皮肤的方法包括在研磨皮肤的同时将物质运送到皮下。
2.如权利要求1的方法,其特征在于:所述物质是核酸。
3.如权利要求2的方法,其特征在于:核酸含有抗原。
4.如权利要求3的方法,其特征在于:抗原的表达产生免疫反应。
5.如权利要求1的方法,其特征在于:物质是氨基酸,氨基酸衍生物,肽和多肽。
6.如权利要求5的方法,其特征在于:物质是变态反应原。
7.如权利要求1的方法,其特征在于:皮肤至少被研磨两次。
8.如权利要求7的方法,其特征在于:皮肤至少被研磨六次。
9.如权利要求8的方法,其特征在于:皮肤被研磨六至十二次。
10.如权利要求1的方法,其特征在于:研磨是在皮肤上不同方向进行的。
11.如权利要求1的方法,其特征在于:物质以液体形态施加于皮肤上。
12.如权利要求11的方法,其特征在于:物质利用一研磨装置施加于皮肤上。
13.如权利要求11的方法,其特征在于:在研磨之前将物质施加于皮肤上。
14.如权利要求1的方法,其特征在于:干燥的物质在研磨的同时被溶解。
15.如权利要求14的方法,其特征在于:物质呈粉状并置于研磨装置的研磨表面。
16.如权利要求15的方法,其特征在于:是在研磨前将溶解液独立施加于皮肤上。
17.如权利要求15的方法,其特征在于:在研磨的同时将溶解液施加于皮肤上。
18.如权利要求1的方法,其特征在于:利用包含有微型针头阵列的装置对皮肤进行研磨。
19.一种将物质运送入皮肤的装置,包括一涂敷有运送物质的研磨表面和一容纳有溶解液并与研磨表面液体性相连通的贮存器。
20.如权利要求19的装置,其特征在于:研磨表面是一微型针头阵列。
21.如权利要求20的装置,其特征在于:物质被施加于微型针头上。
22.如权利要求19的装置,其特征在于:贮存器通过研磨表面的突起中的通道与研磨表面相连通。
23.如权利要求19的装置,其特征在于:贮存器通过研磨表面的突起之间的通道与研磨表面相连通。
24.如权利要求19的装置,其特征在于:贮存器通过贮存器与研磨表面之间的多孔材料与研磨表面相连通。
25.如权利要求19的装置,其特征在于:所物质是核酸,氨基酸,氨基酸衍生物,肽或多肽。
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-
2000
- 2000-05-22 US US09/576,643 patent/US6595947B1/en not_active Expired - Lifetime
-
2001
- 2001-05-18 AT AT01935686T patent/ATE272423T1/de not_active IP Right Cessation
- 2001-05-18 BR BRPI0111345-3A patent/BR0111345B1/pt not_active IP Right Cessation
- 2001-05-18 CA CA002410561A patent/CA2410561C/en not_active Expired - Lifetime
- 2001-05-18 ES ES01935686T patent/ES2222376T3/es not_active Expired - Lifetime
- 2001-05-18 AU AU2001261757A patent/AU2001261757B2/en not_active Ceased
- 2001-05-18 MX MXPA02011557A patent/MXPA02011557A/es active IP Right Grant
- 2001-05-18 DE DE60104686T patent/DE60104686T2/de not_active Expired - Lifetime
- 2001-05-18 AU AU6175701A patent/AU6175701A/xx active Pending
- 2001-05-18 CN CNB018099157A patent/CN100394995C/zh not_active Expired - Fee Related
- 2001-05-18 EP EP01935686A patent/EP1289599B1/en not_active Expired - Lifetime
- 2001-05-18 JP JP2001585860A patent/JP4801309B2/ja not_active Expired - Fee Related
- 2001-05-18 WO PCT/US2001/016121 patent/WO2001089622A1/en active IP Right Grant
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2003
- 2003-05-13 US US10/436,757 patent/US20030191085A1/en not_active Abandoned
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- 2007-09-07 US US11/851,956 patent/US7731968B2/en not_active Expired - Fee Related
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AU6175701A (en) | 2001-12-03 |
BR0111345B1 (pt) | 2010-10-05 |
DE60104686T2 (de) | 2005-08-11 |
AU2001261757B2 (en) | 2004-04-01 |
WO2001089622A1 (en) | 2001-11-29 |
ES2222376T3 (es) | 2005-02-01 |
ATE272423T1 (de) | 2004-08-15 |
US20030191085A1 (en) | 2003-10-09 |
JP2003534065A (ja) | 2003-11-18 |
CA2410561C (en) | 2009-05-12 |
US7731968B2 (en) | 2010-06-08 |
EP1289599B1 (en) | 2004-08-04 |
JP4801309B2 (ja) | 2011-10-26 |
CA2410561A1 (en) | 2001-11-29 |
US6595947B1 (en) | 2003-07-22 |
EP1289599A1 (en) | 2003-03-12 |
US20080009785A1 (en) | 2008-01-10 |
MXPA02011557A (es) | 2004-09-06 |
DE60104686D1 (de) | 2004-09-09 |
CN100394995C (zh) | 2008-06-18 |
BR0111345A (pt) | 2004-02-03 |
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