CN1454104A - 具有刺入限制机构的物质真皮内输送针 - Google Patents
具有刺入限制机构的物质真皮内输送针 Download PDFInfo
- Publication number
- CN1454104A CN1454104A CN01811882A CN01811882A CN1454104A CN 1454104 A CN1454104 A CN 1454104A CN 01811882 A CN01811882 A CN 01811882A CN 01811882 A CN01811882 A CN 01811882A CN 1454104 A CN1454104 A CN 1454104A
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- Prior art keywords
- pin
- skin
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- outlet
- infusion
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- Pending
Links
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供一种向人体或动物体进行药物或其它物质的ID输入的改进方法。该方法将小号规格的针,特别是显微针放置在真皮内空间中,以便将物质作成散射体或采用输注方式输送到真皮内空间。现已发现,采用小号规格的针来有效输送活性物质,以防止物质泄漏到皮肤外面,并提高真皮内空间的物质吸收能力的关键之处是针的出口在皮肤内的放置和针出口露出的高度。已发现,按照本发明的方法输送的激素药物的药物动力学状况与传统的SC输送的药物动力学状况非常类似,这表明根据本发明的方法的ID给药能够获得相似的临床效果(即相似的效力),同时具有减少或消除病人疼痛的优点。将针出口放置在真皮内空间中一合适的深度,并控制流体输送的输送量和速率的输送装置能够在不泄漏的情况下将物质精确输送到期望位置。
Description
技术领域
本发明涉及将物质输送到皮肤内的方法和装置。
背景技术
传统的针长期以来用于经皮肤将药物或其它物质输送到人体或动物体中,并且在采用传统的针实现经皮肤的反复、有效的输送,同时减少或消除疼痛方面已卓见成效。某些真皮内的输送系统完全避免使用针,并依赖于化学介质或外部驱动力,如离子电渗流或声传递(sonophoresis)来无痛穿破角质层,并经皮肤输送物质。但是,这种真皮内输送系统重复性不够好,并且临床效果不稳定。
机械穿破角质层仍被认为是经皮肤给送物质的重复性最好的方法,它具有最大程度的可控制性和可信性。肌肉(IM)和皮下(SC)注射是最常用的给药途径。真皮位于角质层和表皮下方,开始于人体皮肤表面下深约60-120μm处,并且厚度约为1-2mm。然而,真皮(ID)注射很少采用,因为很难将针放置到真皮内空间的正确位置,难于维持针在真皮内空间中的位置,并且缺少许多用于ID输送药物的药物动力学曲线的知识。另外,人们基本上不了解流体在真皮组织内的吸收极限和贮存时间与药物稳定性之间的效果关系。但是,药物和其它物质的ID给送可以有一些优点。真皮内空间靠近毛细血管床,有利于物质的吸收和全身的分布,但是它又位于神经末梢网之上,这样可以减少或消除注射疼痛。另外,与目前推荐的SC给药位置(基本上限定为腹部和大腿处)相比,对于一个病人来说,ID给药有更多合适并且可接受的ID注射位置。
目前在针设计方面的改进已减少了注射的疼痛。采用较小号规格和更锋利的针减少了对皮肤的损伤,因而减少了因释放介质而引起炎症的可能。出于这方面的考虑,最好是选择显微针。显微针一般直径(width)小于0.2mm,长度小于2mm,它们通常由硅,塑料或金属制成,并且可以是空心的,以便于通过一内腔输送或采样物质(例如参见下述专利文献:US3,964,482;US5,250,023;US5,876,582;US5,591,139;US5,801,057;US5,928,207;WO96/17648)。或是针可以是实心的(例如参见US5,879,326;WO96/37256)。通过选择合适的针长度、显微针的刺入深度可以控制避免触及皮肤的神经末梢网,并减少或消除疼痛感。采用直径非常小并且非常锋利的显微针还有利于降低注射时的感觉。显微针被认为是用于机械穿孔角质层,并增加皮肤的渗透性(US5,003,987)。但是,本发明已发现,在采用显微针的情况下,仅穿破角质层对于临床上有效地进行物质的真皮内输送来说是不够的。因此,采用小号规格的针来进行真皮内输送物质,以便使物质产生有益的临床效果还受其它因素的影响。
US5,848,991公开了一种装置,该装置用于在受控状态下将药物输送到皮肤的有限深度中,该深度约为0.3-3.0mm。该专利还指出,所述装置可用于各种药物,包括激素的输送。US5,957,895也公开了一种在受控状态下输送药物的装置,其中针可刺入皮肤的深度达3mm或小于3mm。该装置的压力储液室中的流体在气压作用下,在预定的时间内渐渐地通过针被排出,例如对于输送胰岛素而言在24小时内输送完。上述专利均没有表明采用所述装置的输送能够产生临床上有益的效果。Kaushik等曾描述采用显微针将胰岛素输送到患有糖尿病的老鼠的皮肤中,从而可检测到血糖水平降低。这些作者既没有公开显微针的刺入深度,也没有给出采用这种给药方法是否能获得临床上有益的葡萄糖浓度的响应的教导。另外,现有技术中也没有表明采用这种装置能够精确输送或同一容量的重复输送。WO99/64580指出可以采用显微针以临床上相应的速率来将物质输送到皮肤中,但是它没有考虑到临床效果取决于药物物质输送的精度、数量和同一容量或质量的重复输送,以及真皮组织对该物质从药物动力学方面而言的摄取与分布。
发明内容
本发明改进了将药物或其它物质ID输送到人体或动物体内的临床应用。该方法采用小号规格的针,特别是显微针放置在真皮内空间中,以便将物质作为散射体或采用输注方式输送到真皮内空间。现已发现,采用小号规格的针来有效输送活性物质,以防止物质泄漏到皮肤外面,并提高真皮内空间的物质吸收能力的关键之处是针的出口在皮肤内的放置。根据本发明,ID输注是优选的方法,因为它仅需要较低的输送压力。这样做还减少了因流体在被吸收前淤积在皮肤内而使内部压力增高,从而使物质流失到皮肤表面的数量。也就是说,输注使物质最少量地渗出到组织之外。输注还降低了肿胀疼痛和组织的肿胀,并且与散射体剂量相比还降低了内部压力。已发现,按照本发明的方法输送的激素药物的药物动力学状况与传统的SC输送的药物动力学状况非常类似,这表明根据本发明的方法的ID给药能够获得相似的临床效果(即相似的效力),同时具有减少或消除病人疼痛的优点。将针出口放置在真皮内空间中一合适的深度,并控制流体输送的输出量和速率的输送装置能够在不泄漏的情况下将物质精确输送到期望位置。
附图说明
图1示出了例1的结果,表示在SC输注和ID输注胰岛素时的血浆胰岛素水平。
图2示出了例1的结果,表示在SC输注和ID输注胰岛素时的血糖水平。
图3示出了例1的结果,表示在SC输注和ID输注时的PTH血浆PTH水平。
图4示出了例2的结果,表示在以2U/hr进行胰岛素的SC输注和ID输注时的血浆胰岛素水平。
图5示出了例2的结果,表示在以2U/hr进行胰岛素的SC输注和ID输注时的血浆中葡萄糖水平。
具体实施方式
本发明提供借助刺入皮肤直至真皮内空间的深度的装置将药物或其它物质输送到人体或动物体对象中。药物或物质通过装置的一根或多根空心针被给送到真皮内空间中。已发现,按照本发明的方法输注的物质所呈现出的药物动力学状况与观察到的相同物质通过SC注射给送时的状况相似,但ID注射基本上为无痛的。该方法特别适合应用到激素治疗中,包括胰岛素和副甲状腺激素(PTH)的给药。
按照本发明,用于ID给药的注射装置不是发明关键,只要它刺入治疗对象的皮肤中的深度足以达到真皮内空间,但不穿过它即可。在大多数情况下,装置将刺入皮肤约0.5-3mm深,最好约为1-2mm。装置可包括传统的注射针、所有公知类型的导管或显微针,采用单根针或多根针阵列。这里所用的“针”或“针组”将包含所有这种针状的结构。针最好为小号规格的,如显微针(即约小于25号规格;一般为约27-35号规格)。针刺入的深度可由医生人工控制,可采用或不采用指示已达到期望深度的辅助指示机构。但是,该装置优选有一个结构性的机构用于限制刺入皮肤达到真皮内空间的深度。这种结构性机构可包括限制用于刺入的针或导管的长度,这样它的深度不会超过真皮内空间的深度。实现上述目的最常采用的方式是采用加宽区域或以针的轴相关联的“毂”,或者对针阵列来说可采用针附着在其上的背衬结构或平台(例如参见US5,879,326;WO96/37155;WO96/37256)。显微针特别适于实现上述目的,因为显微针的长度在制造过程中易于改变,并且显微针通常制造成其长度小于1mm。显微针也十会锋利,并且规格很小(一般约为33号规格或更小),因而在注射或输注时更能减少疼痛和其它感觉。它们可作为单个的单腔显微针用于本发明中,或者多根显微针组装成或构造成线性阵列或二维阵列,以便在给定的时间内提高输送速率或物质的输送数量。显微针可与其它部件,例如夹具和外壳等一起构成多种装置,其中所述外壳也可用于限制刺入或进入导管组的深度。本发明的装置也可包括一个储液室,以便在输送或泵送或其它机构输注物质前盛装物质,从而在压力作用下输送药物或其它物质。另外,罩住显微针的装置可与这些附加部件外部连接。
已发现,真皮内给药方案的某些特征是获得具有临床效果的药物动力学状况和获得精确剂量的基础。首先,已发现皮肤内针出口的放置明显影响这些参数。具有一斜面的较小号规格的针的出口具有相对较大的露出高度(出口的垂直“抬起”)。尽管针尖可以放置在真皮内空间中一定深度,但针出口的较大露出高度使得被输送的物质淤积于靠近皮肤表面的很浅深度处。这样,物质会因为皮肤本身的反压力和注射或输注的堆积流体所产生的压力作用而渗出皮肤。例如,通常认定200μm的显微针为合适的通过皮肤输送物质的装置。然而,我们已发现,即使针出口位于这种显微针(无任何斜面)的尖端,物质也会淤积在很浅的深度范围内,以使皮肤能够环绕着针密封,并且物质很容易渗出到皮肤表面上。例如这些较短的显微针仅用于刺入皮肤,从临床应用上说不能给予足够的剂量控制。相反,本发明的显微针具有足以刺入真皮内空间的长度(“刺入深度”),并且针出口在真皮内空间的深度(“出口深度”)使得皮肤能够环绕针密封,以抵抗迫使输送物质朝皮肤表面渗出的反作用力。总的来说,针的长度不超过约2mm,优选为约300μm至2mm,最优选的是约500μm至1mm长。当针插入到皮肤中时,针出口的深度一般约为250μm至2mm,优选深度约为750μm至1.5mm,最优选的是约为1mm深。针出口的露出高度和在真皮内空间中该出口的深度影响着皮肤环绕针密封的程度。这就是说,针出口的深度较深时,即使针出口的露出高度较高也能具有有效的密封,而当放置在真皮内空间的深度较浅时,同样的露出高度则不能具有有效的密封。一般来说,针出口的露出高度将从0至约1mm,优选从0至约300μm。露出高度为0的针出口无斜面,并且位于针的尖端。在这种情况下,出口的深度与针刺入的深度相同。由一斜面或者通过在针的侧面设有开口而形成的针的出口具有可测出的露出高度。
其次,已发现应仔细控制注射或输注的压力,因为在ID给药时可呈现高的反压力。现有技术中所用的气压驱动装置易于偏离输送速率。因此,优选输送物质的方法在液体表面上施加一恒定的压力,因为这样能够提供较恒定的输送速率,该恒定的输送速率是使吸收最优化,并且获得期望的药物动力学效果。控制输送速率和输送量还为了防止在输送点处形成伤痕,并防止产生能够将针推出皮肤外的反压力。普通技术人员仅凭经验即可根据所选物质确定合适的输送速率和输送量,以获得上述效果。这就是说,总的来说当伤痕的尺寸增加时,对输注而言,其输送速率增加;对散射体注射而言,其输送量增加。然而,显微针的尺寸和数量以及它们放置时的靠近程度可以调节,以便在不影响皮肤上的效果和针在皮肤中的稳定性的前提下维持期望的输送速率或输送量。例如,增加显微针阵列装置中针之间的距离,或采用较小直径的针来降低皮肤中未吸收流体所产生的压力。这种压力会引起伤痕,并将针推出到皮肤之外。选择直径较小的针并且增加多根针之间的距离能够在输送速率增加或输送量增大的情况下使吸收速度增快。另外,我们已发现,ID输注或注射与传统的SC给药相比,通常能够使血浆药物水平较高,特别是对那些易于在体内降解或从体内清除出的药物而言。这样,在某些情况下可以允许借助ID通道,通过显微针来较少量地给送物质,进而可以较少考虑产生气泡和反压力的问题。
本发明实现的给药方法包括将药物或其它物质输送到人体或动物体对象的散射体输送或输注两种方式。散射体剂量为在相对较短的时间段内,一般在少于5-10分钟内以单一体积单元输送的单一剂量。输注给药包括以所选速率(可以是恒定的或是变化的),在相对较长的时间段内,一般为在大于约5-10分钟的时间内给送一种流体。根据本发明输送物质时,针放置在真皮内空间中,物质通过针的内腔输送到真皮内空间中,该物质可以局部起作用或被血流吸收并分布到全身。针可以与一盛装有输送物质的储液室相连。从储液室到真皮内空间的输送可以是被动的(不对输送物质施加外力),也可以是主动的(通过施加外力)。优选的压力产生装置例如包括泵、注射器、弹性膜、渗透压或Belleville弹簧或洗涤器。例如参见US5,957,895;US5,250,023;WO96/17648;WO98/11937;WO99/03521。如果需要,可以通过压力产生装置来变化控制物质输送速率。这样,物质进入到真皮内空间并被吸收一定的量,并且物质以足以产生临床有益效果的速度进入。“临床有益效果”是指物质的给送能够产生临床上有益的生物反应。例如,防止或治疗一种疾病或病症为一种临床上有益的效果,如临床上适当控制血糖水平(胰岛素),临床上适当处理激素缺乏(PTH,生长激素),保护性免疫的表达(疫苗),或临床上适当处理毒性(抗毒素)。作为另一个例子,临床上有益的效果还包括控制疼痛(例如采用triptans,类鸦片,止痛剂,麻醉剂等),血栓症(采用肝磷脂,香豆定,苄丙酮香豆素等)以及控制或消除传染(采用抗生素)。
例1
胰岛素ID输注的例子为采用不锈钢30号规格的针,其尖端部分弯成90度角,这样用于刺入皮肤的可用长度为1-2mm。当将针插入皮肤中时,针出口(针的尖端)的在皮肤中的深度为1.7-2.0mm,针出口的露出高度为1.0-1.2mm。针在输送装置中的构成与US5,957,895公开的内容相似,储液室中盛装的胰岛素的输注压力由塑料Belleville弹簧提供,经重量分析测得的流动速率为9U/hr(90uL/hr)。采用MiniMed507胰岛素输注泵和Disetronic SC导管组来设定相应于SC受控输注的流动速率。输注醋酸奥曲肽,以抑制猪的基础胰岛素分泌(Sandostatin,Sandoz Pharmaceuticals,East Hanover,NJ),同时输注10%的葡萄糖,使之产生高血糖症。经过两小时的诱导和基本的时间之后,输注胰岛素两小时,然后经过三小时的清除时间。采用公知的放射免疫测定法(Coat-A-Countinsulin,Diagnostic Products Corporation,LosAngeles,CA)来确定血浆胰岛素水平,并采用市售监测器(Accu-chekAdvantage,Boehringer Mannheim Corp,Indianapolis,IN)来测量血糖值。图1和图2示出了重量规度的血浆胰岛素水平和相应的血糖值。数据表明,通过ID途径和传统的SC途径输注时具有相似的血浆胰岛素水平和起作用时间。两者之间血糖降低响应也类似。尽管给药率为9U/hr与医学中的常规用法相比较高,但这些结果也表明,真皮组织能够在采用上述途径输注的情况下很容易吸收和分布药物。
类似的试验还采用人体副甲状腺激素1-34(PTH)进行。在四小时的时间内输注PTH,然后进行两小时的清除。通过Harvard注射泵来控制流速。采用“捏起”技术,通过插入到皮肤侧面的SC空间的标准31号规格针来控制SC输注。ID输注通过前述弯曲的30号规格的针。以75uL/hr的速率输注0.64mg/mL的PTH溶液。图3示出了重量规度的PTH血浆胰岛素水平。该数据表明,该给药途径对于附加激素药物来说是有效的,并且事实上ID输注对于易于在体内被生物降解或清除的药物来说能够提供较高的血浆水平。
例2
ID胰岛素输注以猪为例,采用与标准导管相连的空心硅显微针。导管与MiniMed507胰岛素输注泵相接,以控制流体的输送。
空心单腔显微针(总长为2mm,200*100um OD,相应于33号规格)的出口距尖端1.0μm(100μm的露出高度),由公知的工艺制成(US5,928,207),并与通常用于胰岛素输注中的微孔导管(Disetronic)相匹配。显微针的远端放置到塑料导管中,并用环氧树脂粘接,形成深度限制毂。针出口位于超过环氧毂约1mm的位置,这样将针出口刺入皮肤内的深度限定为约1mm,该位置相应于猪的真皮内空间深度。肉眼观察确定明显的流体流动通路,并观察在标准1cc注射器产生的压力下无障碍。导管通过导管出口处的组装的Luer连接器与外部胰岛素输注泵(MiniMed507)相连。
泵内充有HumalogTM(LisPro)胰岛素(Lilly),并且根据制造商的说明,导管和显微针预先充有胰岛素。通过IV输注向麻醉猪给送Sandostatin溶液,以抑制基础胰腺功能和胰岛素分泌。经过适当时间的诱导和基本的采样之后,预先充有胰岛素的显微针垂直插入到动物侧腹的皮肤表面中,直至毂使之停止刺入。胰岛素的输注以2U/hr的速率开始,并持续4.5小时。定时取出血样,并采用例1中的方法分析血清胰岛素浓度和血糖值。输注前的原始的胰岛素水平为该化验基础检测水平,如图4所示。输注开始以后,血清胰岛素水平呈现为相应于预定输注速率而增高。血糖水平也呈现为相应于反相控制(NC)而相应降低,这种降低与传统SC输注(图5)所观察到的类似。
在该实验中,显微针表现为能够充分刺破皮肤阻挡物,并以药学上相应速率来向体内输送药物。胰岛素的ID输注表现为是药物动力学上可接受的给药途径。这些数据表明,按照本发明的方法,在人体内以ID给送激素或其它药物会取得药理学上的成功效果。
Claims (24)
1.一种将物质输送到皮肤中的方法,包括采用插入到真皮内空间的小号规格的针将物质输送到皮肤内的真皮内空间中,其中针的出口插入到皮肤中一定深度,从而基本上防止物质泄漏到皮肤表面上。
2.如权利要求1的方法,其中针从包括显微针、导管针和注射针的一组中选择。
3.如权利要求1的方法,其中插入单根针。
4.如权利要求1的方法,其中插入多根针。
5.如权利要求1的方法,其中物质为液体,通过直接作用在该液体上的压力被输送。
6.如权利要求1的方法,其中输送的是激素。
7.如权利要求6的方法,其中激素包括从胰岛素和PTH的一组中选择。
8.如权利要求1的方法,其中物质被输注。
9.如权利要求1的方法,其中物质以散射体方式被注入。
10.如权利要求1的方法,其中针的长度约为300μm至2mm。
11.如权利要求10的方法,其中针的长度约为500μm至1mm。
12.如权利要求1的方法,其中当针插入时,针出口的深度约为250μm至1mm。
13.如权利要求12的方法,其中当针插入时,针出口的深度约为750μm至1.5mm。
14.如权利要求12的方法,其中针出口的露出高度约为0至1mm。
15.如权利要求14的方法,其中针出口的露出高度约为0至300μm。
16.如权利要求1的方法,其中通过配置多根针、针的直径或针的数量来控制输送速率或输送容量。
17.一种将物质真皮内输送到皮肤中的针,包括用于限制针刺入皮肤和针出口位置的装置,这样当针插入到皮肤中时,插入深度由刺入限制装置确定,从而基本上防止物质泄漏到皮肤表面。
18.如权利要求17的针,其中当针插入到皮肤中时,针出口的深度约为500μm至2mm。
19.如权利要求18方法,其中当针插入到皮肤中时,针出口的深度约为750μm至1.5mm。
20.如权利要求1 7的针,其长度约为300μm至2mm。
21.如权利要求20的针,其长度约为500μm至1mm。
22.如权利要求17的针,该针包含在一用具中,该用具包括一个与所述针流体连通的储液室。
23.如权利要求22的针,该针包含在一用具中,该用具还包括一个压力产生装置,用于通过所述针输送物质。
24.如权利要求23的针,其中压力产生装置提供可变化地控制物质的输送速率。
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103687643A (zh) * | 2011-07-27 | 2014-03-26 | 久光制药株式会社 | 施放器 |
US9216252B2 (en) | 2011-07-27 | 2015-12-22 | Hisamitsu Pharmaceutical Co., Inc. | Applicator |
CN103687643B (zh) * | 2011-07-27 | 2016-04-20 | 久光制药株式会社 | 施放器 |
TWI561262B (zh) * | 2011-07-27 | 2016-12-11 | Hisamitsu Pharmaceutical Co | |
CN105073180A (zh) * | 2013-03-22 | 2015-11-18 | 3M创新有限公司 | 包括计数器组件的微针施用装置 |
CN105073180B (zh) * | 2013-03-22 | 2016-08-10 | 3M创新有限公司 | 包括计数器组件的微针施用装置 |
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