CN100591386C - 用于药物输送及其它用途的速溶微穿孔器 - Google Patents
用于药物输送及其它用途的速溶微穿孔器 Download PDFInfo
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Abstract
一种系统，所述系统包含一个溶剂源以及一个具有多个与所述溶剂接触后快速溶解的微穿孔器(113)的阵列。所述微穿孔器能方便地包含一种药物，尽管该系统能用于输送治疗用、预防用和/或化妆用化合物，用于营养物输送和诊断用途。所述溶剂优选包含在可含有药物的贴片(110)或其它贮器中。
Description
发明领域
本发明涉及药物的经皮输送领域。
发明背景
任何药物必须以对治疗有效的速率和数量被输送穿过体内一道或更多生物屏障才能有效。很多情况下药物可经口给予(口服)并有足够功效，但在其它很多情况下由于胃肠道内的严重降解、肠粘膜的微少吸收和/或肝脏的首过分解使经口途径效果较差。对于很多较新的药物包括蛋白质、肽类以及DNA成分而言，这些问题尤其难以解决。例如重组人胰岛素、生长激素、促红细胞生成素、干扰素和其它蛋白质，目前都必须以口服以外的某些方式用药。
一种代替方法为经皮即通过或穿过皮肤输送药物。典型地，这要通过使用标准注射器或导管精心注射来完成。不幸的是，针注射法在很多患者中可引起注射针恐惧症、严重疼痛和局部皮肤损伤。对于持续性给药或诊断而言针注射法也存在问题。
解决这些问题的方法之一为经真皮用药，通常包括药物穿过皮肤扩散。一旦一种药物达到真皮的深度(在表皮层之下)，该药物即通过血液循环向深部组织层和系统的其它部分迅速扩散。但是皮肤的最外层即角质层成为药物经真皮渗透的主要障碍，因此很多药物低效的皮肤渗透性影响着经真皮给药的广泛应用。
化学增强剂、电离子渗入疗法、电穿孔法、超声波法以及加热元件均已被用于提高药物的经真皮输送。然而，这些技术对某些类药物不适用，并且其输送的药物常不能达到治疗水平。再者，这些技术有时导致不良的皮肤反应，和/或不能应用于在数小时或数天的时期内持续可控制地给药。
一些方法尝试使用粒子或液体注射以提高经真皮药物输送。那些技术的主要优点是不使用注射针和减少污染的发生率。然而，液体注射常引起疼痛和/或真皮下出血。一种技术即冲击粒子注射，它难以精确和持续给药并可导致微出血。
其它方法使用微注射针(直径＜1mm)以实现经皮药物输送。微注射针用于通过注射针内的腔输送药物、沿着针杆外部输送药物或为随后应用的贴片药物充当皮肤穿孔器。例如硅制微注射针，已采用源于半导体工业的制造程序被研制。实例在Allen等的US 6334856(2001年1月)、Yuzhakov等的US 6256533(2001年7月)、Sherman等的US 6312612(2001年11月)和Gartstein等的US 6379524(2002年4月)中描述。不幸的是，硅制注射针在皮肤中不能溶解，如果使用时断裂可产生相当严重的刺激甚至感染。
可溶性植入物是公知的，但仅有缓慢溶解配方。例子有Buch-Rasmussen等的US6485453(2002年11月)、Yamahira等的US 5021241(1991年6月)以及Societe deConseils de Recherchéet d’Application Scientifiques，S.A.的WIPO WO/9608289，S.A.(1996年3月出版)。因此，可溶性植入物的应用很大程度上局限于激素和其它想要在较长时期内低剂量用药的物质。
结论为尚没有生产微注射器或其它微植入物阵列的动机。只要产品为缓慢溶解的，通过应用单个微注射针输送小剂量或单个较大的注射针或小丸以输送较大剂量，用药能够较好地控制。(参见例如Sandhage等的US 4077406(1978年3月))
速溶微植入物将是理想的，因为它们允许中间剂量用药且仅有轻微的疼痛和不适。但是由于角质层和表皮缺乏血管而阻止了微植入物的可控性溶解，迄今实现这个想法仍很困难。因此，仍有研制速溶经皮药物输送工具的需要，特别包括微注射针或其它皮肤微穿孔器的阵列。
发明概述
描述了使用速溶微穿孔器(“RDMP”)经皮输送药物的装置和方法。术语“微穿孔器”在这里通常指注射针、刀片、切削刀(cutting)、穿孔器或其它任何平均直径小于1mm的装置，不论其横截面的形状。
微穿孔器优选地包括一个可选择地容纳一种或更多已选择药物的可溶解(包括可融性或可生物降解性)材料的固体基质。基质材料中的药物可孔隙样或以其它任何合适的方式分布。微穿孔器可与容纳相同或不同药物的贮器以液体方式连通，所述药物可被微注射器本身或通过微注射器在皮肤上穿孔所产生的通道运送至皮肤内。在优选的实施例中所述贮器包含一种在微穿孔器应用于皮肤后能加速微穿孔器溶解的溶剂。该贮器可方便地包含在一个带有一粘合剂环的贴片内，所述粘合剂环在穿孔区域的皮肤上粘合贮器并使其紧靠患者的皮肤。
所述基质中包含可膨胀材料，这可使切口开放更长时间而易化药物传输通道的形成。这样的通道，尤其在皮肤的最外层，可以方便地为可控性药物输送或为提供监测体内液体或其它分析物的入口消除皮肤的屏障特点。
微穿孔器在此设想为包含单一药物或药物的混合物，根据药物的使用目的和物理/化学性质而定。在优选的实施例中微穿孔器迅速溶解，迅速溶解在此定义为在用药一小时内至少50％的微穿孔器在皮肤内或皮肤上溶解。
参考以下对本发明优选实施方案的具体描述以及附图，本发明的各个目的、特征、方面和优点将更加清晰，图中同样的数字代表同样的组件。
附图简述
图1是患者皮肤横截面的示意图。
图2A-2G是合适的微穿孔器实例的透视图。
图3是一个微穿孔器阵列及其周围作为RDMP系统一部分的环形粘合剂环的平面图。
图4-9图解了可用于RDMP皮肤微穿孔器的激活装置。
图10图解了一种药物贮器系统。
图11A-11C和12A-12F图解了一些设想的贴片系统的操作。
最佳发明模式描述
图1是皮肤11顶层的横截面图，包括角质层13，表皮层或表皮15和真皮层或真皮17。皮肤的最外层即角质层13是死细胞层，厚度通常在10和20微米(μm)之间。角质层13包含被疏水的细胞外脂质基质包围的亲水角化细胞，所述脂质主要为神经酰胺。由于结构和组成的独特性，角质层13成为经真皮药物或其它分子流通入体内以及体内液体或其它分析物流通出体外的最大障碍，角质层13由角质细胞的脱落而持续更新，平均周转期为2-3周。
角质层13下是有生长能力的表皮或表皮层15，其厚度在50和100μm之间。表皮层不存在血管，代谢物通过扩散向和扩散自直接位于表皮15之下的真皮层17而自由交换。真皮厚度在1和3mm之间并包含血管、淋巴和神经。一旦药物到达真皮层即能灌注进入系统循环。
优选的药物输送系统包含一个速溶微穿孔器的阵列，优选地，所述阵列在1cm2的区域内至少有5、10、25、50、100或甚至200个微穿孔器。至少其中一个被制成一个或多个注射针或刀片样的固体基质，每一个均在头端被弄尖或磨快以在皮肤穿孔。每一个微穿孔器都足够坚固和完整以刺穿角质层，并且当微穿孔器(和药物)穿入患者体内后，所述微穿孔器能被体内液体和/或药物贮器内的溶剂生物降解或溶解。生物降解和溶解过程可方便地在所需的几十秒和几小时之间的时间段内发生。
本发明揭示了所需的溶解速率可通过提供一种外源性溶剂而有效完成，且所述溶剂可通过位于上方的贴片方便地提供。很多设想的微穿孔器以被证实，其中的贴片给予水作为主要溶剂，一种药物随同水一起给予。微穿孔器可为一个包含同种或不同药物的固态溶液的基质，并且根据基质的组成、微穿孔器的尺寸和形状，至少50％的微穿孔器能在使用后任何需要的、从几十秒、到几分钟、到一或几小时的时间段内溶解。
图2A-2G是用于一个阵列的微穿孔器的一些设想的形状的透视图。图2A中的微穿孔器是一个带有一可提供额外穿孔压力的尖角样尖端的圆锥。图2C中的微穿孔器是一个带有一常规线形穿孔尖端的常规的圆锥形。图2B和2E中的微穿孔器是柱-加-锥形，各自采用圆柱和长方柱(或更常见的多边形柱)。图2D中的微穿孔器是多边形锥形。图2F和2G中的微穿孔器提供了与皮肤接触和在皮肤穿孔的一个或多个锋利的或切片的用的刀片(直的或锯齿状的)的序列。其它带有尖样和刀片样末端的形状也可应用于此。
微穿孔器可有任何适合的形状，包含例如图2A-2G中图解的直或锥形的杆状、角锥状、楔状、或刀片状。在一个优选的实施例中，微穿孔器的外径在基端或第二末端最大，约1-1000μm，且微穿孔器近头端的外径优选为5-500μm，在头端更优选5-25μm。微穿孔器可有利地具有不超过20μm的最小尖端直径。微穿孔器的长度典型地在1-2000μm的范围内，更优选在100-1000μm的范围内。皮肤是不平滑和粗糙的表面，在显微镜下具有不同的深度。并且人与人之间以及任何特定的人体部位和部位之间角质层的厚度和皮肤的弹性不同。为了药物的有效输送和相对无痛且不出血的穿透，理想的刺入深度具有一个范围而并非单一的数值。一个微穿孔器的刺入深度可影响痛觉和输送效率。在经真皮使用时，所述微穿孔器的“刺入深度”优选小于100μm以使微穿孔器插入皮肤穿过角质层而不越过表皮。这是避免接触神经和血管的最佳方法。在这样的使用中，微穿孔器的实际长度可长一些以对付额外的弹性和/或皮肤的粗糙不平，与RDMP系统相连的基层不能完全插入皮肤。
根据医学需要，在某些使用中微穿孔器可能需要穿刺进入真皮。在这些情况下，微穿孔器的刺入部分可通过调整一些变量(长度、尺寸、基层或底层的机械特征以及微穿孔器插入的冲击和速度)被最优化，同时解决靶皮肤的弹性、皮肤的硬度和表面的粗糙。
基层(如图3和10所示)提供保护以使穿孔的皮肤区域不被污染，并且基层可包含抗菌制剂且可阻止已穿孔皮肤的水化以增强液体的流通。根据微穿孔器材料的特性在微穿孔器溶解或膨胀后入口通道将缩小或扩张。
微穿孔器的主要功能是刺透角质层以提供药物输送的迅速开始和切断，并可选择性地为随后的药物输送和体液监测辅助保持通道的开放。只要微穿孔器合理迅速地溶解(依赖于周围环境)且足够坚固以刺透角质层，任何生物相容性材料均可用于制造微穿孔器。
制造微穿孔器时，可采用精密加工、微加工(例如MEMS)、或以激光为基础的加工方法或放电加工方法制造铸模。当铸模制造好后，一种液态溶液，包括基质材料和所选择的药物，浇铸于铸模内并干燥。根据液态溶液的粘性和其它物理化学性质，可能需要外加的力如离心力或压力以填充铸模。为了形成一个固态溶液，溶剂需被空气干燥、真空干燥或冷冻干燥。一旦形成了固态溶液，微穿孔器即从模具分离并切割成适当的形状和尺寸。
当粉末形态用作基质材料，所述粉末可方便地布满铸模。然后根据粉末的化学和物理性质，适当加热以融化粉末或在铸模中嵌入粘质的材料。代替地，粉末可被压力和/或加热的使用嵌入铸模，同时使用或不使用粘合剂。当微穿孔器被制成一个阵列后，该阵列被冷却、由铸模分离并装入RDMP系统。
另一种合适的制造一个阵列的方法是光致交联。一种包含光引发剂的聚合物溶液浇铸于铸模上，并经过放射被固化。一旦所述溶液固化，固态的溶液可被剥落、切割并定形于合适的尺寸。另一种可行的制作微穿孔器阵列的方法是多个缠绕、排列和结合于一个轴体的微纤维的制造。
很多聚合物是微穿孔器的合适基质材料，包扩但并不局限于聚乙烯吡咯烷酮(PVP)、聚乙二醇(PEG)、聚乙烯醇(PVA)、纤维素、羟丙基纤维素(HPC)、羟乙基纤维素(HEC)、羟丙基甲基纤维素(HPMC)、糊精、单糖和多糖、羧甲基纤维素钠、多元醇、凝胶、阿拉伯胶、藻酸盐、壳聚糖、环糊精及其它生物多聚物。
碳水化合物衍生物例如糖衍生物(海藻糖、葡萄糖、麦芽糖、乳糖、乳果糖、果糖、松二糖、棉子糖、松三糖、右旋糖苷、山梨醇、木糖醇、异麦芽糖醇和甘露醇)可被应用。水溶性玻璃，例如磷酸盐、硝酸盐和羧酸盐玻璃以及氯化镁、氯化钾和氯化钙也可单独或与一种基质多聚物混合用作基质材料。
其它合适的基质材料实例包括由以下材料中选出的非离子型亲水剂或离子型表面活性剂或亲脂添加剂：烷基配糖物、烷基麦芽苷、烷基葡糖硫苷酶、十二(烷)醇聚乙二醇甘油酯、聚氧乙烯烷基醚、聚氧乙烯烷基酚、聚乙烯乙二醇脂肪酸酯、聚乙烯乙二醇甘油脂肪酸酯、聚氧乙烯山梨聚糖脂肪酸酯、聚氧乙烯-聚氧丙烯嵌段共聚物、聚丙三醇脂肪酸酯、聚氧乙烯甘油酯、聚氧乙烯甾醇、它们的衍生物和类似物、聚氧乙烯植物油、聚氧乙烯氢化植物油、多元醇与以下物质组成的组中至少一种成分的反应混合物：脂肪酸、甘油酯、植物油、氢化植物油、以及甾醇、生育酚聚乙烯乙二醇琥珀酸盐、糖酯、糖醚、甘素甘油酯以及它们的混合物。
合适的离子型表面活性剂包括烷基铵盐；胆汁酸及其盐以及它的类似物和衍生物；氨基酸、肉碱、寡肽和多肽的脂肪酸衍生物；氨基酸、寡肽和多肽的甘油酯衍生物；乳酸酯酰；单-甘油二酯的单-二乙酰酒石酸酯；琥珀酰单甘油酯；单甘油二酯的柠檬酸酯；藻酸盐；丙稀乙二醇藻酸盐；卵磷脂和氢化卵磷脂；溶血卵磷脂和氢化溶血卵磷脂；溶血磷脂及其衍生物；磷脂及其衍生物；烷基硫酸盐；脂肪酸盐；多库酯钠；及它们的混合物。
合适的亲脂添加剂包括乙醇、聚氧乙烯烷基醚、脂肪酸、胆汁酸、甘油脂肪酸酯、乙酰化甘油脂肪酸酯、低乙醇脂肪酸酯、聚乙烯乙二醇脂肪酸酯、聚乙烯乙二醇甘油脂肪酸酯、聚丙稀乙二醇脂肪酸酯、聚氧乙烯甘油酯、单/甘油二酯的乳酸衍生物、丙稀乙二醇甘油二酯、山梨聚糖脂肪酸酯、聚氧乙烯山梨聚糖脂肪酸酯、聚氧乙烯-聚氧丙烯嵌段共聚物、转酯基植物油、甾醇、甾醇衍生物、糖酯、糖醚、甘素甘油酯、聚氧乙烯植物油、聚氧乙烯氢化植物油、多元醇与至少一种下列物质组成的反应混合物：脂肪酸、甘油酯、植物油、氢化植物油、甾醇以及它们的混合物。
微穿孔器的“阵列”在这里意为任何至少有9个微穿孔器的组。不管它们是否规则地间隔开。典型地，阵列将包含更多的微穿孔器，优选100个或更多。为了制作方便，一个阵列中的微穿孔器通常(单非必须)全是同样的尺寸和形状且全部具有实际上相同的组成。
图3是构成于一个微穿孔器阵列31之上的一个贴片系统的平面图。所述贴片系统可选择地被一个包含环形区域33的基层包绕，环形区域33含有粘合剂和抗菌剂(可选择的)以将穿孔区域由患者皮肤的其它区域分隔出来。粘合剂的环形区域33意在将阵列固定于皮肤并防止或减少外源物质和/或外部感染侵入的可能。可选择地，一个药物贮器(图3中未显示)可以位于微穿孔器阵列31之上并/或也可以被粘合剂的环形区域33封闭。
图4是一个侧视剖面图，图解了一种穿孔器激活/失活的装置40，该装置导致一个或更多微穿孔器41穿刺进入或退出患者的皮肤42以启动和/或切断包含在微穿孔器内的药物的输送。通过插入或取出微穿孔器41，药物输送的启动或切断可在小到约5分钟内发生。微穿孔器的刺入深度由穿孔调节装置43A和43B(可选择的)，例如一个旋钮或螺杆调整。微穿孔器41被一个由穿孔装置扳柄45控制的弹簧或相似装置44驱动进入患者的皮肤42。
图5是一个侧视剖面图，图解了一种穿孔器激活/失活的装置50，其中一个或更多微穿孔器51被一个由螺杆旋钮或马达或类似装置55控制的螺杆54驱动进入或退出患者的皮肤52。
图6是一个侧视剖面图，图解了一种穿孔器激活/失活的装置60，其中一个或更多微穿孔器61被一个真空装置65推进入患者的皮肤62，然后被导致微穿孔器62伸出或退入激活室66的弹簧64注入。在皮肤穿孔区内温和真空的应用可帮助减少皮肤的变异。
图7是一个侧视剖面图，图解了一种穿孔器激活/失活的装置70，其中一个或更多微穿孔器71被一个气体膨胀装置74驱动进入或退出患者的皮肤72，所述气体膨胀装置包含一个气压室75和一个气体贮器76。
图8图解了一种方法，通过该方法在图4、5、6和/或7中所示的微穿孔器装置可被应用以控制运转，包括但并不局限于相应微穿孔器82进入或退出患者皮肤81的穿孔深度。该设计可和腹腔镜或内窥镜一起使用用于内部给药。
图9是一个侧视剖面图，图解了一种微穿孔器激活装置90，其中一个或更多微穿孔器91被由一个手指或其它压力装置93人工实施于微穿孔器一侧的压力驱动进入患者的皮肤92。
可选择地，一种药物贴片系统100，如图10所示，包含一个容纳与第一种药物相同或不同的第二种药物的药物贮器101，所述药物贮器101位于微穿孔器阵列102之上并与之相毗邻并具有一个独立控制的贮器药物输送系统103。药物贴片系统100优选地包含一个背衬膜104(基层，在图3中最好的显示)，所述背衬膜包绕药物贮器101并包含一个围绕并封闭皮肤穿孔区106的环形粘合剂区域105。一个塑料释放衬垫107在皮肤穿孔前被剥离并保护阵列直到衬垫被剥离。
在一个优选实施例中，贴片系统中的贮器容纳一种药物并可选择地在液体贮器中容纳一种化学增强剂、一种皮肤抗刺激物、一种抗感染化学物和/或其它液体形式的化学药品。所述化学增强剂可由以下物质中选出：烷基乙醇、α-没药醇(α-bisabodol)、癸乙醇、右旋泛醇、十二(烷)醇、乙烯乙二醇、脂肪乙醇、甘油、十六醇、异丙醇、十八(烷)醇、四氢化糠基乙醇、三氯乙醇、三氟乙醇、烷基乙酰胺、克罗米通、十二烷基乙醇酰胺、妥鲁香酰胺、二甲基乙酰胺、二甲基甲酰胺(dimethylformide)、甲酰胺、烟碱、酰基氨基酸、丙胺酸、精氨酸、脯氨酸、丝氨酸、天(门)冬氨酸、半胱氨酸，谷氨酸、氨基乙酸、缬氨酸、亮氨酸、异亮氨酸、蛋白抑肽酶、月桂氮卓酮，精华油类如香芹酮、桉树脑、桉油精、丁子香酚、薄荷醇、5，5-二甲基-1，3-环己二酮、萜烯脂肪酸，例如羧基酸、羊蜡酸、二异丙基己二酸、异丙基豆蔻酸酯(IPM)、异硬脂酸、甘油基单月桂酸酯(GML)、甘油基单油酸盐(GMO)、乳酸、亚油酸、十二(烷)酸、甲基月桂酸酯、甲基豆蔻酸盐、油酸、聚乙烯乙二醇单月桂酸酯、山梨聚糖油酸盐(SMO)、蔗糖可可酯、蔗糖单液态金酸盐、蔗糖单油酸盐、甘油三酯、大环增强剂如环丙烷糊精、环丙烷十五烷酮、环丙烷十五烷醇化物、磷脂、磷脂/磷酸盐增强剂例如二烷基磷酸盐、卵磷脂、二氧杂环乙烷、二氧戊环、烷基砜、十六(烷)基醚、环二甲基硅氧烷、十甲基甲硅氧烷、二烷基亚砜、二甲基亚砜、癸甲基亚砜、六甲基二硅氧烷、甲基辛烷基亚砜、烷基西托溴铵、苯甲基烟酸盐、丁基偶氮环戊烷、辣椒辣素、巯基乙酸钙、环胺、二乙基癸二酸酯、二甲基胺醋酸盐、乙烯乙二醇单乙烷醚、咪唑、甲基原甲酸酯、唑啉、脯氨酸、尿素、尿烷、大环类物质(macrocyclis)、胺、烷基吡咯烷酮、N-甲基吡咯烷酮、乙烯基吡咯烷酮、吡咯烷酮、羟甲基吡咯烷酮、己基吡咯烷酮、月桂醇吡咯烷酮、吡咯烷酮-羧基酸、月桂醇吡咯烷酮-羧基酸、焦谷氨酸、二癸甲硫酸钠、脱氧胆酸钠、月桂醇硫酸钠、山梨聚糖单棕榈酸酯、山梨聚糖三油酸、大豆酪蛋白、萜烯、哌嗪衍生物、牛磺胆酸盐(traurocholate)、脂质体、没药醇(bisbolol)、二硫苏糖醇和维生素E(口-生育酚)。
图11A/11B/11C是一个侧视剖面图，图解了一次经真皮使用时一个贴片嵌入程序的优选实施例。图11A中，贴片110的基层中的粘合剂111应用于皮肤112以将贴片固定于紧贴皮肤。此时，微穿孔器113从皮肤112移开。图11B中，一个活塞或其它装置114被激活以移动微穿孔器113与皮肤112接触并穿透角质层进入表皮或真皮。图11C中，微穿孔器113和基层115仍与皮肤112接触并且，可选择的，贴片系统的剩余部分可由皮肤移开。在一个优选实施例中，位于贴片系统上方贮器内的储存的药物分子流过微穿孔器全部或部分溶解产生的通道进入表皮。然后所述药物分子扩散进入真皮用于局部治疗或用于向体内运送。
阵列中的微穿孔器在与皮肤接触(即进入或在其上)后即溶解是非常重要的。溶解可以化学地或物理地(例如被皮肤的温度融化)或两者兼具地发生。在此微穿孔器足够的溶解定义为至少50％(以重量计)的微穿孔器在用药后四小时内溶解。很多情况下优选更快的溶解速度，这样至少50％(以重量计)的微穿孔器在用药后2小时、1小时、30分钟、或甚至10分钟内溶解。快速溶解在此定义为至少50％(以重量计)的微穿孔器在给药后1小时内溶解。
只要它们足够坚固达到刺入皮肤满足包含在微穿孔器内的药物用药需要的程度，微穿孔器即被认为“相当地坚固”。
优选的贴片系统包含一个容纳一种液体或凝胶形式的第二药物的贮器，并且一个或多个微穿孔器由贮器的至少一部分表面伸出。与贴片相连接的微穿孔器穿透皮肤的角质层以增强经皮给药的效果以及提供快速的药物输送和/或快速药物切断。在贴片系统中，微穿孔器和贮器可被制成单一单元或分离单元的形式。
贴片贮器意在提供一液体或半液体(第二)药物进入或穿过生物屏障的持续的可控制的输送，所以在微穿孔器(基质加药物)插入并溶解后扩散通道产生并保持开放。微穿孔器的尺寸、形状、组成和区域密度影响药物通过皮肤通道的释放速度。代替地，其它控制装置例如电离子透入疗法、超声促渗法、加热元件和机械振动力可以加速、减慢或以另外方式控制药物运送通过角质层。
贴片系统优选应用于皮肤，所以根据使用目的一个或多个微穿孔器穿刺通过角质层进入表皮或真皮。在一个优选实施例中，贴片系统贮器内的药物分子流过微穿孔器全部或部分溶解产生的通道进入表皮或真皮。所述药物分子扩散进入真皮用于局部治疗或用于向体内运送。
贴片和其它RDMP系统能将广范围的治疗和/或预防制剂运送穿过皮肤和其它组织，包括药物和疫苗以及其它生物活性分子。这种系统允许药物穿过皮肤和其它组织屏障输送进入体液而所述组织仅有最小的损坏、疼痛和/或刺激。在药物输送应用中，根据所需药物的特性，一个微穿孔器可方便地主要包含一种活性药物和一种溶解性或膨胀性固体基质。作为直接的药源并作为随后的药物经皮输送的通道产生者。在诊断应用时，微穿孔器通常不含药物，且实际上完全由一种快速溶解的无生物活性的固体或一种用于产生和维持通道的可溶或可膨胀的基质组成。根据应用目的，一种具渗透活性或抗刺激的化合物可产生有益效果。在一些诊断应用中，设想微穿孔器可包含或由对特殊分析物的出现有反应的传感器材料制成。
贮器系统中基层的主要功能是分隔药物贮器，并作为贮器和系统中其它部分之间的传送桥梁。根据使用目的，基层的材料可与固体基质材料相同或可能是不同材料。在不含贮器的RDMP系统中，基层可由用于释放控制的一个或多个添加层或材料碾压而成。最外层基层可作为不渗透的背衬膜以保护穿孔区皮肤不受任何否则可能侵入的病毒和细菌的侵入。为了避免源于RDMP系统其它部分的回返扩散，该层的药物可溶性应很低。在需要增加的和持续的药物释放时，基层可被制成含有更多所述药物或为第二贮器提供通道。基层中具有抗病毒和/或抗菌保护以抑制感染是很有用的。为了改变或控制药物的输送速度，一种应用电离子透入疗法、或超声促渗法、压电反应或类似反应的外部的物理增强装置系统可作为基层和/或覆盖层的一部分被提供。
图12A图解了贴片的一个简单设计120A，包括一个包含一背衬的基层121和一个位置毗邻皮肤123的一个或多个微穿孔器的阵列122。活性成分(药物或药物的固态溶液)包含在微穿孔器中。基层可有不同的厚度但最常是一种非渗透性背衬层。该设计对于有效的药物输送、对于小剂量用药或对于即刻药物输送而言是理想的。
图12B图解了另一种贴片的设计120B，包括一个微穿孔器阵列122和一个基层124。活性成分包含在微穿孔器和基层中。基层124可具有与微穿孔器最外层不同的组成但最常是一种非渗透性背衬层。该设计对于有效的药物输送、对于小剂量全身用药或对于局部应用而言也是理想的。
图12C图解了一种更复杂的贴片设计120C。活性成分包含在微穿孔器和贮器中。基层126的顶端部分包含一个药物贮器贴片125。第一微穿孔器阵列122-1定方向为穿刺皮肤123的角质层，第二微穿孔器阵列122-2定向相反以穿透贮器贴片125中包围和容纳液体的膜。贮器贴片125可在阵列应用后被应用，或可与阵列联合应用。根据靶药物的释放特性贮器可具有很多组成或配方。
图12D和12E图解了分别从图12B和12C改良的RDMP贴片系统的其它设计120D和120E。此处，微穿孔器不含任何药物但确实包含一种溶解的基质。活性成分仅包含在基层和/或贮器中。药物自基层的释放可根据药物的溶解性和浓度来控制。图12D和12E中所示的系统各自主要用于诊断目的和持续的药物释放。
图12F图解了使用可膨胀材料作为贴片系统一部分的120F，可选择的在微穿孔器固态基质中不含药物。该设计延伸皮肤通道的开放至更长(或更短)的时间间隔并延伸药物输送间期或用于诊断用途。
任何药物或其它生物活性制剂都能使用RDMP系统输送。被输送的药物可以是蛋白质、肽类、DNA、基因、多醣以及合成的有机化合物和无机化合物。代表性的制剂包扩但不局限于：抗感染剂、激素、生长调节剂、调节心脏活动或血流的药物和疼痛控制药物。这些药物可用于局部治疗或区域性或全身治疗。下面是代表性的蛋白质药物实例用于治疗时每次注射的剂量。
α-干扰素 11-100μgm
用于多发硬化的β-干扰素 22-44μgm
用于贫血的促红细胞生成素 10-30μgm
卵泡刺激素(FSH) 5-30μgm
粒细胞集落刺激因子(G-GSF) 9-15μgm
粒单核细胞集落刺激因子(G-GSF) 250μgm
人绒(毛)膜促性腺激素 30-300μgm
促黄体生成激素 2-30μgm
鲑降钙素 25-50μgm
升血糖素 1mgm
促性腺激素释放激素拮抗剂 2mgm
胰岛素 0.75-1.5mgm
人生长激素(GHD)) 0.25-1.5mgm
人生长激素(AIDS) 6mgm
睾酮 5-10mgm
利多卡因 2-5％
双氯芬酸钠 100-200mgm
奥昔布宁 5-15mgm
酮基布洛芬 75-200mgm
阿伦膦酸盐 10mgm
马来酸依那普利 10-40mgm
盐酸苯丙醇胺 75mgm
色甘酸钠 3.2-10mgm
异维甲酸 0.5-2mgm/Kgm
催产素 1-2u/min/iv
盐酸帕罗西丁 3.2-10mgm
氟吡洛芬 100mgm
舍曲林 50mgm
文拉法辛 75mgm
醋酸亮丙瑞林 0.125-0.25mgm
利哌利酮 4-6mgm
加兰他敏 16-24mgm
依诺肝素，抗凝剂
依那西普，类风湿关节炎
芬太尼，手术后的和慢性疼痛
非尔司亭，由于化疗产生的白细胞减低
肝素，抗凝剂
甲状旁腺激素(PTH)
生长激素，生长激素
舒马普坦，偏头痛
吗啡
鸦片剂，抗关节炎
药物可以以多种治疗速度输送，通过改变许多设计因素包括阵列的尺寸、基质的溶解速度、阵列中微穿孔器的数目和分布、贴片的尺寸、贮器的尺寸和组成以及阵列应用的频率来控制。例如，设计用于高速输送药物的装置在微穿孔器中可能有更高活性的药物和/或更快溶解的基质。为了持续的药物释放，较少的微穿孔器和/或使用(较)缓慢溶解的固体基质是有用的。所述贴片可应用于皮肤或其它组织以持续或即刻或以不同的速度在数秒到几小时或几天的时间间隔内输送药物。大多数应用RDMP穿真皮输送药物的目标在表皮，虽然通过延长贴片的刺入长度可以直接输送进入血流。
在此揭示的RDMP系统也可用于穿过皮肤以外的其它组织的控制性运送。例如，贴片可被嵌入患者眼中以控制或纠正结膜、巩膜和/或角膜的病变，用一个缓慢运转的调节器易化药物输送进入眼睛。相似地，一个嵌入眼睛的RDMP阵列可易化液体运送出眼睛，这对治疗青光眼是有益的。一个RDMP贴片也可被嵌入口腔(口用的)、鼻腔或阴道区域或在腹腔镜辅助下嵌入一组织内部或嵌入其他可接近的粘膜层以易化进入或穿过那些组织的运送。例如，一种药物可以被穿过口腔粘膜输送用于口腔内的局部治疗。另一例，RDMP阵列可在体内例如在胃肠道内膜上内部应用，以易化经口摄入的药物的吸收或在血管内膜上应用以易化药物穿透进入血管壁。在这个内部组织应用的实例中，使用生物粘性RDMP材料可产生额外的利益。
另一个重要的应用是疫苗。皮肤是有效疫苗输送的理想部位，因为它包含免疫细胞如郎格罕氏细胞的网络。RDMP技术在输送抗原化合物至含有高浓度免疫细胞的表皮从而更有效触发免疫系统的应用中具有一些优越性。对于容易地发展多价疫苗而言RDMP系统是一个实用的设计，并且预期比使用液体运输和储存药物提供更多的稳定性。其中，以下的疫苗可被输送：
B型肝炎
人类免疫缺陷病毒疫苗
流行性感冒
白喉
破伤风
百日咳
莱姆(氏)病
狂犬病
肺炎球菌
黄热病
霍乱
牛痘
结核病
风疹
麻疹
流行性腮腺炎
轮状病毒
肉毒(杆)菌
疱疹病毒
其它DNA疫苗
B型肝炎
人类免疫缺陷病毒疫苗
流行性感冒
白喉
破伤风
百日咳
莱姆(氏)病
狂犬病
肺炎球菌
黄热病
霍乱
牛痘
结核病
另一个应用领域为美容。包含贴片的RDMP系统能更有效和安全地输送A型肉毒毒素或羟酸以去除或减少皱纹的形成和皮肤的老化。该系统也可用于治疗皮肤损害和异常皮肤特征，例如常出现于面部、臂部、腿部或足部的丘疹、鸡眼、疣、胼胝、拇囊炎、光化学角化和过度角化的硬皮。RDMP系统也可用作养料贴片以输送必需氨基酸、脂肪和维生素。营养贴片常在应急时使用。
这样，特殊的实施例和速溶微穿孔器的应用已被揭示。然而，很明显地，对于该领域技术人员而言，除了所描述过的那些之外，不离开此中的发明宗旨更多的改良是可能的。因此，该发明的主题内容除了所附权利要求的宗旨内的部分外不被局限。再者，在解释详细说明和权利要求时，所有术语应以与上下文相一致的最广可能性的方式被解释。尤其，术语“包括”和“包含”应被解释为以非排除性的方式涉及元件、成分、或步骤，提示所涉及的元件、组成、或步骤可能被提出、或使用、或与其它未明确涉及的元件、成分、或步骤结合。
Claims (21)
1.一个药物输送系统，所述药物输送系统包含一个溶剂源以及一个具有多个与所述溶剂接触后，至少50％以重量计的微穿孔器在给药后1小时内溶解的微穿孔器的阵列，所述微穿孔器包括一个容纳一种或更多已选择药物的可溶解材料固体基质。
2.如权利要求1所述的药物输送系统，其中，所述药物包含在多聚物基质材料内。
3.如权利要求1所述的药物输送系统，其中，所述药物实质上100％由微穿孔器组成。
4.如权利要求1所述的药物输送系统，其中，所述药物包含一种肽或一种核酸。
5.如权利要求1所述的药物输送系统，其中，所述药物包含一种多糖。
6.如权利要求1所述的药物输送系统，其中，所述药物包含一种疫苗。
7.如权利要求1所述的药物输送系统，其中，所述微穿孔器足够长以刺入皮肤到达真皮层。
8.如权利要求1所述的药物输送系统，其中，所述微穿孔器具有实际上呈多边形的截面。
9.如权利要求1所述的药物输送系统，其中，所述微穿孔器具有实际上呈尖形的截面。
10.如权利要求1所述的药物输送系统，其中，所述微穿孔器实际上为刀片形状。
11.如权利要求1所述的药物输送系统，其中，所述微穿孔器具有不超过20μm的最小尖端直径。
12.如权利要求1所述的药物输送系统，其中，至少微穿孔器中的5个布置在面积不超过1cm2的区域内。
13.如权利要求1所述的药物输送系统，其中，所述溶剂源包含一个容纳第二药物的液体贮器。
14.如权利要求13所述的药物输送系统，其中，所述贮器包括贴片。
15.如权利要求14所述的药物输送系统，其中，所述包含在微穿孔器中的药物与包含在贴片中的药物相同。
16.如权利要求14所述的药物输送系统，其中，所述包含在微穿孔器中的药物与包含在贴片中的药物互不相同。
17.如权利要求14所述的药物输送系统，其中，所述贴片具有粘合剂周边区。
18.如权利要求1所述的药物输送系统，其中，所述溶剂源包含一种选自以下物质的化学增强剂：乙醇、酰胺、氨基酸、磷脂、砜、吡咯烷酮、表面活性剂。
19.如权利要求1所述的药物输送系统，还包含一个含有第二药物的第二微穿孔器阵列。
20.如权利要求1所述的药物输送系统，还包含一个驱动微穿孔器进入皮肤的人工操作的压力装置。
21.如权利要求1所述的药物输送系统，进一步包含一个驱动微穿孔器进入皮肤10-1000μm距离的压力装置。
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| US10/179,749 | 2002-06-25 | ||
| US10/179,749 US6945952B2 (en) | 2002-06-25 | 2002-06-25 | Solid solution perforator for drug delivery and other applications |
| US41106302P | 2002-09-16 | 2002-09-16 | |
| US60/411,063 | 2002-09-16 |
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| CN100591386C true CN100591386C (zh) | 2010-02-24 |
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| EP (1) | EP1534376B1 (zh) |
| JP (2) | JP4829497B2 (zh) |
| KR (2) | KR100993477B1 (zh) |
| CN (1) | CN100591386C (zh) |
| AU (1) | AU2003243750A1 (zh) |
| CA (1) | CA2490137C (zh) |
| DK (1) | DK1534376T3 (zh) |
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| CN114558241B (zh) * | 2021-12-31 | 2024-01-12 | 北京化工大学 | 一种基于聚合物可溶性微针的给药式内窥镜装置 |
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| US5749376A (en) | 1993-10-18 | 1998-05-12 | Wilk; Peter J. | Medical treatment and waste disposal method |
| US5542920A (en) * | 1994-09-12 | 1996-08-06 | Delab | Needle-less parenteral introduction device |
| DE19525607A1 (de) * | 1995-07-14 | 1997-01-16 | Boehringer Ingelheim Kg | Transcorneales Arzneimittelfreigabesystem |
| DK1037686T3 (da) | 1997-12-11 | 2006-01-02 | Alza Corp | Apparat til forögelse af transdermal gennemströmning af midler |
| ATE221400T1 (de) | 1997-12-11 | 2002-08-15 | Alza Corp | Vorrichtung zur erhöhung des transdermalen wirkstoffeflusses |
| US6503231B1 (en) * | 1998-06-10 | 2003-01-07 | Georgia Tech Research Corporation | Microneedle device for transport of molecules across tissue |
| WO1999064580A1 (en) * | 1998-06-10 | 1999-12-16 | Georgia Tech Research Corporation | Microneedle devices and methods of manufacture and use thereof |
| US6611707B1 (en) * | 1999-06-04 | 2003-08-26 | Georgia Tech Research Corporation | Microneedle drug delivery device |
| US6440096B1 (en) * | 2000-07-14 | 2002-08-27 | Becton, Dickinson And Co. | Microdevice and method of manufacturing a microdevice |
| US6656147B1 (en) * | 2000-07-17 | 2003-12-02 | Becton, Dickinson And Company | Method and delivery device for the transdermal administration of a substance |
| US9302903B2 (en) * | 2000-12-14 | 2016-04-05 | Georgia Tech Research Corporation | Microneedle devices and production thereof |
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- 2003-06-19 CN CN03819714A patent/CN100591386C/zh not_active Expired - Fee Related
- 2003-06-19 CA CA2490137A patent/CA2490137C/en not_active Expired - Lifetime
- 2003-06-19 AU AU2003243750A patent/AU2003243750A1/en not_active Abandoned
- 2003-06-19 KR KR1020047021103A patent/KR100993477B1/ko active IP Right Grant
- 2003-06-19 JP JP2004516176A patent/JP4829497B2/ja not_active Expired - Fee Related
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- 2003-06-19 EP EP03761282.7A patent/EP1534376B1/en not_active Expired - Lifetime
- 2003-06-19 ES ES03761282.7T patent/ES2607128T3/es not_active Expired - Lifetime
- 2003-06-19 KR KR1020107022923A patent/KR101061975B1/ko active IP Right Review Request
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9498611B2 (en) | 2011-10-06 | 2016-11-22 | Hisamitsu Pharmaceutical Co., Inc. | Applicator |
| CN104245041A (zh) * | 2012-04-05 | 2014-12-24 | 久光制药株式会社 | 穿刺装置及其制造方法 |
| TWI566796B (zh) * | 2012-04-05 | 2017-01-21 | Hisamitsu Pharmaceutical Co | Puncture device |
Also Published As
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|---|---|
| KR20050019789A (ko) | 2005-03-03 |
| JP2006500973A (ja) | 2006-01-12 |
| WO2004000389A3 (en) | 2004-03-04 |
| JP4829497B2 (ja) | 2011-12-07 |
| CA2490137C (en) | 2012-01-03 |
| KR100993477B1 (ko) | 2010-11-11 |
| AU2003243750A8 (en) | 2004-01-06 |
| WO2004000389A2 (en) | 2003-12-31 |
| JP5323657B2 (ja) | 2013-10-23 |
| ES2607128T3 (es) | 2017-03-29 |
| CN1674954A (zh) | 2005-09-28 |
| EP1534376A4 (en) | 2013-10-02 |
| CA2490137A1 (en) | 2003-12-31 |
| WO2004000389A9 (en) | 2004-06-10 |
| KR101061975B1 (ko) | 2011-09-05 |
| AU2003243750A1 (en) | 2004-01-06 |
| DK1534376T3 (en) | 2016-12-05 |
| JP2010046548A (ja) | 2010-03-04 |
| KR20100115393A (ko) | 2010-10-27 |
| EP1534376B1 (en) | 2016-08-31 |
| EP1534376A2 (en) | 2005-06-01 |
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