CN100467083C - 微突出物阵列免疫贴剂和方法 - Google Patents
微突出物阵列免疫贴剂和方法 Download PDFInfo
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- CN100467083C CN100467083C CNB028123743A CN02812374A CN100467083C CN 100467083 C CN100467083 C CN 100467083C CN B028123743 A CNB028123743 A CN B028123743A CN 02812374 A CN02812374 A CN 02812374A CN 100467083 C CN100467083 C CN 100467083C
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Abstract
披露了一个具有微突出物阵列(10)、装有免疫原性试剂和免疫应答增强佐剂的储存器(18)的皮肤贴剂(20),以及使用所述贴剂对动物(例如人类)进行免疫的方法。在一种优选实施方案中,微突出物阵列(10)由光蚀刻的和显微穿孔的钛箔(14)构成。用含有疫苗抗原和诸如葡糖胺胞壁酰二肽的佐剂的液体制剂涂布微突出物(12),干燥,并且使用冲击性施用器将其施用在要免疫的动物皮肤上。微突出物(12)产生通过角质层的表面途径,以便有利于抗原性试剂和佐剂的渗透。可以控制抗原剂量和渗透深度。该方法可广泛应用于多种治疗性疫苗,以便提高效力,并且使用方便。
Description
对相关申请的交叉引用
本发明要求2001年4月20日提交的美国专利申请流水号60/285572和2001年12月20日提交的美国专利申请流水号60/342552的优先权。
背景技术
可以通过各种施用途径进行免疫,包括口服、鼻、肌内(IM)、皮下(SC)、和皮内(ID)途径。已经有大量文献记载,施用途径可以影响免疫应答的类型。参见LeClerc等,“对在重组细菌表面表达的外源表位的抗体应答:免疫途径的重要性”Vaccine,1989.7:pp242-248。
大部分商业疫苗是通过IM或SC途径施用的。尽管高速液体喷射注射器业已取得了某些成功,在几乎所有场合下,这些疫苗都是用注射器和针头,通过常规注射施用的。例如,参见Parent du Chatelet等,Vaccine,Vol.15,pp449-458(1997)。
近年来,人们对开发无针头疫苗递送系统的兴趣逐渐增加。不同的实验室业已证实了对包括基于蛋白和DNA的抗原在内的大分子的无针头免疫。Glenn等证实了将含有与佐剂、霍乱毒素混合的破伤风类毒素的溶液涂在未处理过皮肤上能够诱导抗霍乱毒素抗体。Glenn等,Nature,Vol.391,pp851(1998)。Tang等证实了表面施用编码人癌胚抗原的腺病毒载体能诱导抗原特异性抗体。Tang等,Nature,Vol.388,pp 729-730(1997)。Fan等也证实了表面施用编码乙型肝炎表面抗原的裸露DNA能够诱导细胞和体液免疫应答。Fan等,Nature Biotechnology,Vol.17,pp 870-872(1999)。
皮肤是已知的免疫器官,例如,参见Fichtelius,等,Int.Arch.Allergy,1970,Vol.37,pp607-620,和Sauder,J.Invest.Dermatol,1990,Vol.95,pp 105s-107s。进入皮肤的病原体要面对特化细胞的高度组织化的和多样化的群体,这些细胞群能通过多种机制清除微生物。表皮朗氏细胞是有效的抗原呈递细胞。淋巴细胞和真皮巨噬细胞能渗透通过皮肤。角质形成细胞或朗氏细胞表达或可以被诱导产生多种免疫活性化合物。总而言之,所述细胞协调一系列复杂的事件,这些事件最终控制了先天的和特异的免疫应答。实际上,业已探索过用该器官作为免疫途径。例如,参见Tang等,Nature,1997,Vol.388,pp729-730;Fan等,Nature Biotechnology,1999Vol.17,pp 870-872;和Bos,J.D.,ed.Skin Immune System(SIS),Cutaneous Immunology and Clinical Immunodermatology,2nd Ed.,1997,CRC Press,pp 43-146。一份最近的报导披露了用贴剂进行经皮免疫。参见Glenn等,“经皮免疫:使用贴剂的人类疫苗递送方法”Nature Medicine,Vol.6,No.12,December 2000,pp 1403-1406。不过,迄今为止,尚未开发出用于将抗原特异性地递送到人类表皮和/或真皮中的可行的、可靠的、和伤害最小的方法。用常规针头进行皮内注射的一个显著制约是,需要很高水平的眼-手协调和手指灵活性。
皮肤的主要屏障——角质层,是亲水性和高分子量药物和诸如蛋白、裸露DNA和病毒载体的大分子不能渗透的。因此,经皮递送一直被局限于被动递送具有有限亲水性的低分子量化合物(<500道尔顿)。
为了避开角质层屏障,业已评估了多种方法。化学渗透增强剂、脱毛剂、包含体和水合技术,可以提高皮肤对大分子的渗透性。不过,所述方法在没有很长的附着时间的情况下不能递送治疗剂量,并且,它们是效力较低的递送方法。另外,在非刺激性浓度下,化学渗透增强剂的效果是有限的。业已评估了渗透增强的物理方法,包括砂纸摩擦,胶带剥离,和分叉的针头。尽管上述技术能提高渗透性,但是难于预测它们对药物吸收影响的程度。另一种物理渗透增强剂,激光剥离,可以提供可再现性更高的效果,但是,目前该技术烦琐并且昂贵。经皮递送的主动方法包括离子电渗、电穿孔、sonophoresis,和含有固体药物的颗粒的轰击递送。使用主动运输(例如sonophoresis)的递送系统正在开发之中,并且用该系统可以递送大分子。不过,在现阶段,尚不了解所述系统是否能在人体内成功地和可再现地递送大分子。
正在开发微突出物(microprojection)阵列贴剂技术,以便增加可以通过皮肤经皮递送的药物的数量。在施用时,微突出物能产生穿过皮肤的运送障碍(角质层)的表面途径,以便促进亲水性和大分子递送。
发明说明
具有多个角质层穿刺微突出物的微突出物阵列被用于皮内递送抗原性试剂和免疫应答增强佐剂,以便在哺乳动物体内,特别是在人体内诱导有效免疫应答。免疫应答增强佐剂是以能有效增强皮肤对抗原性试剂的免疫应答的量皮内递送的。所述佐剂的使用,优选可以递送较少数量的抗原性试剂,但仍然能在患者体内获得治疗有效的抗原抗体滴度,即剂量节省效果。
所述抗原性试剂优选包括疫苗抗原,所述抗原通常是蛋白、多糖、寡糖、脂蛋白和/或减毒或灭活病毒形式的。用于本发明的特别优选的抗原性试剂包括肝炎病毒、肺炎疫苗、流感疫苗、鸡痘疫苗、天花疫苗、狂犬病疫苗和百日咳疫苗。
免疫应答增强佐剂优选选自已知能增强哺乳动物对抗原的免疫应答,并且不会促进患者体内的不良皮肤反应的材料。最优选的是Gerbu佐剂:N-乙酰葡糖胺-(β1-4)-N-乙酰胞壁酰-L-丙氨酰-D-谷氨酰胺(GMDP)。
含有抗原性试剂和免疫应答增强佐剂的储存器可以是凝胶材料,优选是层压在微突出物阵列上的薄膜形式,不过,更优选是作为涂层直接涂在微突出物上的材料。最优选的是将所述涂层仅涂在微突出物的皮肤穿刺尖端。
在使用时,将微突出物阵列施用在要免疫的动物皮肤上,并且将所述阵列压在动物皮肤上,导致微突出物刺穿皮肤的最外层(即角质层)。最优选的是,用施用器将微突出物阵列施用在要免疫的动物皮肤上,所述施用器能将微突出物阵列冲击在皮肤上,导致微突出物刺穿皮肤。根据本发明,为了皮内递送抗原性试剂和佐剂,微突出物应当刺穿角质层,并且进入下面的表皮和皮肤的真皮层。所述微突出物优选不穿透皮肤达到导致明显出血的深度。为了避免出血,微突出物穿刺皮肤的深度应当小于大约400微米,优选小于大约200微米。微突出物产生通过角质层的表浅通路,以便有利于抗原性试剂和佐剂的渗透。抗原剂量和微突出物穿透的深度可方便地加以控制。这种皮内疫苗和免疫动物的方法可广泛应用于多种治疗性疫苗,以便提高效力,并且使用方便。
附图简述
图1是本发明微突出物阵列的透视图;
图2是在微突出物上具有含固体抗原的涂层的微突出物阵列的透视图;
图3是在实施例1中使用的皮内抗原递送装置的侧面剖视图;
图4是表示在动物皮肤中微突出物的皮肤穿透深度的曲线图;
图5是在实施例1中进行的研究的卵清蛋白递送与时间的曲线图;
图6是来自通过微突出物阵列递送用OVA免疫的各个豚鼠的卵清蛋白-特异性抗体(IgG)滴度与时间的曲线图,其中,箭头表示初次免疫和加强免疫的时间;
图7是用OVA免疫的无毛豚鼠的卵清蛋白特异性抗体(IgG)的曲线图,比较了微突出物递送和皮内、皮下和肌内递送;
图8是在加强免疫之后1周用单独的OVA,以及同时用免疫应答增强佐剂免疫的豚鼠的抗体(IgG)滴度的曲线图,比较了通过微突出物阵列的递送和皮内注射;
图9是表示涂在微突出物阵列上的卵清蛋白量,以及在附着5秒钟和1小时之后递送到动物体内的卵清蛋白数量的曲线图,如在实施例2中的详细讨论;
图10是表示用实施例2所述方法获得的卵清蛋白递送效力的曲线图;
图11是比较卵清蛋白涂布的微突出物阵列和通过皮内注射施用的若干种剂量卵清蛋白的抗体滴度的曲线图;和
图12是表示涂在微突出物阵列上的GMDP和卵清蛋白的数量,和随各种附着时间递送到动物体内的数量的曲线图,如例2所述。
实施本发明的方式
本发明提供了一种皮内疫苗,以及通过皮内递送免疫原性试剂和免疫应答增强佐剂用于免疫动物的方法。术语“皮内(intradermal,intracutaneous,intradermally,intracutaneously)”在本文中被用于表示将抗原试剂(如疫苗抗原)和佐剂递送到皮肤中,特别是递送到皮肤的表皮层和/或下面的真皮层。
术语“微突出物”表示穿刺部件,它适合剌穿或切割活的动物,特别是人类皮肤的角质层,进入下面的表皮层、或表皮层和真皮层。所述穿刺部件应当不会将皮肤穿刺到会导致出血的深度。通常,所述穿刺部件具有小于500微米,并且优选小于250微米的微突出物长度。所述微突出物的宽度通常为大约75-500微米,厚度为大约5-50微米。可以将微突出物制成不同的构形和/或形状,如针头、空心针头、刀片、钉、打孔器及其组合。
此处使用的术语“微突出物阵列”是指排列成阵列,用于刺穿角质层的多个微突出物。微突出物阵列可以通过用一种薄的片材蚀刻或穿刺多个微突出物,并且将所述微突出物折叠或弯曲离开所述片材的平面,形成如图1所示以及在Trautman等的US 6,083,196中所披露的构形而制成。所述微突出物阵列还能够以其他已知方式形成,如通过形成一个或多个条,沿每一个条的边缘具有微突出物,如Zuck的美国专利6,050,988中所披露的。在以下专利中披露了其他微突出物阵列及其生产方法:Godshall等,US 5,879,326和Kamen,US5,983,136。所述微突出物阵列还可以是多个空心针头形式的,所述针头装有干燥抗原性试剂和佐剂。
本发明的皮内疫苗包括一种微突出物阵列,它具有多个由其延伸的角质层穿刺微突出物,并且具有一个装有抗原性试剂(例如疫苗抗原)和免疫应答增强佐剂的储存器。该储存器相对于所述微突出物的位置是与由所述穿刺微突出物在角质层上切割的缝形成抗原性试剂和佐剂传递关系。在一种实施方案中,所述储存器可以是层压在微突出物阵列的皮肤近端或皮肤远端侧的聚合物薄膜形式的材料(例如凝胶材料)。这种类型的储存器披露于Theeuwes等的WO 98/28037中,该专利的内容被收作本文参考。更优选将抗原性试剂和佐剂在涂层中直接施用在微突出物上,最优选施用在微突出物的穿刺尖端。用于施用这种涂层的合适的微突出物涂层和装置,披露于以下美国专利申请流水号中:2001年10月26日提交的10/045,842;2001年3月15日提交的10/099,604;以及从属于2001年4月20日提交的美国临时申请流水号60/285,576并且与之同时提交的另一份申请,以上申请的内容被收作本文参考。所述微突出物适合穿刺角质层,并且进入下面的表皮层或表皮层和真皮层,但是,优选不会穿刺过深而到达毛细血管床,并导致明显出血。通常,微突出物的长度可以穿透皮肤达到小于大约400微米的深度,并且优选小于大约300微米。在穿刺皮肤的角质层时,容纳在涂层中的抗原性试剂和佐剂被释放到皮肤中,进行免疫治疗。
图1表示用于本发明的角质层穿刺微突出物部件10的一种实施方案。图1表示具有多个微突出物12的部件10的一部分。微突出物12以大体上90度的角度从具有开口16的片材14上延伸。可以将部件10整合在试剂递送或取样系统20(如图3所示)上,包括一个背衬22,和用于将系统粘在皮肤上的粘合剂24。在图1、2和3所示的微突出物部件10的实施方案中,微突出物12是通过以下方法制成的:用一个薄的金属片材14蚀刻或穿刺多个微突出物12,并且使微突出物12弯曲偏离开所述片材的平面,诸如不锈钢和钛的金属是优选的。金属微突出物部件及其生产方法披露于以下专利中:Trautman等,美国专利6,083,196;Zuck美国专利6,050,988;和Daddona等,美国专利6,091,975,以上专利的内容被收作本文参考。可用于本发明中的其他微突出物部件是通过以下方式生产的:通过硅芯片蚀刻技术蚀刻硅,或通过用蚀刻的微型模具模制塑料。Godshall等在美国专利5,879,326中披露了硅和塑料微突出物部件,该专利的内容被收作本文参考。
图2表示具有微突出物12的微突出物部件10,它具有一种含有抗原的涂层18。涂层18可以部分或完全覆盖微突出物12。可以通过将微突出物浸入蛋白抗原以及任选含有任何免疫应答增强佐剂的挥发性液体溶液或悬浮液中,将所述涂层施用在微突出物12上。所述液体溶液或悬浮液的抗原性试剂的浓度应当为大约1-20wt%。所述挥发性液体可以是水、二甲亚砜、二甲基甲酰胺、乙醇、异丙醇及其混合物。其中,最优选的是水。
可用于本发明的合适的抗原性试剂包括蛋白、多糖、寡糖、脂蛋白、减毒或灭活病毒形式的抗原,所述病毒如巨细胞病毒、乙型肝炎病毒、丙型肝炎病毒、人类乳头瘤病毒、风疹病毒、和水痘-带状疱疹病毒;减毒或灭活细菌,如百日咳杆菌、破伤风梭菌、白喉棒杆菌、A族链球菌、侵肺军团菌、脑膜炎萘氏球菌、铜绿假单胞菌、肺炎链球菌、苍白密螺旋体、和霍乱弧菌及其混合物。多种含有抗原性试剂的现已商业化的疫苗也可用于本发明中,并且包括流感疫苗、莱姆病疫苗、狂犬病疫苗、麻疹疫苗、腮腺炎疫苗、鸡痘疫苗、天花疫苗、肝炎疫苗、百日咳疫苗和白喉疫苗。
可以与抗原性试剂一起用于本发明的合适的免疫应答增强佐剂包括磷酸铝凝胶、氢氧化铝;藻类葡聚糖、β-葡聚糖;霍乱毒素B亚基、热激蛋白(HSPs);γ菊粉,GMDP(N-乙酰葡糖胺-(β1-4)-N-乙酰胞壁酰-L-丙氨酰-D-谷氨酰胺);GTP-GDP;Imiquimod;ImmTherTM(DTP-GDP);Loxoribine,MTP-PE;Murametide;Pleuran(β-葡聚糖);Murapalmitine;QS-21;S-28463(4-氨基-α,α-二甲基-1H-咪唑并[4,5-c]喹啉-1-乙醇);Scalvo肽(IL-1β[β163-171肽];和TheramideTM。
本发明的微突出物阵列皮内疫苗优选在冲击条件下施用在患者皮肤上。例如,可以用由Trautman等在2001年10月12日提交的美国专利流水号09/976,798中所披露类型的偏压(例如弹簧驱动)冲击性施用器施用本发明的涂布过的微突出物阵列。最优选的是,所述涂布过的微突出物阵列是以在10毫秒或更短时间内每平方厘米的微突出物阵列至少0.05焦耳的冲击力施用的。
用于本发明的优选的含有抗原性试剂和含有佐剂的储存器是直接施用在微突出物表面上的固体涂层形式的。所述涂层优选以液态施用,然后干燥。可以通过浸泡、喷雾和/或其他已知微流化分散技术将含有抗原性试剂和佐剂的所述挥发性液体溶液或悬浮液施用在所述微突出物阵列上。然后让所述涂层干燥,以便形成含有抗原和佐剂的固体涂层。优选仅在微突出物阵列的刺穿皮肤组织的部分涂布抗原性试剂。Trautman等在2002年3月15日提交的美国专利申请流水号10/099,604中披露了合适的微突出物涂布方法和装置,该专利申请的内容被收作本文参考。使用该专利所披露的涂布方法和该专利所披露的涂布组合物,我们能够精确地并且均匀地仅对典型的金属(即钛)的微突出物阵列上的皮肤穿刺微突出物的尖端进行涂布,所述微突出物阵列的微突出物长度小于500微米。
尽管按照本发明通过皮内递送的佐剂和抗原性试剂的相对量可以根据被递送的具体抗原性试剂和佐剂而改变,通常,被递送的佐剂和被递送的抗原的重量比例为大约0:5-50:1,更优选为大约1:1-10:1。为了获得上述佐剂:抗原性试剂的递送比例,所述储存器优选装有与上文所述相同重量比的抗原性试剂和免疫应答增强佐剂。
另外,通过微突出物尖端涂层,可以方便地获得每平方厘米微突出物阵列至少0.2微克的抗原性试剂和佐剂加载量,优选每平方厘米微突出物阵列至少2微克。对于典型的5平方厘米的阵列来说,可以换算出至少1微克的抗原性试剂和佐剂加载量,并且优选至少10微克,对于大部分免疫来说,这是非常合适的。使用通过抗原性试剂和佐剂涂布的微突出物尖端,大大提高了递送效率(Edel)。Edel被定义为在每一个预定时间段内从所述涂层中释放出的抗原性试剂和佐剂的重量百分比。通过含有抗原性试剂和佐剂的溶液或悬浮液的尖端涂层,可以在1小时内获得至少30%的Edel,优选在15分钟内获得至少50%的Edel。因此,本发明与现有技术中所采用的常规macrotine皮肤穿刺装置相比具有显著的成本优势。
在以下实施例中,将用豚鼠评估微突出物皮肤穿透深度、模型抗原(即OVA)递送,和皮内递送模型抗原以便刺激免疫应答的能力。在以下实验中,微突出物穿透皮肤的平均深度为大约100微米。通过改变涂布溶液浓度、附着时间、和系统尺寸,获得了不同的OVA剂量。通过2平方厘米的微突出物阵列,递送了1-80微克的OVA,并且获得了在5秒时间内的高达20微克的递送速度。诱导了剂量依赖型一级和二级抗原特异性抗体应答。在1和5微克的剂量下,抗体应答与皮内施用所出现的抗体应答相同,而比在皮下或肌内施用之后出现的抗体应答高50倍。佐剂GMDP与OVA的固体涂层导致了增强的抗体应答。因此,微突出物阵列贴剂技术可以经皮施用干燥抗原。
用微突出物阵列控制皮内OVA递送,是通过改变涂层溶液的浓度、附着时间、和系统尺寸而实现的,并且以上变量的组合使得在剂量方面可以有更大的灵活性。以上结果还可应用于其他蛋白抗原。另外,由于大部分化合物在干燥状态下更稳定,微突出物阵列技术具有消除冷冻链储存的潜力。
豚鼠对微突出物阵列系统具有相当好的耐受力。在初次免疫之后,轻微的和临时施用部位红斑与微突出物很浅地穿透皮肤是一致的。在用微突出物阵列或ID注射进行加强施用之后,中等程度的红斑和水肿表明出现了混合的免疫应答。
实施例1
免疫研究具有两个目的:测定用微突出物阵列在无毛豚鼠(HGPs)体内递送各种量的OVA所导致的免疫应答,并且比较使用低含量OVA和GMDP佐剂一起用微突出物阵列进行免疫的结果。远交的雄性和雌性有胸腺HGP是从Biological Research Labs(Switzerland,ibm:GOHI-hr株)和Charles River Labs(Michigan,IAF:HA-HO-hr株)获得的。动物重量为250-1000克。对动物进行检疫,单独圈养,并且在得到Association for Assessment and Accreditation ofLaboratory Animal Care认可的设施中保持。本研究遵守Principlesof Laboratory Animal Care(NIH publication#85-23,1985年修订)的规定。
用于这些研究的微突出物阵列在1或2平方厘米的面积上具有密度为190个微突出物/平方厘米的330微米的突出物。所述微突出物阵列是使用受控制的生产工艺生产的,该生产工艺采用了自动CAD-产生的微突出物阵列设计,光化学蚀刻和成型。首先,在大约30微米厚的钛片材上施加一薄层抗蚀膜。用一种具有理想样式的掩模对所述抗蚀膜进行接触-暴露。并且通过一种非常类似于用于生产印刷电路板的方法进行显影。然后对显影的片材进行酸蚀刻,并且使用成型工具使微突出物相对所述片材的平面弯大约90度的角。所形成的微突出物阵列是具有图1所示精密微突出物的筛。
用卵清蛋白(OVA)和葡糖胺胞壁酰二肽(GMDP)涂布微突出物阵列,或仅使用OVA作为对照。对于用GMDP(Pharmitra,UnitedKingdom)进行的研究来说,将微突出物阵列浸泡在含有OVA(1%)和GMDP(10%)的溶液中。对于仅用OVA进行的对照研究来说,通过浸泡在含有1%,5%或20% OVA(Grade V,SIGMA Chemical Co,St Louis,MO)的无菌水中,用OVA对所述阵列进行涂布。通过强制通风除去多余的溶液,并且在室温下将所述阵列风干1小时或1小时以上。对于使用荧光素异硫氰酸酯(FITC)-标记的OVA(Molecular Probes,Portland,OR)进行的研究来说,将单独的荧光化合物用于含有5%OVA或更低含量的任何涂布溶液。对于浓度为20%的OVA涂布溶液来说,将未标记过的OVA(15%)与FITC-OVA(5%)混合。
用FITC-OVA测定涂布在微突出物阵列上的OVA的量。涂在所述装置上的干燥OVA,是通过将该装置在室温下在玻璃闪烁小瓶中的10毫升硼酸(0.1M,pH9)中浸泡1小时进行萃取的。用硼酸对萃取材料的等份试样进行进一步稀释,以便通过发光光谱相对已知标准物进行定量(激发波长494nm,发射波长520nm)。还通过荧光显微技术,检查了用FITC-OVA涂布的微突出物阵列。
在涂布和干燥之后,用聚异丁烯粘合剂将微突出物阵列固定在低密度聚乙烯背衬上。最终的系统具有图3所示的结构,总面积为8平方厘米,并且所述阵列的皮肤接触面积为1平方厘米或2平方厘米。
用异丙醇拭子(70%)清洁麻醉HGPs的治疗部位(胸侧面),并使其干燥。在用冲击性施用器施用所述系统时,用手略微拉伸所述皮肤部位。在施用之后,解除所述拉伸张力,并且让该系统留在皮肤上规定的时间。对于在皮肤上保持5秒钟以上的装置来说,用(3M,St Paul,MN)包裹HGPs,并且单独圈养。
为了评估微突出物的穿透深度,在施用之后马上去掉该系统,并且用蘸有印度墨水的棉签对所述皮肤部位进行染色。所述染料以圆形运动的方式沿两个相反的方向施用大约15秒时间。然后用纱布擦掉多余的染料,并且用异丙醇拭子除去皮肤上的所有染料,直到仅仅可以看到由微突出物阵列所产生的通道。然后,对HGPs实施安乐死,除去所述皮肤部位,并且冷冻。用一个8毫米的活检打孔器对每一个冷冻的皮肤部位进行活检。平行于皮肤表面对活检组织进行切片,第一个切片为20微米,而其余的为50微米。然后将各个皮肤切片封固在显微镜载玻片上,并且统计每一切片上染色孔的数量。根据所述统计数据和微突出物的已知密度,计算出在特定皮肤切片上染色的通道的百分比,并且作为深度的函数进行作图。在某些研究中,用摄像显微镜系统(Hi-Scope KH2200,Hirox Co,Japan)对皮肤进行照相。
每一只HGP接受一个干燥涂布的FITC-OVA微突出物阵列,该阵列是按上述方法施用的。在除去系统之后,用70%的异丙醇充分洗涤处理过的皮肤部位,以便除去皮肤表面上任何残留的OVA。对HGPs实施安乐死,并且采集8毫米的皮肤活组织。将每一个组织样品放入装有0.1毫升去离子水的闪烁小瓶中。然后添加氢氧化季铵盐(0.9mL,1M,溶解在甲醇中,JT Baker,Phillipsburg,NJ),并且在60℃下温育该样品过夜。然后,用2毫升氢氧化季铵盐/水(9:1)进一步稀释溶解的材料,并且通过荧光测定对荧光进行定量,并且与已知标准物进行比较。本底对照样品包括未处理过的皮肤。将最少三个重复用于每一种实验条件。
在免疫当天之前,从每一只动物体内获得基线血液样品。在免疫当天对HGPs进行麻醉,并且用70%的异丙醇清洁处理部位,并使其干燥。对于通过针头注射进行的免疫来说,将OVA溶解在无菌水中。使用具有25号针头的无菌1毫升注射器(Becton Dickinson,FranklinLakes,NJ)。ID和SC注射是在HGPs的后背侧面进行的。将后腿的四头肌用于IM注射。按上述方法施用包括干燥涂布的OVA的微突出物阵列。
每只HGP进行一次初次免疫(第0天),4周之后进行第2次(即加强)免疫,使用相同的工具。在初次免疫之后,对HGPs进行麻醉,并且从前腔静脉中采集血液。通过免疫测定评估血清样品中抗OVA抗体的存在。
通过酶联免疫测定(ELISA)检测来自未免疫过的和免疫过的HGPs的血清中抗OVA抗体的存在。简单地讲,用0.1毫升/孔的OVA(10μg/mL,溶解在0.2M的碳酸氢钠/碳酸钠缓冲液中,pH9.6)涂布96孔聚丙乙烯平板(Maxisorp,NUNC,Rochester,NY),并且在4℃下温育过夜。用PBS-Tween缓冲液洗涤平板,然后用200微升的PBS/酪蛋白(0.5%)/Tween-20(0.05%)缓冲液在室温下封闭1小时。然后再次洗涤所述平板,并且添加测试血清(100微升/孔,2-5倍的系列稀释比例,3次重复,在室温下温育1小时)。在洗涤之后,添加100微升过氧化物酶偶联的山羊抗豚鼠IgG抗体(JacksonImmunoResearch Laboratories,West Grove,PA),并且在室温下温育1小时。在温育之后洗涤平板,添加100微升底物(ABTS,BectonDickinson,Franklin Lakes,NJ),并且在室温下温育35分钟。用SpectraMAX 250(Molecular Devices Corporation,Sunnyvale,CA)测定吸光度(405/490nm)。结果以相对未免疫对照血清样品的终点抗体滴度形式表达。
结果是以平均值以及平均值的相关标准误形式提供的。通过方差分析(ANOVA),进行各组结果之间的比较。
将微突出物阵列贴剂施用在HGP上,并且肉眼评估皮肤红斑、浮肿和出血的迹象。与未处理过的皮肤相比,在施用过程之后,通常观察到了检测不到的红斑至轻度反应。所形成的所有红斑都是暂时的,通常会在24小时或更短时间内消除。没有出现水肿或出血的现象。用印度墨水技术评估微突出物穿透力,表明95%以上的微突出物穿透了角质层屏障。另外,观察到了相对均匀的穿透形式。从处理过的部位采集的皮肤活检样品表明大约50%的微突出物穿透了大约100微米的深度(图4)。没有微突出物能穿透300微米以上的深度。
提高涂布溶液中OVA的浓度,会导致OVA在微突出物阵列上的加载量增加。采用1%OVA涂布溶液,OVA的涂布量大约为7微克/平方厘米。用5%OVA涂布溶液涂布的微突出物阵列含有大约40微克/平方厘米的干燥涂布OVA,而用含有20%OVA的涂布溶液涂布的微突出物阵列,含有大约240微克/平方厘米的干燥涂布OVA(表1)。通过荧光显微术观察发现,所述涂层是作为薄的无定形玻璃形式存在的。在最大浓度下,平均计算厚度为大约3微米,这一结果与显微镜观察结果吻合。通过施用在HGP皮肤上的系统,用5秒钟时间评估通过2平方厘米的涂有三种OVA浓度的微突出物阵列递送的OVA。所述研究证实,1%、5%和20%的OVA涂布溶液分别导致了平均为大约1、6和10微克/平方厘米的蛋白递送量(表1)。
表1
涂在微突出物阵列上并且递送到无毛豚鼠皮肤中的卵清蛋白量a
卵清蛋白涂层浓度(%) | 涂在微突出物阵列上的卵清蛋白量(微克/平方厘米;平均值±SEM) | 递送的卵清蛋白量(微克/平方厘米;平均值±SEM) |
1 | 7.4±0.6 | 0.9±0.1 |
5 | 42.2±1.9 | 5.8±1.4 |
20 | 238±20 | 9.9±0.6 |
用荧光素异硫氰酸酯(FITC)-标记的卵清蛋白对微突出物贴剂阵列(2平方厘米)进行涂布。将该阵列施用在无毛豚鼠(n=3)上5秒钟时间。
使用用20%OVA溶液涂布的2平方厘米的装置,蛋白向皮肤的递送随着施用时间的延长而增加(图5)。5秒钟的施用时间能将大约20微克的OVA递送到皮肤中。30分钟的施用时间能递送大约50微克的OVA,1小时的施用时间能递送大约80微克。以上结果表明了递送量受时间影响的线性关系。
进行了免疫研究,以便确定通过微突出物阵列递送OVA是否能在HGPs体内诱导免疫应答。将动物分成四个处理组(n=3-5/组),接受1,5,20或80微克的OVA/组。按照递送研究所确立的方案进行。表2归纳了OVA涂层浓度,贴剂附着时间,以及用于递送大致剂量抗原的装置表面积。
表2
从卵清蛋白涂布的微突出物阵列向无毛豚鼠皮肤中递送卵清蛋白
每一只HGP接受初次免疫。4周之后在相同的激发条件下进行加强免疫。为了通过ELISA测定OVA-特异性抗体(IgG)的含量,每隔一周从每只动物体内采集血清。
在图6中示出了每一只HGP对通过微突出物递送的1,5,20和80微克OVA的免疫应答。在初次免疫之后2周,观察到了相对低含量的OVA特异性抗体。在随后的四周时间,观察到了抗体滴度的普遍提高。随着抗原剂量的加大,以及随着时间的延长,血清转变速度加快。在初次免疫之后2周,所有接受20或80微克剂量OVA的动物都发生了血清转变。在加强免疫之后,在所有测试过的剂量下,所有动物都发生了血清转变。在加强免疫之后1周,观察到了抗体的显著增加。一般,在加强免疫之后1周,观察到峰抗体滴度。然后,抗体滴度降低,直到进行下一次加强治疗。
为了比较用微突出物阵列进行的免疫和常规ID,SC和IM注射进行的免疫,进行了其他研究。测试过的OVA剂量为1,5,20和80微克。在初次免疫之后采集的血清样品表明,对用针头施用OVA的抗体应答的动力学类似于用微突出物阵列观察的结果。在所有处理组中,0VA剂量的提高,导致了OVA-特异性抗体滴度的提高。在初次免疫之后,较高的抗体剂量与较高的血清转变速度相关(数据未发表)。除了少数几只用低剂量OVA免疫的动物(即SC,1微克,IM,1微克和5微克)之外,所有其他的HGPs在加强免疫之后2周,都具有可检测的抗OVA抗体。
进行ANOVA,以便评估在各个处理组之间的可能的差异,在加强免疫之后1周分析抗体滴度(图7)。所有抗原递送方法都出现了明显的剂量反应作用。通过微突出物阵列用20或80微克OVA免疫的动物所具有的抗体滴度与通过常规ID,SC或IM注射免疫的动物的抗体滴度相当。通过微突出物阵列接受5微克OVA的动物所具有的抗体滴度明显高于(24倍)通过IM针头施用所观察到的滴度。通过微突出物阵列递送1微克剂量的OVA导致了比SC(10倍)或IM(50倍)注射途径更高的抗体水平。
为了测定与佐剂共同配制并且干燥涂布在微突出物阵列上的OVA是否能增强抗体应答,进行了有关研究。用由OVA和GMDP干燥涂布的微突出物进行的免疫研究,递送了大约1微克的OVA,同时递送了大约15微克GMDP,并且导致了与无佐剂对照相比抗体滴度的明显提高。在ID施用之后,抗体滴度的提高为250%。在微突出物阵列施用之后,抗体滴度的提高为1300%(图8)。
通过共同递送佐剂GMDP,可以增强递送低剂量(1微克)抗原的抗体应答。用OVA和GMDP干燥涂布的阵列进行的递送研究表明,佐剂的存在不会明显影响所递送的OVA量(数据未发表)。尽管不能直接定量用微突出物阵列递送到皮肤中的GMDP的量,根据质量传递计算估计有大约15微克的GMDP被递送到皮肤中。在该剂量下,GMDP在ID和微突出物施用途径中加强了抗体应答,但是在通过微突出物阵列共同施用GMDP和OVA之后的作用明显更大。另外,通过微突出物阵列递送的GMDP和OVA所产生的抗体滴度接近在没有GMDP的条件下用20微克或更高剂量的OVA所获得的抗体滴度水平,这证实了显著的剂量节省效应。在这种情况下,所观察到的微突出物阵列递送和ID之间的增强作用的差异是无法理解的,不过,可能是在ID或微突出物阵列施用之后抗原和佐剂在皮肤的不同层中定位的微小差异所导致的。事实上,实验业已证实,在微突出物阵列递送之后,OVA主要定位于表皮层中(数据未发表)。这种优选的定位,可能导致诸如朗氏细胞的相关的表皮细胞暴露于所述佐剂增加,这有可能引发增强的激活作用。
HGP能很好地耐受微突出物阵列。在初次免疫之后,在施用部位出现的红斑很轻微,并且在24小时内消失。另外,在任何动物上都没有出现感染的迹象。在通过微突出物阵列或ID注射进行加强施用之后,观察到了中度皮肤红斑和水肿。这种皮肤反应迅速出现,并且持续数天时间,这表明出现了混合的免疫应答。
所述皮肤富含抗原呈递细胞和皮肤相关的淋巴组织,这使得它成为理想的免疫靶位。实际上,有很多研究业已证实,ID或表皮施用抗原,能导致有效的免疫应答,并且与其他施用途径相比具有剂量节省效果。不过,常规ID施用的明显限制是,难以精确控制穿透的深度,需要熟练的技术人员。我们的结果表明,涂布在微突出物阵列上的OVA能够以可再现的方式递送到皮肤内。另外,通过微突出物阵列递送OVA,诱导了特异性免疫应答。用涂在微突出物阵列上的干燥抗原产生了一级和二级抗原特异性抗体应答。所述应答是剂量依赖型的。针对通过微突出物阵列系统施用的OVA的抗体应答动力学,类似于用常规注射方式观察到的结果。1和5微克剂量的微突出物施用所产生的免疫应答,比用相同的剂量皮下或肌内注射所产生的免疫应答强50倍。将佐剂、葡糖胺胞壁酰二肽、和OVA干燥涂布在微突出物上,导致了增强的抗体应答。
实施例2
制备了含有20wt%卵清蛋白的水溶液。为了进行随后的分析,用FITC标记卵清蛋白。微突出物阵列(微突出物长度为250微米,每个阵列有595个微突出物)的面积为2平方厘米。使用2002年3月15日提交的共同未决的美国专利申请流水号10/099,604中所披露的装置和方法,通过让微突出物阵列通过携带有OVA溶液的转筒,用该溶液涂布微突出物的尖端。在某些阵列上,进行了多次涂布。荧光显微术发现,在所有情况下,所述涂层都局限于微突出物尖端的前100微米。通过荧光测定进行定量,证实了在1次、2次和4次涂布之后,分别将1.8微克,3.7微克和4.3微克的量涂在所述阵列上。
将一些所述微突出物阵列施用在无毛豚鼠上(每组3只动物),以便评估递送到皮肤中的卵清蛋白。在施用所述系统时,用手将动物胁腹皮肤双向拉伸(向左向右和向上向下)。用冲击性施用器进行施用(总能量等于0.4焦耳,用少于10毫秒的时间递送),使用披露于2001年10月12日提交的美国专利申请流水号09/976,798中所披露的弹簧驱动的冲击性施用器。所采用的系统包括一个卵清蛋白涂布的微突出物阵列,该阵列用丙烯酸粘合剂(7平方厘米的圆片)粘接在低密度聚乙烯薄膜背衬的中央。在施用之后,解除拉伸张力,并且在与皮肤接触5秒钟或1小时之后除去该系统。在除去该系统之后,将残余的药物从皮肤上彻底洗净,并且在施用的部位采集8毫米的皮肤活检样品。通过将所述皮肤活检样品溶解在氢氧化季铵盐(1M,溶于甲醇中)中测定递送到皮肤中的卵清蛋白的总量。通过荧光测定进行定量。图9和10中所示的结果表明,可以将高达4.5微克的OVA递送到无毛豚鼠皮肤中,在5秒钟和1小时附着时间之后,递送效率分别高于55%和85%。还发现递送效率相对独立于涂层的厚度。
使用类似方法用未标记过的卵清蛋白涂布相同的微突出物阵列。通过总蛋白测定评估涂布在该阵列上的蛋白量。使用20wt%OVA的涂布溶液以可接受的可再现性(4.6±0.5微克)涂布5微克卵清蛋白(OVA)的目标剂量。用6只一组的无毛豚鼠,通过所述阵列进行免疫研究。系统以及在动物上的系统施用与上文所述相同,所不同的是,在所有豚鼠上的附着时间为5秒钟。其余3组动物接受皮内注射0.1,1.0和10微克的卵清蛋白。以不同的时间间隔采集血液样品,并且通过ELISA评估抗卵清蛋白的抗体(IgG)滴度。在初次免疫2-3周之后,用微突出物阵列贴剂进行免疫的所有动物都产生了抗卵清蛋白IgG抗体,这表明抗原尖端涂布的微突出物阵列能有效诱导免疫应答(参见图11)。随着皮内施用的卵清蛋白剂量的提高,出现了剂量反应。来自这种剂量反应的外推表明,用微突出物阵列获得的抗体应答与皮内递送大约1.4-4微克卵清蛋白的抗体应答一致。
用含有2wt%卵清蛋白和10wt%GMDP的含水涂布溶液进行与上文所述类似的实验。每个阵列进行8次涂布。根据涂布的和递送的卵清蛋白的量,以及在涂层制剂中GMDP与卵清蛋白的比例估算所涂布的GMDP和递送到皮肤内的GMDP。分析表明,每一个微突出物阵列涂布了11微克GMDP和2.2微克卵清蛋白。扫描电子显微术检查表明,所述涂层是以玻璃状无定形基质形式存在的,在不同的微突出物之间具有良好的涂层均匀性。所述涂层局限于微突出物的前150微米。在无毛豚鼠上进行的递送研究表明,GMDP是以类似于卵清蛋白的递送效率递送的(图12)。
本发明的微突出物阵列贴剂可广泛应用于皮内递送多种治疗性疫苗,以便提高效力,并且提供方便性。
Claims (24)
1.一种皮内疫苗递送装置,包括:
一个微突出物阵列,该阵列具有多个角质层穿刺微突出物,所述微突出物具有适合通过穿刺皮肤至小于500微米的深度在角质层上切割小孔的尺寸;
一个装有抗原性试剂和免疫应答增强佐剂的储存器,该储存器相对于所述微突出物的位置是与所述孔形成试剂和佐剂传递关系;
其中所述储存器包括涂布在所述阵列上的干燥固体或层压在所述阵列上的薄膜,其中所述阵列的所述微突出物是用所述储存器均匀涂布的;并且
其中所述阵列具有一个皮肤接触面积,并且所述储存器具有每平方厘米的所述阵列的皮肤接触面积至少0.2微克的抗原性试剂加载量.
3.如权利要求1的皮内疫苗递送装置,其中,所述佐剂包括葡糖胺酰胞壁酰二肽。
4.如权利要求1的皮内疫苗递送装置,其中,所述阵列具有一个皮肤接触面积,并且所述储存器具有每平方厘米的所述阵列的皮肤接触面积至少2微克的抗原性试剂含量。
5.如权利要求1的皮内疫苗递送装置,其中,所述抗原性试剂选自:蛋白、多糖、寡糖、减毒或灭活病毒、减毒或灭活细菌及其混合物。
6.如权利要求5的皮内疫苗递送装置,其中,所述蛋白是脂蛋白.
7.如权利要求1的皮内疫苗递送装置,其中,所述抗原性试剂包括疫苗。
8.如权利要求7的皮内疫苗递送装置,其中,所述疫苗选自:流感疫苗、莱姆病疫苗、狂犬病疫苗、麻疹疫苗、腮腺炎疫苗、鸡痘疫苗、天花疫苗、肝炎疫苗和白喉疫苗.
9.如权利要求1的皮内疫苗递送装置,其中,所述阵列是由金属构成的,并且包括一个粘性背衬。
10.如权利要求1的皮内疫苗递送装置,其中,所述阵列具有高达5平方厘米的皮肤接触面积。
11.如权利要求1的皮内疫苗递送装置,其中,所述储存器中佐剂加载量与抗原性试剂加载量的重量比为0.5:1-50:1。
12.如权利要求1的皮内疫苗递送装置,其中,所述储存器中佐剂加载量与抗原性试剂加载量的重量比为1:1-10:1。
13.微突出物阵列和装有抗原性试剂和免疫应答增强佐剂的储存器在制备皮内疫苗递送装置中的用途,其中所述阵列具有多个皮肤穿刺微突出物,所述微突出物具有适合穿刺皮肤至小于500微米的深度的尺寸,该储存器相对于所述微突出物的位置是与通过穿刺用的微突出物在角质层上形成的切口形成试剂和佐剂传递关系,其中所述储存器包括涂布在所述阵列上的干燥固体或层压在所述阵列上的薄膜,其中所述阵列的所述微突出物是用所述储存器均匀涂布的;并且
其中所述阵列具有一个皮肤接触面积,并且所述储存器具有每平方厘米的所述阵列的皮肤接触面积至少0.2微克的抗原性试剂加载量.
15.如权利要求13的用途,其中,所述佐剂包括葡糖胺酰胞壁酰二肽。
16.如权利要求13的用途,其中,所述阵列具有一个皮肤接触面积,并且所述储存器具有每平方厘米的所述阵列的皮肤接触面积至少2微克的抗原性试剂含量。
17.如权利要求13的用途,其中,所述抗原性试剂选自:蛋白、多糖、寡糖、减毒或灭活病毒、减毒或灭活细菌及其混合物。
18.如权利要求17的用途,其中,所述蛋白是脂蛋白.
19.如权利要求13的用途,其中,所述抗原性试剂包括疫苗。
20.如权利要求19的用途,其中,所述疫苗选自:流感疫苗、莱姆病疫苗、狂犬病疫苗、麻疹疫苗、腮腺炎疫苗、鸡痘疫苗、天花疫苗、肝炎疫苗和白喉疫苗.
21.如权利要求13的用途,其中,所述阵列是由金属构成的,并且包括一个粘性背衬。
22.如权利要求13的用途,其中,所述阵列具有高达5平方厘米的皮肤接触面积。
23.如权利要求13的用途,其中,所述储存器中佐剂加载量与抗原性试剂加载量的重量比为0.5:1-50:1。
24.如权利要求13的用途,其中,所述储存器中佐剂加载量与抗原性试剂加载量的重量比为1:1-10:1。
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- 2002-04-22 MX MXPA03009601A patent/MXPA03009601A/es unknown
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- 2002-04-22 KR KR10-2003-7013730A patent/KR20040014502A/ko not_active Application Discontinuation
- 2002-04-22 BR BR0209041-4A patent/BR0209041A/pt not_active IP Right Cessation
- 2002-04-22 CA CA002444551A patent/CA2444551C/en not_active Expired - Fee Related
- 2002-04-22 EP EP02739170A patent/EP1383571A2/en not_active Withdrawn
- 2002-04-22 JP JP2002583019A patent/JP4382356B2/ja not_active Expired - Lifetime
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2003
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Also Published As
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BR0209041A (pt) | 2005-01-18 |
US20090143724A1 (en) | 2009-06-04 |
JP2004538048A (ja) | 2004-12-24 |
WO2002085446A2 (en) | 2002-10-31 |
WO2002085446A3 (en) | 2003-03-06 |
US20020193729A1 (en) | 2002-12-19 |
EP1383571A2 (en) | 2004-01-28 |
CA2444551C (en) | 2009-11-17 |
MXPA03009601A (es) | 2004-12-06 |
JP4382356B2 (ja) | 2009-12-09 |
CA2444551A1 (en) | 2002-10-31 |
NO20034683L (no) | 2003-12-09 |
CN1602216A (zh) | 2005-03-30 |
KR20040014502A (ko) | 2004-02-14 |
US20060074377A1 (en) | 2006-04-06 |
NO20034683D0 (no) | 2003-10-20 |
IL158479A0 (en) | 2004-05-12 |
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