CN101189016B - 治疗鼻窦病症的装置 - Google Patents
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Abstract
本文描述了治疗鼻窦病症的鼻窦装置。所述的装置包括腔体部件、鼻窦口部件和鼻部分。一个或多个腔体部件、鼻窦口部件和鼻部分可缓释递送活性剂以治疗鼻窦病症。示例性的鼻窦病症为由于功能性内窥镜鼻窦手术(FESS)的鼻窦炎症和鼻窦炎。
Description
相关申请
本申请要求2005年4月4日提交的美国临时申请系列号60/668,569的优先权,本文整体引用作为参考。
技术领域
本文所述的装置、系统和方法涉及治疗鼻窦病症的局部药物递送领域。更具体地,描述了鼻窦炎症和鼻窦炎的治疗。
背景技术
鼻窦炎通常理解为包括鼻窦炎和/或鼻炎的常见的鼻窦病症。一般地,鼻窦炎是以以下的这些主要症状表征的,例如,鼻涕、鼻塞、面部充血、面部疼痛/压力、嗅觉丧失、发烧,以及少量以下症状,如头痛、耳痛/耳压、口臭、牙痛、咳嗽及疲劳。
鼻窦是面部骨骼中充满空气的腔道。每个鼻窦邻近鼻腔并通过窦孔开向鼻腔。正常鼻窦功能的关键是由上皮杯形细胞组成的纤毛转运系统和每天在窦中产生接近四分之一粘液的粘膜下层浆液粘液腺,和排列于窦的具纤毛的、假复层的、柱状上皮,并将粘液移向天然窦口。窦口开放、纤毛功能或粘液质量的任何改变均可能干扰体系并导致鼻窦炎。
鼻窦炎发病机理的一个重要因素是窦口的开放。窦口的部分阻塞常导致粘液分泌的滞留、窦内pH和氧压力的下降。这些生理变化被认为是产生微生物感染的有利环境。微生物感染常常引起或加深可能进一步降低窦口开放或彻底阻塞窦口的粘膜炎症。
鼻窦炎的药物治疗一般包括口服抗生素、局部或口服减充血剂、甾体 鼻喷剂或口服甾体药物例如泼尼松的组合。当药物治疗失败时,对于鼻窦炎是经常的情况,鼻窦手术是另一种选择。当前实施的最常见的手术是功能内窥镜鼻窦手术(PESS)。PESS的目的是通过扩大上颌骨和额窦的口改善粘液的排出,并且在直视下通过移除筛骨气房打开筛窦区。但是,PESS本身产生炎症,可导致术后纤维症、狭窄和/或频繁阻塞新开放窦的息肉,需要外科医生的再次手术以矫正口部并放入保持窦口开放的支架装置。
美国专利No.5,246,455(Shikani)和5,693,065(Rains)描述了插入窦口和/或鼻窦造口术的支架或改善鼻窦排液、降低粘连形成的程度及预防鼻窦口狭窄的开窗术。进一步,为了相同的目的,内窥镜鼻窦手术后常用的是例如Parrell额窦T-形支架(Medtronic Xomed,Inc.,Jacksonville,Fla.)、Jasin额窦OstentTM支架(Medtronic Xomed,Inc.,Jacksonville,Fla.)和SalmanFES支架(Boston Medical Products,Westborough,MA.)等支架。但是,这些支架是非生物降解的,且因此需要后面的去除方法。再者,因为这些支架不向鼻窦递送治疗活性剂,它们通常由于术后炎症和正常的伤口愈合过程仅能延迟狭窄。因此,它们一般地与全身口服甾体激素组合使用,这样它们施用时间较长,可能导致不想要的副反应。
有其他人提出洗脱药物的鼻窦支架。例如,在美国公开的申请No.U.S.2004/0116958中Goferich等人描述了用于放置到手术产生的额窦开窗中的非生物降解或可生物降解聚合物的“间隔器”装置。间隔器是管状或时漏状,且能够在新的开窗周围释放药物,例如糖皮质激素、酪氨酸激酶抑制剂,和有丝分裂抑制剂。据描述时漏状或管状是优选的,因为可允许分泌液从鼻窦排出。间隔器单独地放置在窦口边,且不能承受结构变化,例如,向窦口递送时突然缩小或突然膨胀的外形变化。再者,间隔器主要位于天然鼻窦口内或手术产生的窗内。没有可以延伸至鼻窦腔内与鼻窦腔壁接触的部分。
在美国公布No.2005/0245906中Makower等人描述了另一个用于治疗鼻窦炎的可植入装置。该申请描述了有用于在鼻窦口内定位的间隔器的可生物降解的聚合物装置,且装置本体包含多个洗脱物质的撑杆。撑杆沿着 鼻窦腔基本上不接触腔壁与粘液流动方向平行地放置,以便不干扰粘液纤毛转运。不确定这样设计的装置是如何构建或应用的。再者,假定鼻窦粘膜是装置降解与药物释放所需的水的来源,装置能否提供有效治疗鼻窦炎给药方案是有疑问的,因为它基本地不接触鼻窦腔壁。
治疗鼻窦炎的其他组合物,也被配制成例如局部应用于鼻的水溶液、乳膏或凝胶剂,但通常在鼻内不能穿行太远以达到鼻窦,就由于阻塞的口阻断其进入鼻窦,或与鼻窦粘膜有这样短暂的接触以致药物吸收量很低。由于相似原因,已开发用于治疗鼻窦炎的鼻吸入甾体药和抗感染气雾剂是同样无效的。
描述的另一种局部治疗鼻窦炎的方法是放置可生物降解植入剂至鼻窦内。例如,研究了氨比西林从卷起来的1.5cmx1.5cm聚乳酸--乙醇酸共聚物(PLGA)膜中递送增加了抗生素在家兔鼻窦中的滞留时间用于治疗鼻窦炎(Min等人.在实验性上颌窦炎中鼻窦粘膜的粘液纤毛活性和组织病理学:抗生素的全身施用与抗生素通过聚乳酸聚合物递送的比较,Laryngoscope 105:835-342(1995)及Min等人,聚乳酸聚合物在治疗家兔急性上颌窦炎中的应用,Acta Otolaryngol 115:548-552(1995))。尽管鼻窦炎的临床征象在28天中有所改善,放置膜的方法是相当有侵害性的,需要在上颌窦的前壁钻孔。
放置可生物降解植入剂至鼻窦用于治疗鼻窦炎的侵害性小一些的方法描述于共同拥有的美国公布No.2005/0043706中。在该申请中,植入剂一般通过鼻窦口递送至鼻窦,且有至少一种防止其由粘液纤毛转运系统清除的特性。例如,植入剂一般形成具有基本上可防止植入剂从鼻窦清除的粘膜粘附性。粘膜粘附聚合物引入植入剂中使其具有粘膜粘附性。粘膜粘附聚合物通常是亲水的,且润湿后吸收水分膨胀并变得有粘性。该植入剂缺少可物理地保持鼻窦口开放的结构部件。
因此,需要用于向鼻窦局部施用活性剂治疗鼻窦病症例如鼻窦炎症(包括但不限于鼻窦炎和鼻窦手术,例如FESS)并用于保持鼻窦口的开放的新装置以及递送装置到鼻窦腔的方法。
发明概述
本发明的装置、系统和方法一般用于治疗有鼻窦病症的患者。要治疗的鼻窦病症一般是由于治疗鼻窦炎的功能性内窥镜鼻窦手术(FESS)手术后鼻窦炎,但也包括但不限于涉及鼻窦和鼻通道的以下病症,诸如:急性鼻窦炎、慢性鼻窦炎、过敏性鼻炎、鼻窦炎、FESS后复发的鼻窦炎、上呼吸道感染、中耳炎、支气管炎、细支气管炎、哮喘、扁桃体炎及其他扁桃体和腺的慢性疾病、喉炎、气管炎、鼻和鼻窦息肉、大气道和小气道新生物、及鼻、鼻窦或鼻咽肿瘤例如鼻咽癌、浆细胞瘤、内翻型乳头状瘤、横纹肌肉瘤、扁平细胞癌、和淋巴瘤。本文使用的术语“鼻窦炎症”(″paranasal sinus inflammation″)或“鼻窦炎症”(″sinus inflammation″)指涉及炎症响应的鼻窦组织、鼻窦口组织、或鼻窦口近端鼻通道的任何组织的任何反应。炎症可能由以下过程引起,诸如:过敏(超敏反应),由于例如外伤、手术引起的鼻窦粘膜损伤,细菌、病毒、真菌、化学品或药物引起的感染,和良性或恶性肿瘤。
装置被做成用于局部递送一种或多种活性剂至鼻窦腔、鼻窦口、和/或鼻道内至少约一周以治疗鼻窦病症。所述装置在手术的、非手术的和涉及鼻窦和鼻道的用于恢复解剖功能和治疗任何前面提及的任何病症的其他治疗干预中是有用的。因此,装置可用于支持鼻窦和鼻腔手术,减少对外科修正的需要,和/或预防、延迟或减少鼻窦炎的复发。
治疗鼻窦病症的装置包括第一个允许装置穿过鼻窦口的缩瘪的外形和第二个在放置到鼻窦腔内可膨胀的外形的腔体部件。本文使用的术语“膨胀”(″expand″)、“膨胀”(″expansion″)或“膨胀”(″expanding″)指装置承受物理膨胀,例如从压缩状态到膨胀状态,而不是由于吸水膨胀。
在其膨胀的外形中,在一些变体中本装置有基本上从装置到其缩瘪外形的装置上未变化的表面积与体积的比。在其他变体中,膨胀后,腔体部件亦至少局部符合鼻窦的外形,并基本上与鼻窦腔粘膜接触。装置可用任何生物相容材料制作。例如,可用各种金属和其合金、可生物降解或非生 物降解聚合物及其组合制作。
除腔体部件外,装置可包括鼻部分和配置用于放置在鼻窦口内的鼻窦口部件。腔体部件与鼻窦口部件的远端相接。鼻部分与鼻窦口部件的近端相接,且位于鼻道内。活性剂可加入装置的所有部分,或仅包括在膨胀的腔体部件、鼻窦口部件或鼻部分中。一方面,活性剂从腔体部件和鼻窦口部件中释放。另一方面,活性剂从腔体部件和鼻部分中释放。再一方面,活性剂从鼻部分和鼻窦口部件释放。腔体部件、鼻窦口部件和鼻部分可包含和递送相同或不同的活性剂。
鼻窦装置可在至少约一周的时间里、至少约两周的时间、至少约三周的时间、至少约一个月的时间、至少约两个月的时间、至少约三个月的时间、至少约四个月的时间、至少约五个月的时间、或至少约六个月的时间或更长的时间递送活性剂。一般地,活性剂递送约四周的时间。
装置可用一种或多种聚合物的易弯折的丝制作。例如,丝可制成与缨状结构、易弯折的筛网、扫帚状结构及此类相似的腔体部件。腔体部件可做成可膨胀的。在一些变体中,腔体部件自膨胀。在另一些变体中,在施加膨胀力或机械力后装置膨胀。例如,装置在气球打气后可膨胀。在一些情况下,腔体部件膨胀在鼻窦内展开后可以基本上接触鼻窦腔壁。与鼻窦腔壁的接触可通过在腔体部件上或内加入不透X线的标记物,或使用内窥镜或其他成像方式目视证实。
在另一个变体中,易弯折的丝可包含增塑剂或可软化可生物降解或非生物降解聚合物的溶剂。气球打气或其他机械类型的膨胀力可用于不能自膨胀的增塑的腔体部件的膨胀变化。加增塑剂的腔体部件接触到粘膜组织后,增塑剂从腔体部件扩散出来。增塑剂的扩散使腔体部件变硬,腔体部件基本上符合鼻窦腔的形状。举一实例,用丙交酯/乙交酯聚合物制备的丝可用诸如枸橼酸三乙酯、丙酮和其他酮、乙醇和其他醇、N-甲基吡咯烷酮、乙酸乙酯及其混合物增塑。丝放置入鼻窦后,增塑剂例如枸橼酸三乙酯从丝聚合物中扩散出来得到基本上符合窦腔形状的变硬的丝。
本文描述的用于治疗鼻窦病症的装置包括分散在装置包含的腔体部 件、鼻窦口部件及任选地鼻部分中的可生物降解聚合物骨架中的活性剂,并呈现体内累积释放特性,所述治疗有效量的活性剂在装置植入后保持在鼻窦组织中至少约4天、至少约14天、至少约25天、或至少约35天。
鼻窦装置可使用各种设计的插入器递送入鼻窦。典型的插入器包括有内腔的导管,例如导管、针头或血管导管。例如,导管可做成沿着其长向有可变硬度。另外,导管的远端可预弯成角度以方便进入窦口,或制成远端部分是有延展性的以便医师在进入窦口前可弯折导管。
用于展开的鼻窦装置和插入器可用于治疗鼻窦病症的系统中。一般地,系统通过首先将有一个或多个缩瘪、折叠或扭曲造形的装置的插入器放置在窦口内或穿过窦口至其远端而发挥作用。一旦在窦口内,装置的腔体部件从首先的缩瘪、折叠或扭曲外形向第二个膨胀外形转变。例如,护套可收缩、滑动地展开自膨胀与鼻窦腔壁实质部分接触的腔体部件。气球膨胀或其他机械类型的膨胀可用于未做成自膨胀的腔体部件的膨胀变体。
附图说明
图1是上颌窦和额窦的截面图。
图2A-2M各种易弯折丝的横截面图。
图3A是依照发明的一种变体的有缨状结构上颌窦装置的截面图。
图3B是图3A在上颌窦内的鼻窦装置截面图。
图4A依照发明的一种变体的有缨状结构的额窦装置截面图。
图4B是图4A在额窦内的鼻窦装置截面图。
图5A是依照本发明的另一种变体包括可膨胀筛网的鼻窦装置侧视图。
图5B是图5A鼻窦装置在膨胀之前的侧视图。
图6A-6F是锚固机制的各种丝的侧视截面图。
图7A-7R是各种腔体部件形态的透视图。
图8A-8C显示线圈状窦口部件的透视图、开口端图和底端视图。
图9A-9C显示手风琴状窦口部件的透视图、开口端图和底端视图。
图10A-10C显示筛网状窦口部件的透视图、开口端图和底端视图。
图11A-11C描绘了星状窦口部件的透视图、开口端图和底端视图。
图12A-12C显示了六角形窦口部件的透视图、开口端图和底端视图。
图13A-13C描绘了卷起的片状窦口部件的透视图、开口端图和底端视图。
图14A-14C描绘了管形窦口部件的透视图、开口端图和底端视图。
图15A-15C显示了由多个可弯折的丝制成的窦口部件的透视图、开口端图和底端视图。
图16A-16C描绘了由多个可弯折的带状或条状细丝制成的窦口部件的透视图、开口端图和底端视图。
图17A-17C显示了做成可膨胀褶状管的窦口部件的透视图、开口端图和底端视图。
图18A-18C显示了由凝胶泡沫制备的窦口部件的透视图、开口端图和底端视图。
图19A-19C显示了有多个腔体的圆柱形窦口部件的透视图、开口端图和底端视图。
图20A-20F描绘了各种鼻部分外形图。
图21描绘了示例性鼻窦装置的透视图。
图22A-22C显示了有腔体部件和由多个易弯折丝线圈制成的鼻部分的鼻窦装置的透视图、侧截面图和底端视图。
图23A-23C显示了有线圈腔体部件和鼻板的鼻窦装置的透视图、侧截面图和底端视图。
图24A-24F显示了鼻窦装置的示例性药物释放曲线。
图25是显示糠酸莫米松从各种鼻窦装置中在30天时间中的体外累积释放图。
发明详述
本发明的鼻窦装置可采取各种形式。例如,有的设计成包括腔体部件、鼻窦口部件、鼻部分,并且递送活性剂用于治疗鼻窦病症,例如鼻窦炎症。 腔体部件可有第一个允许其插入鼻窦口或外科产生的窗内的缩瘪的外形,和第二个放置到鼻窦腔内可膨胀的外形。在这一变体中,一旦膨胀,腔体部件结构一般不具有与其在缩瘪外形的腔体部件不同的表面积与体积比。这一点可能重要,因为鼻窦粘膜是活性剂从鼻窦装置中释放所需水的来源。因此,如果降低装置能够接触鼻窦粘膜的例如与体积有关的表面积,活性剂的溶出(和相继的吸收)应该也是下降的。再者,一旦膨胀,腔体部件也可以基本上接触鼻窦腔壁。
鼻部分一般功能是定位和/或锚固装置于鼻窦口,防止偏向中鼻甲的一侧,阻塞中部的道口,以及组织粘附的形成。鼻窦口部件位于腔体部件的近端,一般功能为保持鼻窦口开放。但是,如下文进一步的描述,装置的每个部件可根据例如腔体部件、鼻窦口部件或鼻部分的独特结构以及部件是否能够释放活性剂等因素而具有不同的功能。
本文使用的术语“鼻窦”(″paranasal sinus″)和“鼻窦”(″sinus″)可互换使用,指所有的鼻窦,即,上颌窦、额窦、筛窦和蝶窦。每个鼻窦腔通过鼻窦口开放进入鼻腔。如图1所示,上颌窦10在上颌窦口14开放进入鼻腔12,额窦16在额窦口18开放进入鼻腔12。本文使用的术语“治疗”(″treat″)、“治疗”(″treating″)或“治疗”(″treatment″)指消除、减少或防止鼻窦病症或其症状,预防由鼻窦病症引起的并发症、或向鼻窦提供有益物质。例如,有益物质可用于促进鼻窦的一般健康。
一旦膨胀,腔体部件可做成以至少部分适应鼻窦腔壁的形状,并基本上与鼻窦腔壁接触。通过“基本上接触”,意味着在整个治疗期间,例如,至少一周,至少两周,至少三周,或至少四周或更长,提供活性剂适当的释放动力学一般需要接触鼻窦腔壁(鼻窦粘膜)的腔体部件表面积的百分数。因此,根据需要接触的表面积的量,“实质性接触”可指约10%至约100%,约20%至约100%,约30%至约100%,约40%至约100%,约50%至约100%,约60%至100%,约70%至约100%,约80%至约100%,或约90%至100%的装置的表面积与鼻窦腔壁接触。重要的是,腔体部件在鼻窦粘膜上的压力足以保持腔体部件与鼻窦粘膜的接触,但不会引起粘 膜的显著损伤或坏死。
如本文使用的术语“活性剂”、“治疗剂”和“药物”可互换使用,指用于治疗鼻窦病症的任何物质。再者,本文使用的术语“治疗量”指适当地安全治疗鼻窦病症的局部递送至鼻窦或鼻道的活性剂的浓度。
一般原理:本文描述的鼻窦装置可以各种方式造型。例如,它们可由一根或多个丝制成,包括任何线性结构例如链、毛细管和管状和非管状结构,但也可以由膜或片状起始材料制成。丝可以是各种硬度并采用各种适合的形式,例如线状、丝带状、贴状、串珠状结构,管状等,只要它们弹性足以在展开后基本上接触鼻窦腔壁的部分,呈现所需的释放动力学,并递送治疗鼻窦病症治疗量的药物。丝一般可以是不同形状,有各种截面形状,按所需或对用于保持粘膜接触和持续地展开。例如,如图2A-2M所示,它们可做成不同形状,环状(2A)、方形(2B)、椭圆形(2C)、翼形(2D)、钻石形(2E)、矩形(2F)、楔形(2G)、梯形((2H)、管形(2I)、平行四边形(2J)、弧形(2K)、犬骨/哑铃形(2L)、微凹形(2M)等的横断面。如果需要,易弯丝亦可合并制成编织结构例如束、绳、辫、筛等。管状丝可同心合并或毗邻合并成多腔体的结构,或直接做成有多腔体的丝。膜和片亦可包括非编织的筛网和大量的二维材料,其中二维厚度大大小于维长度或宽度。其他材料例如凝胶泡沫可在其应用时做成这种丝。
在一些变体中,易弯丝可做成包括一种或多种锚固元件以帮助丝附着于鼻窦粘膜上或另外增强丝在鼻窦粘膜上的接触。例如,如图6A-6F所示,锚固元件可以是一个或多个钩(6A)、钉(6B)、反向钉(6C)、箭头(6D)、脊(6E)、倒钩(6F)等。在图6E中,脊可以做成三角形、方形、圆形、半圆形等。
腔体部件。腔体部件一般是可生物降解的,但亦可以是非生物降解的。另外,不管做成的是可生物降解的或非生物降解的,腔体部件可与部件相连,例如,线或缝合线,从腔体部件延伸并通过鼻窦口穿出来,这样可以通过仪器抓起将其从鼻窦去掉。
在一个变体中,可弯折丝被做成缨状结构。如图3A所示,缨状结构20的截面包括多个可弯折的丝或尖头22(膨胀的外形)。可弯折的丝22在 其近端24向管状鼻窦口部件26是闭合的。一旦在鼻窦内例如上颌窦21展开,见图3B,可弯折的丝22放射状地膨胀、展开、或者另外在插入鼻窦内后适合承受外形的变化,基本上接触鼻窦腔壁23并向鼻窦21递送活性剂。可弯折丝22的长度通常在约1cm至约6cm之间,更通常地在约2cm至6cm之间,更通常地在约3cm至6cm之间。另外,鼻窦部件26置于窦口25以保持鼻窦口开放以便从鼻窦21向鼻腔的排液不间断。鼻部分28亦可提供至装置的近端上。鼻部分28延伸至鼻腔内,并可尽量减少偏向中鼻甲的一侧使外侧鼻壁和鼻窦口开放,进一步减少可能的阻塞风险,并在鼻中部道口形成粘附。
在另一个变体中,如图4A和4B所示,可弯折的丝32在额窦31做成缨状结构30。像图3A和3B一样,可弯折的丝32在其近端34向鼻窦口部件36方向是闭合的,且一旦展开,基本上与鼻窦腔壁38接触以递送药物至额窦31。可弯折丝32的长度通常在约1cm至约5cm之间,更通常地在约2cm至约5cm之间。但是,因为从鼻腔至额窦口33与至上颌窦口相比通道更长,且因为额窦装置30受重力的拖拉,以及被易于狭窄、粘连和瘢痕的更长、更窄的腔道包围,管状口部件36一般在额窦装置中做得更长。但是,如果缨状结构30(或其他腔体部件)做成可在鼻窦腔内锚固装置,或如果通过改变手术技术(更广义地或狭义地)或改变解剖结构这种前文提及的合并症风险降低了,鼻窦口部件36的长度可缩短。
转向图5A和5B所示的变体,可弯折丝做成有弹性的筛网。在图5B中(缩瘪的外形),易弯折的筛网向鼻窦口部件42(并且在一些实例中,亦向鼻部分46)用本领域公知的方法闭合,例如焊接、煅烧、加热粘合、固位带或粘合剂诸如热塑性粘合剂,热固性粘合剂、橡胶-树脂混合粘合剂、及其他本领域技术人员公知的粘合剂。膨胀后,如图5A所示,有弹性的筛网40做成能够至少部分与鼻窦腔形状符合的球状结构。筛网的编织可调得更松或更紧,或可弯折丝的宽度可调节以相应地适合筛网的弹性。有弹性的筛网可向径向膨胀约1cm至约5cm,更通常地在约2cm至约5cm之间,如下文的进一步描述,可做成自膨胀、可控的膨胀或气室可膨胀的腔体部 件。
腔体部件可以是各种其他设计。在一个变体中,腔体部件70可做成为单根可弯折丝72(图7A)。单根可弯折丝72可以这样的方式弯折,至少部分适形于植入的鼻窦,并基本上接触鼻窦腔壁。在另一个变体中,如图7B所示,腔体部件74包含单根做成线圈76的可弯折丝。线圈卷动的数量可根据植入鼻窦、使用的放置和展开技术,及线圈是否用作锚固或用于药物递送,及丝的弹性这些因素而变化。相似地,腔体部件78可由单根可弯折丝和/或插入成随机线圈80的单根可弯折丝做成(FIG.7C)。
在其他变体中,腔体部件是由多条具有一种或多种弧形或圆圈形的丝做成。例如,在图7D中,膨胀的腔体部件82是由两根可弯折的丝84做成的。可弯折丝84做成为彼此交叉的同心环。环通常用以上描述的方法彼此附着形成远端86。可弯折丝84的近端88可结合,且另外做成窦口部件230和/或鼻部分232,例如,如图21所示。在另一个变体中,膨胀的腔体部件90由多根可弯折丝92做成以形成多个游离环(图7E)。可弯折丝92的近端94亦可相连或另外做成装置的鼻窦口部件和/或鼻部分。在另一个变体中,如图7F所示,膨胀的腔体部件可用多根可弯折的丝98做成扫帚状结构。可依据独特需要的腔体部件外形改变丝之间留的间隔100。丝可通过调节弹性的程度成形,例如,通过加入增塑剂、使用各种塑型、铸件、粘合及挤压技术,及通过其他本领域技术人员共知的方法。每个环形丝之间的角度亦可依据所需腔体部件独特外形而变化。亦可使用任意数量的丝制作有任意数量的弧形或环形腔体部件的装置。
在其他变体中,腔体部件可用丝带或条状丝制作。例如,如图7G所示,腔体部件100是用多根从单根管状丝结构切开得到的条状亚丝102制作的。在图7H中,腔体部件104是用多根条状丝106制作为尖端分叉的结构。在图7I中,腔体部件108是用多个从单根“母”管状丝结构的一端切开并变形得到的“子”丝——条状丝110制作的。
图7J-7O显示另一种腔体部件设计变体。在图7J中,腔体部件112是用多个皱的丝带状丝制作的。在图7K中,腔体部件116是用多条丝制 作,外形像弹簧118。腔体部件亦可用一条或多条含有凝胶泡沫的丝122制作。图7M-7O亦包含允许一条或多条打开或收紧外形的丝不可逆的展开的特色,通过在丝上使用脊(例如134、136),并在相邻的腔体上使用相对的脊,或在插入部位使用其他结构。在图7M中,由单个脊环组成的腔体部件124插入鼻窦并穿过在装置的窦口部件126上有相对的脊125的内腔并靠着窦壁(箭头)。图7N中,由两个相反的环129组成的腔体部件128被相似地插入。这些脊130可交替使窦腔部件的结构变形。图7O中,以上图7I中描述类型的腔体部件131通过在条状丝135内部加入脊133作了改动,另外的有相对脊137的内部管状部件在母体切开管内同心放置。当同心部件137被独立地拉后(对着近端方向)同时保持外部窦腔母体切开管位置不变时,通过沿着带状脊和相对的内部脊的交叉处变形,装置的腔体部件条状丝135展开。结果是切开的“子”丝沿着窦腔壁的张开的和变形的打开模式。
图7R中,腔体部件132是用多根丝134编织成筛网并做成漏斗型结构。腔体部件亦可由膜、非编织的或片状材料制作。例如,膜或片可以起皱,如图7P和7Q所示。在图7P中,片140具有有皱褶138,后者可允许腔体部件136做成起皱的圆锥体。在图7Q中,片142有皱褶144,后者可允许腔体部件146做成有皱褶的扇形。
本发明的腔体部件可适合自膨胀,例如,如果它们是用形状记忆特性聚合物制作的或如果它们在插入鼻窦前是被护套束缚的,在去掉护套后在鼻窦伸展开。它们亦通过涉及机械膨胀的方法膨胀。例如,它们可通过向气球中加压膨胀,或拉接在装置远端的带子或金属丝,或通过在装置近端施加膨胀力,或沿着鼻窦壁使腔体部件弯曲或变形。但是,除前文描述的方法外,本发明亦考虑由安装有一个或多个接头或铰链的不易弯折的丝制作的腔体部件的机械膨胀,腔体部件通过在接头或铰链处可弯折丝的移动而膨胀。由于在有较低硬度的区域使用聚合物、减少了丝的宽度、或通过调整其他表面特征或该区域丝的质量密度,接头或铰链可能是沿着丝方向的较大弹性的区域。
活性剂可包含在装置的任何部分,例如,腔体部件、鼻窦口部件和/或鼻部分。当使用丝时,活性剂可以当作药物分散或溶解在聚合物骨架中、或包衣在易弯折的丝表面、或首先囊化、例如微囊化、并装入或包衣在易弯折的丝内(上)从而加至丝中。在一些实例中,易弯折的丝可构建有贮藏药物小丸的一个或多个小药囊或药袋。递送的活性剂的剂量可以通过腔体部件调整,例如增加或降低含药丝的数量,增加或降低丝内或丝表面衣层中包含的药量,或通过形成可弯折丝以便它们不管在插入鼻窦腔前或后,可被折断或切成更小的丝。例如,可弯折的丝可包含预设的折断的线或标记,医师可以在插入前用作调整丝长度的指导,或在插入鼻窦内后,可调整丝先降解至折断线为较短的丝。在一些实例中,可能需要在腔体部件中包含有不同活性剂的丝。
腔体部件亦可用可弯折的丝外形的组合或丝与其他描述的腔体部件外形的组合做成。例如,图3A-3B和图4A-4B的结构可用于支持图5A的弹性筛网。如果需要,不透X线的标记物亦可包含在一根或多根可弯折的丝上,用以在X线成像下标示腔体部件膨胀的程度。通常,如果是非生物降解的,标记物通过荧光镜透视检查,如果在膨胀的腔体部件已经降解后,标记物将在正常的粘液流动下离开鼻窦。亦可使用可生物降解的射线不能透过物质诸如碘造影剂或铋盐粒子。与鼻窦腔壁的接触可通过在腔体部件上或内加入射线不能透过的标记物进行验证,或使用内窥镜或其他成像方法目测。
可通过向可弯折丝中加入可以是也可以不是聚合物的粘膜粘着材料改善腔体部件与鼻窦腔壁的接触和/或锚固,如下文的进一步描述,通过调整丝的大小(如,减少丝的直径或另外减小外观比例),或通过把丝做成如图6A-6F所示,可包括钩状(7A)、粗短刺状(7B)、双刺状(7C)、箭头状(7D)、脊状(7E)、或倒钩状结构(7F)、或其他锚固或编织成分用于抓住鼻窦粘膜。在其他变体中,丝可以像螺丝或弹簧一样对着其远端配置,能够通过插入或张力固定在粘膜或其他鼻窦组织中。在其他变体中,丝可通过纤维包扎或缝合固定在鼻窦腔壁。腔体部件亦可通过调整其大小固定在鼻窦里,太 大不能移出窦口,或做成腔体部件,使其膨胀充满整个窦腔或膨胀产生足够的压力使其保持在窦腔内。再者,鼻窦装置可以使可弯折的丝做成有弹性的,使腔体部件的部分可以有区别地弯曲适形于其展开的鼻窦。
鼻窦口部件。鼻窦口部件可用于维持鼻窦口开放和/或锚固装置的鼻部分或腔体部件。在一些变体中,其包含物可简单地将腔体部件与装置的鼻部分或其他鼻窦外部件相连。鼻窦口部件是装在腔体部件的近端上的,且放置在鼻窦口上或接近鼻窦口处。再者,由鼻窦部件在鼻窦粘膜表面产生的压力足以保持鼻窦口打开,但没有那么大以至于减少了血液流向鼻窦粘膜。
鼻窦口部件可以是各种设计。在一些变体中,鼻窦口部件由一根或多根可弯折丝做成。例如在图8A中,鼻窦口部件148是用单根可弯折的丝150制作的做成可膨胀的卷曲的丝或线,后者的螺距、数目和线圈密度、线圈的线形和非线形或图案结构和其他的类似特征是可以变化的。图8B显示了放置在鼻窦口内的拔钻形的鼻窦口部件148,图8C显示了鼻窦口部件148的端视图。内腔151允许粘液流出鼻窦腔。鼻窦口部件148适合被侧面压缩和/或弯折,如图8B的箭头所示,这种情况下卷的直径将增加或减少。在另一个变体中,如图15A所示,多根丝154,其可以是管状丝(有内腔),被连接做成管状鼻窦口部件152。图15B显示在鼻窦口内的管状鼻窦口部件152,图15C显示鼻窦口部件152的端视图。内腔156允许粘液流出鼻窦腔,如果用其结构任何管状丝的内腔均可。除了丝160做成带状,图16A-16C所示的鼻窦口部件158与图15A-15C相似。鼻窦口部件158亦有允许粘液从鼻窦腔流出进入鼻道的内腔162。
在其他变体中,鼻窦口部件由膜或片状材料做成。例如,在图9A中,鼻窦口部件164是用带皱褶的片(或可以用多根管状环结构连接起来做成)166做成,做成可逆地压缩和/或可弯折(如图9B的箭头标明的)的手风琴状的管状结构。图9B描绘了鼻窦口内的窦口部件164,图9C显示了鼻窦口部件164的端视图。内腔168允许粘液流出鼻窦腔。关于图10A,鼻窦口部件170包含多个从膜或片状材料174中切割或冲压出的孔172,形 成非编织的筛网。尽管孔形状上显示六角形,应该理解可使用其他的不同孔形状。例如,孔172可以是三角形、方形、八角形、钻石形等。图10B显示鼻窦口内的窦口部件170。在图10C中,显示了这种设计的鼻窦口部件怎样允许粘液通过内腔176以及通过孔172流出(见箭头方向)。鼻窦口部件170亦可以做成可压缩的、可膨胀的、可弯折的等。参见图12A-12C、14A-14C、和13A-13C,膜或片状材料176亦可以做成简单的管178,管状六角形180和卷起的管子182。内腔184、186和188允许粘液从鼻窦腔中流出到鼻道。向箭头方向施加压力至图13C中的卷起的管子182以调节内腔188的直径。
在另一个变体中,鼻窦口部件164用多个片状或带状丝166制作做成星或或星状结构。每个带子之间的空间168允许粘液通过鼻窦口部件164流出,并任选通过中央内腔165流出。图11B显示鼻窦口内的窦口部件164,图11C描绘了鼻窦口部件164的端视图。进一步的变体描绘于图17-19。参看图17A-17C,管状鼻窦口部件190(上)是用皱褶或打褶的膜或片192做成的。鼻窦口部件190可按箭头方向膨胀(示于图17C)以形成更大直径的鼻窦口部件194。图18A-18C中,管状鼻窦口部件196是用凝胶泡沫198做成的,有穿孔的内腔199,可以通过加管子支撑,也可以不加。图19A-19C中的鼻窦口部件200是实心的,但多孔的圆柱体204有多个内腔202。内腔202延伸穿过管状鼻窦口部件200,直接地(在管中)或间接地通过其他内腔和/或管腔(未显示)连接以便粘液可以流出圆柱体204的端壁206和外壁208。
鼻窦口部件可以作成刚性的或有弹性的,亦可以作成用药包衣,用微囊化药物包衣,或做成分散或溶解了药物的聚合物骨架。包括在鼻窦口部件中的药物可以是与膨胀的腔体部件递送的药物相同的或不同的。鼻窦口部件可用可生物降解或非生物降解的聚合物、金属或其组合制成。
鼻窦口部件的大小一般随着预期的鼻窦展开而变化。例如,对于上颌窦,窦口部件的长度可少于2mm,但通常在约2mm至约6mm之间,更通常地在约2mm至约5mm之间,更通常地仍在约2mm至约4mm之间。
上颌窦口部件的外径通常在约5mm至约10mm之间,更通常地在约5mm至约9mm之间,更通常地在约8mm至约10mm之间。上颌窦口部件的内径通常在约3mm至约9mm之间,更通常地在约3mm至约8mm之间,更通常地在约3mm至约7mm之间。
对于额窦,窦口部件的长度可在约0.5mm至5cm之间,在约0.5cm至约4cm之间,在约0.5cm至约3cm之间,在约0.5cm至约2cm之间,或在约0.5cm至约1cm之间。窦口部件的外径通常约5mm,内径通常约3mm。但是,内径和外径可更小些,特别是在装置固定通过腔体部件或鼻部分完成的情况下。
鼻部分。本发明的鼻窦装置可包括鼻部分,例如,鼻板210(图20D),帮助保持鼻窦口部件在鼻窦口的位置,或帮助减少螺纹单侧化、可能的鼻窦口周围中部导管的阻塞、和可能的组织粘连。如果包括,鼻部分(例如,图5A-5B中的元件46,及图21中的元件232)在延伸到鼻道的鼻窦口部件的近端是闭合的,可位于靠着鼻粘膜。鼻部分做成有至少一个从鼻窦口部件流出的粘液可以排入鼻道的开口。开口可偏心排布,或做成在鼻部分的中心。在图20D中,开口212是在鼻板210的中心。在图20E中,鼻板214有多个允许粘液从鼻窦排出到鼻道的开口216。
在其他变体中,鼻部分用一个或多个可弯折的丝构建。参看图20A,鼻部分218用多根丝220制做成放射状延伸的辐条,以更紧密的一捆对齐平行排列的辐条的形式被插入,然后展开或舒展以便环绕插入点(见箭头和插入视图)。相似地,在图20C,鼻部分226用多个带状丝228做成。在图20B中,鼻部分222是用单根可弯折的丝224制作成螺旋状/螺旋状(spiral/helical)结构。另一个示例性鼻部分描绘于图20F中,包含可压缩编织的或非编织的翼形管形式的折叠片状物质,为了可调节地符合并支持中间管的空间和鼻窦口的正外侧的鼻甲解剖结构。
鼻部分可以做成刚性的、弹性的或自膨胀的,并且亦可做成用药包衣,用微囊化药物包衣、或做成以聚合物骨架中分散了的或溶解了的药物的聚合物骨架。包括在鼻部分的药物可与通过腔体部件递送的药物相同或不同。 鼻部分可用可生物降解或非生物降解的聚合物、金属或其组合做成。
亦可根据展开的鼻窦及要治疗的窦是否包括其他的窦例如筛窦等因素而改变鼻部分的形状。例如,在需要治疗的颌窦和筛窦炎症的个体中,特别需要将有鼻部分的上颌鼻窦装置做成能接触筛骨气腔部分的形状。
鼻窦装置可包括任何前文所述的腔体部件、鼻窦口部件和鼻部分的任意组合。例如,如图21所示,装置可包括多个线圈状腔体部件228(前面的图7D已描述)和管状鼻窦口部件(前面的图15A已描述)。鼻部分232也是用多根丝234制作成展开的尖头。装置的每个部件,即腔体部件、鼻窦口部件和鼻部分可相连地(每根丝、管、片或膜做成所有的元件)或单独地形成,然后通过前文所述方法连接。每个元件亦可穿孔、包含孔或有其他结构或表面特征,它们可改善或防止粘膜纤毛清除的阻塞,有助于装置的放置和展开。
在另一个变体中,鼻窦装置236包括扫帚状腔体部件238(前文描述,图7F)、管状窦口部件240(前文描述,图14A)、和另一个扫帚状元件242,其类似于腔体部件238,作为鼻部分242。图22C显示了本装置的鼻部分端视图。
在示于图23A-23C的另一个变体中,鼻窦装置244包括多个线圈状的腔体部件246(前文描述,图7D)和鼻板248(前文描述,图20D)。图23B是装置244的侧面的侧截面图,穿过线A-A的截面端视图示于图23C。
活性剂。活性剂可包含在本文所述的装置中,只要它们适于治疗鼻窦病症,并能够实现所需的释放动力学。可能用于鼻窦装置中用于治疗鼻窦病症的活性剂包括但不限于抗胆碱能药物、抗组胺药、抗感染药、抗炎药、去疤药或抗增殖药、化疗药/抗肿瘤药、细胞因子例如干扰素和白介素、减充血剂、愈合促进剂和维生素(例如,维生素A酸、维生素A、及其衍生物)、高渗性泻药、免疫调节剂/免疫抑制剂、白三烯修饰因子、粘液溶解药、麻醉性镇痛药、小分子、酪氨酸激酶抑制剂、肽、蛋白质、核酸、血管收缩药、或其组合。反义核酸低聚物或mRNA表达、转录和蛋白生成的其他直接转活和/或反式阻抑修饰因子亦可使用。抗感染药一般包括抗菌剂、抗真 菌剂、抗寄生物剂、抗病毒剂、和消毒剂。抗炎药一般包括甾体和非甾体抗炎药。
适于用作所述方法和装置的抗菌药的实例包括但不限于,氨基糖甙类、氯霉素类、安莎霉素类、β-内酰胺类、林可酰胺类、大环内酯类、硝基呋喃类、喹诺酮类、氨磺酰类、砜类、四环素类、万古霉素、和它们的任何衍生物、或其组合。在一个变体中,β-内酰胺类是优选的抗菌药。
适于用作所述方法和装置的β-内酰胺类抗生素的实例包括但不限于,碳头孢烯类、碳青霉烯类、头孢菌素类、头霉素类、单酰胺菌素类、氧头孢烯类、青霉素类、和其任何衍生物。在一个变体中,青霉素类(及其相应的盐)是优选的β-内酰胺类。
适于用作所述方法和装置的青霉素类抗生素的实例包括但不限于氮 脒青霉素、氮 脒青霉素匹酯、阿莫西林、氨比西林、萘啶青霉素、阿扑西林、迭氮青霉素、阿洛西林、巴氨西林、苄青霉素酸、青霉素G钠、羧苄青霉素、羧茚青霉素、双氯甲氧青霉素、邻氯青霉素、氨环已青霉素、双氯青霉素、环烯氨甲青霉素、苯氧苄青霉素、氟氯青霉素、缩酮氯苄青霉素、利南西林、甲烯氨苄青霉素、甲氧西林钠、美洛西林、萘夫西林钠、 洒西林、青霉素G双酯、氢碘酸喷沙西林、青霉素G苯乙苄胺、苄星青霉素G、青霉素G二苯甲胺、青霉素G钙、哈胺青霉素G、青霉素G钾、普鲁卡因青霉素、青霉素N、青霉素O、青霉素V、苄星青霉素V、哈胺青霉素V、青四环素、氨苯乙基青霉素钾、氧哌嗪青霉素、匹氨青霉素、苯氧丙基青霉素、喹 啉青霉素钠、磺苄青霉素、青霉烷砜/氨苄青霉素、酞氨苄青霉素、替莫西林、和替卡西林。在一个变体中,阿莫西林包含在鼻窦装置中。在另一个变体中,装置中包括氨比西林。亦可使用青霉素类与克拉维酸的组合例如奥格门汀(阿莫西林与克拉维酸)。
适于用作所述方法和装置的抗真菌剂的实例包括但不限于,丙烯胺类、咪唑类、多烯类、硫代氨基甲酸酯类、三唑类、及其任何衍生物。在一个变体中,咪唑类是优选的抗真菌剂。可使用的抗寄生物药包括:阿托伐醌、克林霉素、氨苯砜、双碘喹啉、甲硝唑、戊双脒、伯胺喹啉、乙胺嘧啶、 磺胺嘧啶、甲氧苄氨嘧啶/磺胺甲基异 唑、曲美沙特、及其组合。
适于用作所述方法和装置的抗病毒剂的实例包括但不限于,阿昔洛韦、泛昔洛韦、伐昔洛韦、依度尿苷、更昔洛韦、磷卡萘替、西多福韦(vistide)、vitrasert、formivirsen、HPMPA、(9-(3-羟基-2-膦酰基甲氧基丙基)腺嘌呤)、PMEA(9-2-膦酰基甲氧基乙基)腺嘌呤)、HPMPG(9-(3-羟基-2-膦酰基甲氧基)丙基)鸟嘌呤、PMEG(9-[2-(膦酰基甲氧基)乙基]鸟嘌呤、HPMPC(1-(2-膦酰基甲氧基-3-羟基丙基)-胞嘧啶)、利巴韦林、EICAR(5-乙炔基-1-β-D-呋喃核糖基咪唑-4-甲酰胺)、吡唑呋喃菌素(3-[β-D-呋喃核糖基]-4-羟基吡唑-5-甲酰胺、3-去氮杂鸟嘌呤、GR-92938X(1-β-D-呋喃核糖基吡唑-3,4-二酰胺)、LY253963(1,3,4-噻二唑-2-基-氨基氰)、RD3-0028(1,4-二氢-2,3-Benzodithiin)、CL387626(4,4′-双[4,6-d][3-氨基苯基-N-双(2-氨甲酰基乙基)-磺酰亚氨基-1,3,5-三嗪-2-基氨基-联苯-2-,2′-二磺酸二钠盐、BABIM(双[5-脒基-2-苯并咪唑基-1]甲烷、NIH351、及其组合。
一般地,如果需要包含抗炎药,使用甾体抗炎药,例如,糖皮质激素。可用在装置中的甾体抗炎药的实例包括21-乙酸孕烯醇酮、阿氯米松、二羟孕酮、安西奈德、倍氯米松、倍他米松、布地奈德、氯强的松、氯氟美松、氯氟美松铜、氯氟土龙、氯泼尼醇、肾上腺酮、可的松、可的伐唑、地夫可特、地奈德、去氧米松、地塞米松、二氟拉松、二氟可龙、醋丁二氟龙、甘草次酸、氟扎可特、氟二氯松、二氟美松、氟尼缩松、氟西奈德、醋酸氟轻松、氟考丁酯、氟考龙、氟米龙、醋酸甲氟龙、醋酸氟甲叉龙、氟泼尼松、氟羟可舒松、丙酸氟替卡松、氟甲酰龙、哈西缩松、丙酸卤倍他索、氯二氟美松、醋酸卤泼尼松、氢可他酯、氢化可的松、氯替泼诺碳酸乙酯、马泼尼酮、甲羟松、甲基强的松、甲基强的松龙、糠酸莫米松、对氟米松、泼尼卡酯、强的松龙、强的松龙25-二乙基氨基醋酸酯、强的松龙磷酸钠、泼尼松、强的松龙戊酸酯、泼尼立定、利美索龙、替可的松、曲安西龙、曲安奈德、苯曲安奈德、己曲安奈德、其任意衍生物,及其组合。在一个变体中,布地奈德包含在装置中作为甾体抗炎药。在另一个变体中,甾体抗炎药可以是糠酸莫米松。仍在另一个变体中,甾体抗炎药可以是倍氯米 松。仍在又一个变体中,甾体抗炎药可以是丙酸氟替卡松。
如果使用非甾体抗炎药,适合的活性剂包括但不限于,COX抑制剂(COX-1或COX非特异性抑制剂)(例如,水杨酸衍生物、阿司匹林、水杨酸钠、三水杨酸胆碱镁、双水杨酯,、双氟尼酸、柳氮磺吡啶和奥沙拉嗪;对氨基苯酚衍生物例如对乙酰氨基酚;吲哚和茚乙酸例如吲哚美辛和舒林酸;杂芳基乙酸例如甲苯酰吡啶乙酸、双氯芬酸、酮咯酸;芳基丙酸例如布洛芬、萘普生、氟吡洛芬、酪洛芬、非诺洛芬和奥沙普嗪;邻氨基苯甲酸(灭酸酯类)例如甲灭酸和美洛昔康;烯醇酸类例如昔康类(吡罗昔康、美洛昔康)和烷酮类例如萘普酮)和选择性COX-2抑制剂(例如,二芳基取代的呋喃酮类例如罗非考昔;二芳基取代的吡唑类例如塞来考昔;吲哚乙酸类例如依托度酸和sulfonanilide类例如尼美舒利)。
可用于鼻窦装置的化疗药/抗肿瘤药包括但不限于抗肿瘤药(例如,癌症化疗药、生物响应调节剂、血管化作用抑制剂、激素受体阻断剂、冷疗剂或其他可破坏或抑制瘤形成或肿瘤发生的药物)例如烷化剂或其他通过攻击其DNA直接杀死癌细胞的药物(例如,环磷酰胺、异环磷酰胺)、亚硝基脲或其他通过抑制细胞DNA修复必需的变化杀死癌细胞的药物(例如,卡氮芥(BCNU)和罗氮芥CCNU))、抗代谢物和其他通过干扰某些细胞功能阻断癌细胞生长的药物,通常DNA合成(例如,6-巯基嘌呤和5-氟尿嘧啶(5FU)、抗肿瘤抗生素和其他通过结合或嵌入DNA和阻止RNA合成的化合物(例如,阿霉素、柔红霉素、表柔比星、去甲氧基柔红霉素、丝裂霉素C和博来霉素)植物(长春花属)生物碱类和其他从植物衍生的抗肿瘤药(例如,长春新碱和长春碱)、甾体激素、激素抑制剂、激素受体拮抗剂和其他影响激素敏感癌症生长的药物(例如,他莫昔芬、赫赛汀、芳香酶抑制剂例如氨鲁米特和福美坦、三唑类抑制剂例如来曲唑和阿那曲唑、甾体抑制剂例如依西美坦)、抗血管生成蛋白质、小分子、基因治疗和/或其他抑制肿瘤的血管发生或血管化的药物(例如,meth-1、meth-1、沙立度胺)、贝伐单抗(Avastin)、角鲨胺、内皮他丁、血管他丁、Angiozyme、AE-941(新伐司他)、CC-5013(Revimid)、medi-522(Vitaxin)、2-甲氧雌二醇(2ME2、Panzem)、 carboxyamidotriazole(CAI)、考布他汀A4前药(CA4P)、SU6668、SU11248、BMS-275291、COL-3、EMD 121974、IMC-1C11、IM862、TNP-470、塞来考昔(Celebrex)、罗非考昔(Vioxx)、α-干扰素、白介素-12(IL-12)或ScienceVol.289,第1197-1201页(2000年8月17日)中已鉴定的任意化合物,本文加入作为参考,生物响应调节剂(例如,干扰素、卡介苗(BCG)、单克隆抗体、白介素-2、粒细胞集落刺激因子(GCSF)、等)、PGDF受体拮抗剂、赫赛汀、门冬酰胺酶、白消安、卡铂、顺铂、亚硝脲氮芥、苯丁酸氮芥、阿糖胞苷、氮烯唑胺、依托泊苷、flucarbazine、氟脲嘧啶、吉西他滨、羟基脲、异环磷酰胺、依立替康、罗氮芥、美法兰、巯嘌呤、氨甲喋呤、硫鸟嘌呤、硫替派、拓优得、托泊替康、苏消安、长春碱、长春新碱、mitoazitrone、奥沙利铂、甲苄肼、灰链菌素、紫杉醇或紫杉酚、紫杉特尔、类似物/同源物、这些化合物的衍生物、及其组合。
可加入鼻窦装置的减充血剂的实例包括但不限于,肾上腺素、伪麻黄碱、氧甲唑啉、苯肾上腺素、tetrahydrozolidine和丁苄唑啉。可使用的粘液溶解药包括但不限于,乙酰半胱氨酸、α脱氧核糖核酸酶和愈创甘油醚。亦可使用抗组胺药诸如氮 斯汀、苯海拉明和氯雷他定。
在需要从组织中除去水的那些实例中,例如,从息肉或水肿组织中除去水,可使用高渗性成分。适合的高渗性成分包括但不限于,呋塞米、氯化钠凝胶、或其他直接或间接改变粘膜层容积渗克分子含量的可从组织或物质中吸水的盐制剂。
活性剂可占装置中释放部分(例如,腔体部件、鼻窦口部件、和/或鼻部分)或释放物质(例如,有活性剂的一层或多层)重量组成的从约0.01%至约95%、从约0.01%至约90%、从约0.01%至约80%、从约0.01%至约70%、从约0.01%至约60%、从约0.01%至约50%、从约0.01%至约40%、从约0.01%至约30%、从约0.01%至约20%、从约0.01%至约10%、从约0.01%至约5%、从约0.01%至约1%、从约0.01%至约0.25%。活性剂的用量通常依赖于诸如加入的个别成分、要治疗的鼻窦病症、和临床症状的严重程度,但在所有情况下通常是通过递送到鼻窦有效治疗鼻窦病症的 量。例如,当治疗鼻窦炎症时,装置可做成每天递送糠酸莫米松入鼻窦的量,从约1μg至约100μg,从约10μg至约50μg,从约10μg至约40μg,从约10μg至约30μg,从约10μg至约25μg,从约10μg至约20μg。在另一个变体中,装置可做成每天递送丙酸氟替卡松入鼻窦的量,从约10μg至约700μg,从约25μg至约400μg,从约75μg至约300μg,或从约100μg至约200μg。在一些实例中,本文所述的方法和装置可使用药物的结晶形式,例如有水和无水结晶形式。例如,可使用糠酸莫米松一水合物。
活性剂可加入腔体部件、鼻窦口部件、和/或鼻部分中并从中释放出来。在另一个变体中,活性剂可包衣在腔体部件、鼻窦口部件、和/或鼻部分的表面。一个包衣的示例性方法可通过活性剂溶解或混悬在溶液或熔化的可生物降解或非生物降解聚合物中实现。在另一个示范性方法中,活性剂可以粉末包衣在已被做成粘性的丝的表面通过例如,加热或用溶剂或增塑剂软化的方法包衣。在又一个变体中,微囊化药物可加在腔体部件、鼻窦口部件、和/或鼻部分的表面。如前面所提及,活性剂可加入到装置的所有部件中或加入到装置的特殊部件中(例如,腔体部件和鼻窦口部件、鼻部分和腔体部件等)。
活性剂可包括在装置中以便使释放结果有差异。差异释放可以是相同活性剂或不同的活性剂。例如,单个活性剂的可调释放可通过使用诸如大量载药、表面包衣(例如,通过较高的载药层)、表面载药(例如,通过包埋、喷雾、或吸附药物在装置表面,等),及其他本技术领域公知的技术实现。不同活性剂的可调释放可通过例如,将药物分成其自身可能有不同的通透性或生物降解特性的不同层、贮库、和/或微球,以及通过本技术领域的其他公知的技术实现。
聚合物。当装置是用聚合物制作时,使用的可生物降解或非生物降解的聚合物的选择将依据所需的滞留时间和释放动力学、装置递送的方法、使用的特定的治疗剂等而不同。在所有的实例中,当降解时可生物降解聚合物产生生理可接受的降解产物。可生物降解或非生物降解聚合物可构成至少约5%、至少约10%、至少约20%、至少约30%、至少约40%、至 少约50%、至少约60%、至少约70%、至少约80%、至少约90%、至少约95%、或至少约100%的装置重量或制作的元件重量(例如,窦腔体部件、鼻窦口部件、或鼻部分)。
适合使用制作鼻窦装置的可生物降解和生物相容聚合物包括但不限于聚合物诸如聚(丙交酯);聚(乙交酯);聚(丙交酯-共-乙交酯);聚乳酸;聚乙醇酸;聚(乳酸-共-乙醇酸);聚丙交酯/聚乙二醇共聚物;聚乙交酯/聚乙二醇共聚物;聚(丙交酯-共-乙交酯)/聚乙二醇共聚物;聚乳酸/聚乙二醇共聚物;聚乙醇酸/聚乙二醇共聚物;聚(乳酸-共-乙醇酸)/聚乙二醇共聚物;聚羧基乙酸内酯;聚羧基乙酸内酯/聚乙二醇共聚物;聚原酸酯;聚磷腈;聚羟基丁酯或包括聚羟基丁酯的共聚物;聚(丙交酯-共-羧基乙酸内酯);聚碳酸酯;聚酯酰胺;聚酐;聚二 烷酮;聚(亚烷基烷基化物);聚乙二醇和聚原酸酯的共聚物;可生物降解的聚氨基甲酸酯;聚氨基酸;聚醚酯;聚缩醛;聚腈基丙烯酸酯;聚氧乙烯/聚氧丙烯共聚物;或其混合物或共聚物。可生物降解形状记忆聚合物,诸如那些由在德国Abachen的nmemoScience公司商品化的,或美国5,189,110或美国5,139,832中描述的那些亦可使用。
如本文所用,聚丙交酯;聚乙交酯;聚(丙交酯-共-乙交酯);聚乳酸;聚乙醇酸;聚(乳酸-共-乙醇酸)全部指的是PLG、PLG聚合物、或丙交酯/乙交酯聚合物。本发明的用于药物递送装置和组合物的丙交酯/乙交酯聚合物是一般地通过丙交酯和乙交酯单体开环熔融聚合而制成。一些有或无羧基端基的聚合物是可获得的。当聚(丙交酯-共-乙交酯)、聚丙交酯、或聚乙交酯的端基不是羧基例如是酯基时,那么得到的聚合物本文是指封闭的或封端的。未封闭的聚合物相反地有末端羧基。在一个变体中,使用了线型丙交酯/乙交酯聚合物;但是,亦可使用星形聚合物。在其他变体中,可使用高分子量聚合物制作本发明的装置,例如,为了适应强度要求并延长生物吸收时间。在其他实例中,当再吸收时间和材料强度不重要时可使用低分子量聚合物。聚合物的丙交酯部分有不对称碳。消旋的DL-、L-和D-型聚合物有商品化的可包括在本发明的装置中。L-型聚合物是更多结晶型 的,且吸收较DL-型聚合物更慢。除了含乙交酯和DL-丙交酯或L-型丙交酯的共聚物以外,L-丙交酯和DL-型丙交酯的共聚物亦可购得。另外,丙交酯和乙交酯的均聚物是可购得的。丙交酯或乙交酯或丙交酯/乙交酯共聚物的星形聚合物也是可购得的。
当可生物降解聚合物是聚(丙交酯-共-乙交酯)、聚丙交酯或聚乙交酯时,丙交酯和/或乙交酯在聚合物中的量可以变化。在一个变体中,可生物降解聚合物包含从约0至约100%摩尔、从约40-约100%摩尔、从约50-约100%摩尔、从约60-约100%摩尔、从约70-约100%摩尔、或从约80至约100%摩尔的丙交酯、和从约0至约100%摩尔、或从约0至约60%摩尔、从约10至约40%摩尔、从约20至约40%摩尔、从约30至约40%摩尔的乙交酯,其中丙交酯和乙交酯的量是100%摩尔。在其他变体中,可生物降解聚合物可以是聚丙交酯,约85∶15聚(丙交酯-共-乙交酯)、约75∶25聚(丙交酯-共-乙交酯)、约65∶35聚(丙交酯-共-乙交酯)、或约50∶50聚(丙交酯-共-乙交酯),其中比例是摩尔比。
在其他变体中,当可生物降解聚合物是聚(丙交酯-共-乙交酯)、聚丙交酯、或聚乙交酯时,聚合物在氯仿中浓度为0.5g/dL、30℃下测量的固有粘度为,从约0.15至约1.5dL/g、从约0.25至约1.5dL/g、从约0.25至1.0dL/g、从约0.25至约0.8dL/g、从约0.25至约0.6dL/g、或从约0.25至约0.4dL/g。
如果使用非生物降解聚合物制作或加入至装置或组合物中,适当的非生物降解聚合物包括但不限于,聚(乙烯乙酸乙烯酯)、聚(乙酸乙烯酯)、硅酮聚合物、聚氨基甲酸酯、多糖诸如纤维质聚合物和纤维素衍生物、酰基取代的纤维素醋酸酯及其衍生物、聚乙二醇和聚(对苯二甲酸丁二醇酯)的共聚物、聚苯乙烯、聚氯乙烯、聚氟乙烯、聚乙烯咪唑、氯磺化聚烯烃、聚氧化乙烯、及其共聚物和混合物。
再者,装置可用任何有粘膜吸附性的生物相容性、可生物降解或非生物降解聚合物制作。在一些实例中,腔体部件、鼻窦口部件、和/或鼻板可用粘膜吸附性材料包衣,粘膜吸附性材料可以是聚合物或不是聚合物。本装置亦可用载有电荷的聚合物制作。
在另一个变体中,可使用天然聚合物。装置中可能包含的代表性天然聚合物包括但不限于蛋白质,诸如玉米朊、改性玉米朊、酪蛋白、甲壳质、明胶、谷蛋白、血清白蛋白、或胶原,和多糖,诸如纤维素、葡聚糖、和聚透明质酸。多糖水凝胶或溶胶-凝胶混合物亦可以使用。
其他材料。在一些变体中,装置可以用金属制作。适合的金属实例包括但不限于钴、铬、镍、铂、不锈钢、钛、钽、和它们的任意合金,如,镍-钛合金、及其组合。
附加剂。本发明的装置和组合物可进一步包括诸如防腐剂、缓冲剂、粘合剂、崩解剂、润滑剂、及任何其他保持装置的结构和/或功能的必需的赋形剂。例如,可弯折丝可做成包含可软化装置的可生物降解或非生物降解聚合物的增塑剂或溶剂诸如丙酮、甲基乙基酮、乳酸乙酯、乙酸乙酯、二氯甲烷、或乙酸乙酯/乙醇混合溶剂。增塑剂或溶剂在腔体部件展开和膨胀后从装置中分散或释放至鼻窦粘膜中,以使聚合物丝(装置的)变硬以便装置能基本上适应鼻窦腔的形状,且一定程度地提供了较好的摩擦力,适合腔体部件抵靠着鼻窦腔壁。
此外,如前文所述,可弯折丝亦可包含粘膜吸附性聚合物以改善腔体部件与鼻窦粘膜的接触。可使用的粘膜吸附性聚合物的实例包括丙烯酸单体的均聚物诸如聚丙烯酸和其任何可药用盐;丙烯酸和甲基丙烯酸、苯乙烯、或乙烯醚的共聚物;乙烯聚合物类诸如聚羟乙基丙烯酸酯、聚羟乙基甲基丙烯酸酯、聚乙烯醇、和聚乙烯吡咯烷酮;纤维素衍生物类诸如甲基纤维素、乙基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、和羧甲基纤维素;多糖诸如海藻酸、海藻酸钠、和黄蓍胶;胶原;明胶;和其任意组合。
释放动力学。本文所述装置可用活性剂分散或溶解在可生物降解聚合物骨架中的粒子制成,并制成以提供活性剂的缓慢释放。如果用非溶胀型聚合物例如丙交酯/乙交酯聚合物制备,活性剂从骨架中的释放最可能通过可生物降解聚合物骨架的溶蚀和/或通过活性剂向鼻窦的粘膜层扩散实现。可能影响释放动力学的因素包括活性剂粒子的大小、活性剂的溶解度、活 性剂和聚合物的比例、聚合物的孔隙率、装置的生产方法、装置暴露的表面积、装置的表面积与体积比、和骨架聚合物的溶蚀速率等特性。
活性剂从装置中释放可在较长的时间阶段,包括但不限于,至少约一周,至少约两周,至少约三周,至少约四周,至少约两个月,至少约三个月,至少约四个月,至少约五个月,至少约六个月或更长。在一个变体中,治疗剂在约两周至约四周的时间里释放。
鼻窦装置的药物释放特性可以用各种技术调节,诸如通过使用不同的药物、聚合物、和赋形剂或调整它们在制剂中用量、使用释放和药物屏障层、差异化小球、微球或微囊的构建(用不同分子量或厚度的壳)等等,这些是本领域熟知的技术。释放的持续时间亦可通过聚合物混合比例、单体平均分子量及衣层进行调节。
如前面已经提及的,亦可实现药物的差异释放。差异释放可以是相同活性剂的或不同活性剂的。例如,单一活性剂的可调释放可使用诸如大量的载药、表面包衣(例如,通过有较高的载药层)、表面载药(例如,通过包埋、喷雾、或在装置表面吸附药物等)、及其他本领域熟知的技术实现。不同活性剂的可调释放可以通过将药物分割至不同层、贮库和/或微球以及通过其他本领域熟知的技术实现。
延迟药物释放,如图24A所示,对辅助治疗是有用的,如当前面给与患者静脉或口服甾体激素逐渐减少时,或当抗瘢痕形成和抗再狭窄成分在愈合过程较晚释放时。
基本上零级药物释放,如图24B所示对无创伤或瘢痕的慢性病维持治疗、或对治疗的抗感染药疗程、提供恒定的平衡药物浓度并使受体靶占据水平最大化是有用的。
如图24C所示,在头5天至10天期间的上前仓推注(upfront bolus)药物释放,对手术后或植入插入外伤的治疗和在靠近手术解剖处产生最大扩散是有用的。
如图24D所示的延迟推注(bolus)药物释放对术后治疗是有用的,特别是清创术治疗的术后外伤改善。
如图24E所示,随着装置完全生物吸收而增加的降解依赖释放,由于可生物吸收,对任何植入/装置除去外伤或并发症的预防是有用的。
通过将不同药物释放方法整合(对一种或多种药物)在一个装置中,以上药物释放曲线的任意组合是可能的。例如,如图24F所示,初始推注的组合,接着是基本上的零级释放,接着是最终的猛烈释放,对装置的术后应用、治疗手术和植入外伤(最初的推注)然后是手术愈合和疾病复发(基本上的零级)、及最终任何植入物的除去外伤(最终的释放爆发)是特别有用的。
应用
装置的治疗作用。鼻窦装置的结构本身亦可以有治疗功能。例如,装置可提供如通过空间填补、固定、偏转固定或分裂组织这样的功能,以便提供支持,并维持身体结构开放,因为在支架或填塞防止中鼻甲单侧化和中部孔道阻塞,或通过对各种术后和/或发炎组织表面之间形成的粘连物提供物理障碍。例如,可使用加有固体、半固体(凝胶)或编织的或非编织筛网结构的任何装置实践本方法。在另一个变体中,装置可以非封闭地保持整个植入特征区开放,提供装置可通过从鼻窦到漏斗管的通道、窗体或孔道、osteomeatal complex、粘液流动可能经过的鼻孔或鼻道的直接提供和维护起作用。这样的途径可能在天然鼻窦口结构之内并支持该结构,或在手术产生的或改善的鼻窦解剖之内并支持该结构,但可能不会全部堵塞开口。例如,有内腔或孔诸如管子或插管、或内腔支架的任何装置,可用于实践该方法,可能用作高度多孔的支持材料,三维筛网、或粘液可能流经的装置表面或内部结构,且通过吸收、膨胀或降解不能成为提供的通道的阻塞物。
降低植入并发症。在另一个变体中,装置可能有帮助降低装置植入并发症的结构特征或活性剂。例如,装置可1)通过使用生物可吸收材料防止由于装置去除产生的外伤;2)通过使用包衣、物理表面处理、和/或抗感染或抗菌物质的加入或洗脱防止生物膜的形成;3)通过加入低剂量抗炎物质包括甾体和非甾体抗炎剂(例如,包括低剂量大环内酯类抗生素的抗炎效应)防止异物反应;和4)通过加到装置中的特别的主动或被动固定和锚固特征 防止装置迁移。可用于防止生物膜形成的物质包括但不限于,乙醇、氯己定、碘、三氯森、六氯酚、和基于银的药物(例如,氯化银、氧化银、银纳米粒)。在其他变体中,装置表面可用改变装置表面的物理性质的方法(例如,离子包埋,血浆蚀刻等)以防止生物膜的形成。
粘膜纤毛清除的利用。正常的粘膜纤毛清除可用于扩展药物扩散,且影响超出装置的物理位置。这对正常和特别是病理状态的粘膜纤毛流动型式两者都是有用的。在后一种情况下,在正常的粘膜纤毛流动被疾病阻断或妨碍时,装置对影响构建在阻断状态下治疗上所需的释放药物浓度和增加在粘膜纤毛功能被疾病影响最严重处的药物浓度梯度是有用的。解剖学阻断和粘膜纤毛机能障碍和或纤毛缺乏活力的区域可能是药物治疗特别需要的区域(例如,抗炎药和抗感染药,但亦包括化疗药),以便“化学开放”阻断并增加对损伤的粘膜的治疗。这样,天然鼻窦和沿着粘膜纤毛清除路径的上流位置可作为药物贮库,药物以此路径移动到下游的所需位置。这与本领域以往的和通常的教训——寻求妨碍或降低活性剂的粘膜纤毛清除以便使剂量持续时间最大化是有差别的。
除了治疗前面提及的鼻窦病症的任何一种以外,本文描述的装置可在手术、非手术、或鼻窦或鼻道的其他治疗干预期间放置,或作为辅助。例如,装置在这些过程期间使用或这些方法的辅助包括但不限于,鼻中隔成形术(鼻中隔的手术除去或调整);鼻甲成形术(鼻甲骨的去除或调整);一般的鼻成形术;鼻窦手术(包括探查、修正、修复、鼻窦的任何一些或部分的组织切割或去除,包括筛窦(像筛房切除术)、上颌窦、额窦或蝶窦);鼻窦和鼻道的任何部分的息肉去除;任何上述鼻窦或鼻道的套管插入术、冲洗、和治疗滴注或注射,包括穿过鼻、穿过窦口、和外部穿刺的方法(例如通过上颌窦穿刺、环钻术或″Caldwell-Luc″法);鼻窦和鼻道的解剖学的手术修正、切割、重建或修复,包括新生物、异物、损伤、粘连、缺损、狭窄、和天然的或术后解剖的瘘管的任何去除或调整;为了控制鼻出血的结扎、烧灼、和切除方法和修复鼻窦和鼻道解剖学上的脉管系统,或作为进行任何这样的手术或非手术方法的技术的辅助。
因此,本文所述的装置可有各种功能。例如,它们可递送活性剂治疗鼻窦炎,有防止中鼻甲单侧化和粘连形成的结构,有直接或间接保持鼻孔开放的结构,以及有防止生物膜形成的衣层。装置可作成包括以上功能的任意数量和组合。
递送装置和使用方法。鼻窦装置可以使用各种类型的鼻窦插入器放置到鼻窦中。插入器可包括导管,例如具有内腔的导管。导管可以是弹性的或刚性的,或可以设计成有沿着长向的各种强直角度,例如,导管的远侧部分可能比近端部分更刚性。另外,导管远侧部分可成各种角度以方便放置及导管通过窦口前进。例如,远侧部分可弯成的角度从约0°至约175°,从约0°至约135°、或从约0°至约90°。如果需要,导管的远侧部分亦可作成有延展性的。
导管可以用任何生物相容性材料做成,包括但不限于,不锈钢和任何其合金;钛合金,例如镍-钛合金;聚合物,例如,聚乙烯和其共聚物、聚对苯二甲酸乙酯或其共聚物、尼龙、硅酮、聚氨基甲酸酯、含氟聚合物、聚氯乙烯、及根据所需弹性或刚性的量这些材料的组合。
插入器可以用单个鼻窦装置在导管远端上或内部预装,但是如果需要可预装多于一个装置。可通过医师在插入前预装插入器上或内部,或在生产过程中预装到插入器上或内部。一旦带着导管通过窦口或手术产生的窗进入,护套可收缩滑动地展开装置的鼻部分。如果腔体部件是自膨胀的,则护套的收缩亦引起腔体部件展开。如果需要使用气球膨胀,任何已知技术的气球插管(包括双气球插管)可以先通过导管内腔进入直到气球位于腔体部件内部。气球打气从而引起腔体部件从第一个瘪的状态到第二个膨胀的状态,并与窦腔壁接触。内窥镜亦可在放置插入器时使用,以有助于窦口的观察。如果需要亦可使用灌洗工具和电烙术。
以下描述提供了单个装置使用鼻窦插入器展开进入鼻窦中的示范方法。鼻窦插入器一般包括远侧部分、远侧部分上缩瘪状态中的鼻窦装置、手柄、有内腔的导管、和连在可缩回把手的护套。在拉开可缩回把手后,把手移动接近手柄近端并滑动展开装置的自膨胀鼻板。气球插管然后可通 过导管内腔进入插入器的远端部分,并充气以扩展鼻窦装置,例如图4A-4B的弹性筛网40。
生产方法。制备本发明装置的方法一般依赖于使用的特别活性剂或聚合物、腔体部件的形式、及所需释放动力学,但可通过本技术领域已知的无数方法中的任意一种制作。例如,装置可用挤出;注射或塑型;击打、成膜、或熔铸;焊接;和其他本领域熟知的生产技术(例如,切割和退火)制作。丝可以湿法或熔法自旋,用激光或其他切割法作成,纵切制作、挤压制作,注射或其他塑型、或铸造。
实施例
以下实施例用于更全面地描述以上所述装置的制作和使用方法。应当理解这些实施例绝非限制本发明的领域,展示是为了达到解释的目的。
另外,除非另外说明,以下实施例将使用药物制剂、药物化学等的传统技术,它们是本领域技术人员了解的。这些技术在文献中完全可以解释。已作努力以确保数字的准确(例如,数量、温度,等),但应当说明会有一些试验误差和偏离。除非说明,份是重量份,温度是摄氏度(℃)且压力是在海平面大气压或接近之。所有元件是可购得的,除非另外说明。
实施例1:含5%重量的糠酸莫米松的纤维的熔融挤出
挤出的带状纤维是用糠酸莫米松和聚(DL-丙交酯-共-乙交酯)做的。装置中所需的糠酸莫米松含量是5%重量的糠酸莫米松。聚(DL-丙交酯-共-乙交酯)是摩尔比为70/30DL-丙交酯/乙交酯封端的酯,固有粘度为0.81dL/g。固有粘度是在30℃、在氯仿中的聚合物浓度为0.5gm/dL时测定的。
首先糠酸莫米松(0.5gm)和聚(DL-丙交酯-共-乙交酯)(9.5gm)溶解于二氯甲烷(40gm)中。从制得的溶液浇铸薄膜。浇铸的膜真空干燥箱中干燥48-96h以除去残留的二氯甲烷。浇铸的膜切割成约10-20mm宽、100-150mm长的窄条。接下来,Tinius Olsen UE-4-78熔化塑性计用于挤出浇铸的膜条。Tinius Olsen是约80mm直径的实心的成块的钢,约160mm高/长,有约13mm直径的空心。核心的出口有基于挤出条所需直径允许使 用不同大小的“模”的肩状物。为此,使用具有内核直径0.3556mmx2.0015mm的定做的机制模。Tinius Olsen的主体部分有被隔离包装的加热带和允许Tinius Olsen被加热到所需温度的护罩。热电偶测量钢块的温度。控制系统则使用热电偶值将加热带打开或关闭。在整个挤出过程中,加热带将关闭并打开以维持所需温度。浇铸的膜条约4gm,装在已在120℃平衡的Tinius Olsen中。装料棒置于Tinius Olsen的核心中以压缩混合物,10kg的重量置于装料棒端以有助于混合物压紧。用于熔化混合的平衡时间至少约20min。在10000gm挤出装载置于装料棒后,塞子从出口区域移去开始挤出操作。当带纤维从排出口挤出时,使用传送带拉出到所需尺寸(0.3-0.4mm*1.0-1.2mm)。4-gm装料提供7-10段每段有约100cm长的挤出纤维。
实施例2:含5%重量的糠酸莫米松和2%重量的枸橼酸三乙酯的纤维的熔融挤出
挤出的带纤维是用糠酸莫米松、枸橼酸三乙酯(增塑剂)和聚(DL-丙交酯-共-乙交酯)做成的。装置中所需的糠酸莫米松含量是5%重量的糠酸莫米松。聚(DL-丙交酯-共-乙交酯)是DL-丙交酯/乙交酯的摩尔比为70/30的封端酯,且固有粘度为0.81dL/g。固有粘度是在30℃在聚合物在氯仿中的浓度为0.5gm/dL下测定的。
首先糠酸莫米松(0.5gm)、枸橼酸三乙酯(0.2gm)和聚(DL-丙交酯-共-乙交酯)(9.3gm)溶于乙酸乙酯(40gm),薄膜从所得的溶液中浇铸出来。浇铸膜在真空干燥箱中干燥48-96h以除去残留的二氯甲烷。浇铸膜切成约10-20mm宽和100-150mm长的薄带。接下来,Tinius Olsen UE-4-78熔化塑性计用于挤出浇铸膜带。Tinius Olsen是约80mm直径、约160mm高/长的有约13mm直径空心的成块的钢。核心的出口有基于挤出条所需直径允许使用不同大小的“模”的肩状物。为此操作,使用具有内核直径0.3556mmx2.0015mm的定做的机制模。Tinius Olsen的主体部分有被隔离包装的加热带和允许Tinius Olsen被加热到所需温度的护罩。热电偶测量钢块的温度。控制系统则使用热电偶值将加热带打开或关闭。在整个挤出过程中,加热带将关闭和打开以维持所需温度。浇铸膜带约4gm,装在已在120 ℃平衡的Tinius Olsen中。装料棒置于Tinius Olsen的核心中以压缩混合物,10kg的重量置于装料棒端以有助于混合物压紧。用于熔化混合的平衡时间至少约20min。在10000gm挤出装载置于装料棒后,塞子从出口区域移去开始挤出操作。当带纤维从出口挤出时,使用传送带拉出到所需大小(0.3-0.4mmx1.0-1.2mm)。4-gm载荷提供7-10段每段有约100cm长的挤出纤维。
带纤维的各种组合物将按照与实施例1和2描述的相似技术制备。下表1列举了有不同量的糠酸莫米松、增塑剂、和孔隙率的这些制剂组合物,并显示使用不同处理溶剂(乙酸乙酯和二氯甲烷)制备放置到挤出机中的材料。
表1-通过熔融挤出的带纤维的组合物
实施例3:含2%重量的氟替卡松丙酸酯纤维的制备
纤维制剂可用氟替卡松丙酸酯与聚(DL-丙交酯)或聚(DL-丙交酯-共-乙交酯)制备。聚丙交酯或聚(丙交酯-共-乙交酯)可以是封端或有酸性端基的。纤维中所需的氟替卡松丙酸酯含量范围可以在0.1%重量至20%重量。为了制备氟替卡松丙酸酯的长效制剂,氟替卡松丙酸酯与聚(DL-丙交酯-共-乙交酯)或聚(丙交酯-共-乙交酯)的粒子可以用包括使用研钵/研棒或通过预制的聚合物和肽粒子在V-型混合器中混合以形成混合粉末的各种方法干混。接下来该混合物可以加至有2-mm直径机制模具的双螺旋挤出机中。挤出机的温度应在约120℃。因为纤维是从挤出机中挤出的,将在传送带上收集。
实施例4:有含5%重量的糠酸莫米松的带纤维的鼻窦装置的制备
如实施例1那样制作的带纤维,以下面的方式制作成鼻窦装置。四条带纤维切成约35mm,并如前文描述地盘成扫帚状结构。
实施例5:在用载有糠酸莫米松的鼻窦装置治疗期间家兔的鼻窦组织中糠酸莫米松水平的定量
如实施例4所述制备的鼻窦装置用2.5Mrad的γ辐射灭菌,并通过背侧鼻上颌窦切开术置于5kg家兔的上颌窦(右侧和左侧)。试验了三种制剂。它们是:
·PLG 69∶31有5%莫米松和0%枸橼酸三乙酯(TEC)
·PLG 69∶31有5%莫米松和2%TEC
·PLG 69∶31有10%莫米松和2%TEC
相同的制剂用于指定家兔的右侧与左侧两侧的鼻窦。植入了15只家兔。每种装置制剂植入5只家兔。在植入后5周的时间里约每周间隔取出装置。在取出装置的时间完全取出右侧和左侧的上颌窦粘膜。迅速冷冻组织,组织中的莫米松的量用液相色谱/质谱(LC/MS)定量。35天的时间里组织中保持的莫米松的量报告如下表,在需要的作用位点相当于10-5M-10-7M,在所有时间点证明了缓释和已知有治疗效果的组织浓度的药物水平的药物生物利用度(见下文)。
实施例6:糠酸莫米松从候选组合物中的体外释放
测定了糠酸莫米松从候选制剂中的体外释放,示于图25。为了实现体外释放研究,每个装置置于接受液——37℃的1.0%重量的十二烷基硫酸钠纳米纯净水中。在每个时间点,完全取走接受液,加入新鲜的接受液。每个时间点释放到接受液的莫米松的量用HPLC定量。
在第一个体外累积释放研究中,如图25所示,2%莫米松/4%TEC纤维中的糠酸莫米松的累积释放在第7天约6%,在第14天约11%,在第21天约14%,在第28天约15%。5%莫米松/0%TEC纤维中,累积的莫米松释放为第7天约4%,第14天约10%,第21天约12%,第28天约12%。5%莫米松/2%TEC纤维中,莫米松的累积释放在第7天约3%,在第14天约7%,在第21天约9%,在第28天约9%。10%莫米松/2%TEC纤维中,测量的莫米松的累积释放在第7天约4%,在第14天约9%,在第21天约12%,在第28天约12%。证实了由于体内聚合物的生物降解和清除的另外的药物释放,并在上文描述的组织浓度数据中可以直接观察到。
已发表的使用培养的人体气道上皮细胞的体外细胞模型指出了最强效的糖皮质激素,糠酸莫米松和丙酸氟替卡松的药物浓度剂量响应曲线开始于低至10-12M(皮摩尔),转录响应的EC50水平在10-10M(100皮摩尔,最大转录响应最多情况见于10-9M(纳摩尔)药物浓度)。已接受这些体外模型与药效的体内模型等价并高度相关(Romestan C.等人,丙酸氟替卡松和糠酸 莫米松有等效的转录效应,Clin Exp Allergy 2003;33:895-901)。
本文引用的所有出版物、专利和专利申请此处整体引用作为参考,相同程度地用于所有目的。仿佛每篇独立的出版物、专利或专利申请是特别地、个别地表明被引用作为参考。尽管上述发明已为了清楚地理解通过例证和实施例的方式描述部分细节,对本领域技术人员在本发明的教导下易于明白可进行某些变化和修改而不偏离所附权利要求书的精神和范围。
Claims (6)
1.治疗鼻窦病症的装置,其包括:
a)鼻窦插入器,其包含具有内腔的导管和远端部分;
b)在腔内或可释放地封闭于鼻窦插入器的远端部分的鼻窦装置,所述的鼻窦装置包含腔体部件、管状鼻窦口部件并任选鼻部分,其中腔体部件的多根可弯折丝被做成缨状结构,
其中的腔体部件具有第一个允许装置穿过鼻窦口或外科产生的窗内的缩瘪的外形和第二个在放置到鼻窦腔内后膨胀的外形。
2.权利要求1的装置,其中所述的鼻窦装置通过经由导管内腔推动推杆被递送入鼻窦腔。
3.权利要求1的装置,还包含护套。
4.权利要求3的装置,其中所述的鼻窦装置通过拉回护套以展开鼻部分和鼻窦口部件并膨胀腔体部件而被递送入鼻窦腔内。
5.权利要求1的装置,其中所述的鼻窦插入器预装鼻窦装置。
6.权利要求1的装置,其中所述的鼻窦病症是由于功能性内窥镜鼻窦手术(FESS)的鼻窦炎症。
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- 2006-04-04 JP JP2008505446A patent/JP5247428B2/ja active Active
- 2006-04-04 CN CN2006800195395A patent/CN101189016B/zh active Active
- 2006-04-04 WO PCT/US2006/012484 patent/WO2006107957A2/en active Application Filing
- 2006-04-04 KR KR1020077025552A patent/KR20080005939A/ko not_active Application Discontinuation
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- 2006-04-04 RU RU2007140909/14A patent/RU2007140909A/ru not_active Application Discontinuation
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