CN105664197A - 冷电离辐射灭菌 - Google Patents
冷电离辐射灭菌 Download PDFInfo
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Abstract
本发明涉及冷电离辐射灭菌。形成可水合凝胶的聚合物的灭菌可通过将该聚合物在周围温度以下冷冻并利用电离辐射(例如,电子束辐射)对该冷冻聚合物灭菌来进行。这样做可以降低周围温度下聚合物的电离辐射灭菌所引起的物理性能的降解,并可以保持或保留期望的水合或形成凝胶的特性。
Description
本发明专利申请是2009年4月23日提交的国际申请号为PCT/US2009/041593、国家申请号为200980117591.8的中国专利申请的分案申请。
技术领域
本发明涉及聚合物灭菌。
背景技术
多种聚合物已用于制备外科植入物和组织密封剂,或用于执行手术修补和药物递送。为了满足患者安全方面的考虑并满足管理要求,含有此种聚合物的医疗产品通常在生产场所灭菌。已采用多种灭菌技术,包括化学处理(例如,环氧乙烷气体或过氧化氢)、加热(例如,蒸汽)和电离辐射(例如,γ辐射、紫外线、X-射线或电子束(E-Beam)处理)。
含有多糖或其他聚合物的医疗产品可以以干燥可水合形式(例如,作为粉末或海绵体)提供给医疗专业人员,并且水合(例如,再水合)以形成供随后安置在患者中的湿性可成形产品(例如,粘性凝胶或可压缩海绵体)。
发明内容
在一些情况下,可水合的医疗产品在水合过程中或之后,或者在患者安置(patientplacement)过程中或之后需要表现出特殊的物理特性。例如,形成可水合凝胶的聚合物可能需要一种或多种性能,例如快速、无团块水合(clump-freehydration);当喷洒或注射时的触变行为;一旦固定就位后的高粘度和粘性凝胶特性;可控的生物降解;对过早生物降解的抗性;或分解或移位而不产生大块固体的能力。可水合海绵体可能需要一种或多种性能,例如拉伸强度;弹性;被压缩之后缓慢或快速的形状回复;可控的生物降解;对过早生物降解的抗性,或分解或移位而不产生大块固体的能力。聚合物分子量可以强烈影响这些性能。利用电离辐射灭菌可能引起大量聚合物断链和分子量大幅度减小,聚合物性能随之发生实质性变化。当使用γ射线灭菌时,聚合物降解程度可能特别严重,但当使用其他电离辐射灭菌技术时也可观察到明显降解。利用蒸汽或环氧乙烷灭菌(典型地在水蒸气的存在下进行)可使聚合物水合并过早地将其转变成凝胶形式,从而限制或防止随后在产品安置的预期时间的再水合。
在一方面,本发明提供了聚合物灭菌的方法,该方法包含:
a)提供在周围温度以下(例如,冷冻到约15℃以下的温度)冷冻的形成可水合凝胶的聚合物;和
b)利用电离辐射对该冷冻聚合物灭菌,从而提供无菌聚合物。
在优选的实施方式中,该冷冻聚合物是利用电子束辐射灭菌的。与周围温度聚合物的电离辐射灭菌相比,所公开的方法可以降低聚合物断链和物理性能的变化。该方法对于维持将要喷射到治疗部位上的形成可水合凝胶的聚合物的可接受物理性能特别有用。
在另一方面,本发明提供了包含形成无菌可水合凝胶的聚合物的医疗设备,该形成无菌可水合凝胶的聚合物的多分散指数比该聚合物在未灭菌时的(即,在灭菌之前该聚合物的)多分散指数大,或者该形成无菌可水合凝胶的聚合物的重均或数均分子量比当该聚合物在周围温度下时利用电离辐射灭菌(例如,利用电子束辐射)时的各自重均或数均分子量大。
在另一方面,本发明提供了治疗方法,该方法包含使公开的形成无菌可水合凝胶的聚合物水合从而形成粘性水凝胶,和将一层粘性水凝胶注射或喷洒到组织(例如,粘膜组织)或其它机体结构上。
具体实施方式
下面的具体实施方式描述了某些实施方式,并且不能认为具有限制性的意义。本文中的所有重量、数量和比率为按重量计,除非另外具体地注明。下面显示的术语具有下列的含义:
术语“周围温度”表示正常的室温,例如20℃。
术语“抗微生物的”是指在金黄色葡萄球菌、铜绿假单孢菌、肺炎链球菌、流感嗜血杆菌或粘膜炎莫拉菌(Moraxellacatarrhalis)的一种或多种的群体中导致大于90%的数值减少(即,至少1个对数数量级的减少)的能力。
术语“生物相容性的”当用来提及物质时是指该物质表现出对身体的不显著的有害或不良作用。
术语“生物可降解的”当用来提及物质时是指该物质在体内将降解或蚀解以形成小的化学或物理种类。此类降解过程可以是酶促的、化学的或物理的。
术语“生物可吸收的”当用来提及物质时是指该物质能够被身体吸收。
术语“粘性的”当用来提及液体或凝胶时是指当置于水平面上时该液体或凝胶将趋于(但不一定在所有情况下)粘住其自身并且形成单一团块。
术语“粉碎的(研细的,comminuted)”当用来提及颗粒物质时是指颗粒已经通过切割、磨碎、粉碎、捣碎或采用外部施加力量的其他颗粒破碎工艺被破碎并且尺寸减小。术语“流体”当用来提及物质时是指该物质是其损耗模量(G″)大于其储能模量(G′)且损耗角正切值(tanδ)大于1的液体。术语“凝胶”当用来提及物质时是指该物质是可变形的(即,不是固体),G″小于G′且tanδ小于1。
术语“胶凝”当用来提及凝胶层的形成时是指G″等于G′且tanδ等于1的时刻。
术语“形成可水合凝胶的”当用来提及聚合物时是指该聚合物在干燥形式下可以与水结合从而形成粘性水凝胶。
术语“水凝胶”当用来提及凝胶时是指该凝胶是亲水性的且含有水。
术语“水合的”当用来提及装置或物质时是指该装置或物质含有均匀分布的化学键合的水。“完全水合的”装置或物质不能吸收额外的水合作用的水。“部分水合的”装置或物质能够吸收额外的水合作用的水。
术语“粘膜粘着剂”当用来提及装置或物质时是指该装置或物质将粘附于粘液被覆上皮。
术语“鼻腔或窦腔”是指在鼻和窦内限定正常充气通道和小室的各种组织,包括但不限于鼻孔(nostrils)或鼻孔(nares)、鼻甲(nasalconcha)或鼻甲骨(turbinate)、额窦、筛窦、蝶窦和上颌窦、窦口(sinusostia)和鼻咽(nasopharnyx)。
术语“多分散性”和“多分散指数”是指比率Mw/Mn,其中Mw是重均分子量,Mn是数均分子量,它们都利用带多角度光散射检测器的尺寸排阻色谱法测得(SEC-MALS)。
术语“多糖”包括多糖的衍生物和改性多糖,以及各多糖种类和改性的各多糖种类的衍生物。例如,术语“羧甲基纤维素”包括羧甲基纤维素衍生物和改性的羧甲基纤维素,术语“壳聚糖”包括壳聚糖衍生物和改性的壳聚糖,术语“淀粉”包括淀粉衍生物和改性淀粉。
术语“保护性的”当用来提及在组织或其他身体结构上的组合物层时是指该层有助于使损伤的、发炎的或手术修补的组织表面恢复至正常状态,例如,通过一种或多种愈合机制诸如炎性应答的调节、吞噬作用、粘膜重塑、纤毛再生或其他正常功能的完全或部分恢复。
术语“停留时间”当用来提及在组织或其他身体结构上的保护性凝胶层时是指在肉眼观察下凝胶层或其一部分在体内仍然就位所持续的时间期限。
术语“溶剂化”是指形成含有溶剂或其他载体的溶液或分散体,溶质溶解或悬浮在所述溶剂或载体内。
术语“无菌的”和“灭菌的”当用来提及装置或物质时是指当根据ISO标准11135:1994(E)评价时该装置或物质不含活的微生物,或者是指装置或方法具有小于10E-3的无菌保证水平(SAL)(SterilityAssuranceLevel),该无菌保证水平是基于灭菌之后产品单元上存在的活的微生物的概率确定的。“未灭菌的”装置或物质不是无菌的装置或物质,并且“未灭菌的”装置或物质是未经历灭菌过程的装置或物质。
术语“基本上不含胶原的”是指含有足够低量的胶原使得不会造成传播或感染牛海绵状脑病(BSE)或变异性克雅氏病(variantCreutzfeldt-Jakobdisease)(vCJD)。
术语“薄的”当用来提及在组织或其他身体结构上的保护层时是指具有小于约2毫米的平均厚度。
所公开的方法和医疗设备中可以采用各种各样的形成可水合凝胶的聚合物。该聚合物可以是可交联的或不可交联的,并且在聚合物的混合物中的一种或所有聚合物可被交联。该聚合物期望地为水溶性的或可以,例如通过适当酸化使其为水溶性的。该聚合物可以是液体、凝胶或固体。如果为液体,该聚合物期望地为可交联的并且与合适的交联剂结合从而致使凝胶形成。如果为固体,该聚合物期望地为颗粒形式从而促进更快速的水合和凝胶形成,例如,为平均颗粒直径小于约1mm、小于约100μm、约1到约80μm或小于约1μm的自由流动的颗粒。聚合物可具有各种分子量,例如灭菌之前重均分子量为约7到约3000kDa、约15到约750kDa或约15到约500kDa,并且灭菌之前数均分子量为约5到约2000kDa、约10到约500kDa或约10到约300kDa.
含有聚合物混合物的组合物是特别期望的,因为此种组合物可以使其性能无法利用单一聚合物提供的水凝胶和海绵体形成成为可能。例如,通过改变共混物中两种聚合物的比率,可以改变该共混物的生物可降解或生物可吸收特性和停留时间。两种聚合物的混合物可以例如含有约99到约1%的第一种聚合物和约1到约99%的第二种聚合物,或约80到约20%的第一种聚合物和约20到约80%的第二种聚合物,或约60到约40%的第一种聚合物和约40到约60%的第二种聚合物。通过适当地选择混合物中聚合物的类型和量,可以获得具有可调性质的可再水合凝胶和海绵体。
用于公开的方法和医疗设备中的示例性聚合物包括聚乙二醇(“PEG”)、甲氧基聚乙二醇(“MPEG”)和其它聚氧乙烯类;包括明胶在内的胶原和胶原衍生物;多糖和多糖衍生物;可水合的聚氨酯类及其组合。聚氧乙烯类和多糖是特别期望的形成可水合凝胶的聚合物。示例性聚氧乙烯类包括来自Dow化学公司的CARBOWAXTM聚乙二醇、也来自Dow化学公司的相应CARBOWAXSENTRYTM食物和药物依从性聚乙二醇以及能够提供形成可水合凝胶的聚合物的其它生物相容性聚氧乙烯。示例性胶原和胶原衍生物可从各种来源获得,包括菜牛和猪的加工器。公开的医疗设备可以是基本上不含胶原的,并且期望地为充分不含胶原的(即,根本不含胶原)以便适于在全世界可销售,并不限于人类使用。示例性多糖包括琼脂、藻酸盐、角叉菜胶、纤维素、甲壳质、壳聚糖、硫酸软骨素、葡聚糖、半乳甘露聚糖、糖原、透明质酸、淀粉,和能够提供形成可水合凝胶的聚合物的其它生物相容性多糖。含有羧甲基纤维素(CMC)和壳聚糖的组合物可以提供特别期望的一组性能。其它期望的组合物包括含有壳聚糖和藻酸盐、透明质酸或硫酸软骨素的那些。
示例性纤维素包括CMC、甲基纤维素、乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素和半纤维素,以及其衍生物,包括氧化的纤维素。示例性纤维素材料可从各种商业来源获得,包括DowWolffCellulosics(例如,羧甲基纤维素钠产品的WALOCELTMCRT系列)、Hercules公司(例如,纤维素胶和羧甲基纤维素产品的AQUALONTM系列)和Sigma-Aldrich公司(例如,No.C4021微粒纤维素).
示例性的未修饰壳聚糖及其盐(包括柠檬酸盐、硝酸盐、乳酸盐、磷酸盐、氯化物和谷氨酸盐)可从多个商业来源获得,包括KitoZymeS.A.、FlukaChemieAG、FMCBioPolymerAS的NovaMatrix部门和Sigma-Aldrich公司。壳聚糖也可以通过水解使甲壳质(聚-N-乙酰基-D-葡糖胺)脱乙酰化以去除氮原子上的乙酰基来合成。生成的聚合物具有多个重复单位(例如,约30到约3000个重复单位,约60到约600个重复单位,或对于所选择的终端用途可能需要的此类其他量),它们的一些或全部含有脱乙酰化氨基(例如,全部重复单位的约30到约100%或约60到约95%),剩余的重复单位(如果有的话)含有乙酰化氨基。聚合物是阳离子的并且可以被认为由葡萄胺单体组成。壳聚糖可以是例如,灭菌之前的数均分子量小于约50kDa的超低分子量物质,灭菌之前的数均分子量为约50到约200kDa的低分子量物质,灭菌之前的数均分子量为约200到约500kDa的中分子量物质或灭菌之前的数均分子量大于约500kDa的高分子量物质。壳聚糖衍生物还可以采用,例如,其中一个或多个羟基或氨基已经被修饰以改变衍生物的溶解度或粘膜粘附特性的衍生物。示例性的衍生物包括硫醇化壳聚糖,以及非硫醇化壳聚糖衍生物,例如乙酰化、烷基化或磺化壳聚糖(例如,O-烷基醚,O-酰基酯,阳离子化三甲基壳聚糖和用聚乙二醇改性的壳聚糖)。壳聚糖衍生物可从多种来源获得。例如,硫醇化壳聚糖可从ThioMatrixForschungsBeratungsGmbH和MucobiomerBiotechnologischeForschungs-undEntwicklungsGmbH获得,或通过壳聚糖与合适的硫醇化试剂反应制备,如公开的PCT申请WO03/020771A1以及Roldo等人的Mucoadhesivethiolatedchitosansasplatformsfororalcontrolleddrugdelivery:synthesisandinvitroevaluation(作为口服控释药物递送平台的粘膜粘着剂硫醇盐化壳聚糖:合成及体外评估,EuropeanJournalofPharmaceuticsandBiopharmaceutics,57,115–121(2004));Krauland等人,ViscoelasticPropertiesofaNewinsituGellingThiolatedChitosanConjugate(新颖原位胶凝硫醇盐化壳聚糖的粘弹性特征,DrugDevelopmentAndIndustrialPharmacy,31,885-893(2005)),Bernkop-Schnürch,Thiomers:Anewgenerationofmucoadhesivepolymers(柳硫汞:新一代粘膜粘着聚合物,AdvancedDrugDeliveryReviews,57,1569-1582(2005));和Bernkop-Schnürch等人,Thiomers:Preparationandinvitroevaluationofamucoadhesivenanoparticulatedrugdeliverysystem(柳硫汞:粘膜粘着性粘膜颗粒药物递送系统的制备及体外评估,InternationaljournalofPharmaceutics,317,76-81(2006))中所述。
其他多糖(例如,琼脂、藻酸盐、角叉菜胶、甲壳质、硫酸软骨素、葡聚糖、半乳甘露聚糖、糖原、透明质酸、淀粉)的来源和类型可以由本领域技术人员基于与上面对纤维素和壳聚糖所给出的那些类似的选择特性来选择。当在多糖混合物中组合时,每种多糖的量可以广泛地变化以获得所需的性质组合。例如,CMC和壳聚糖的共混物可由于具有壳聚糖而具有良好的抑菌性能,和由于CMC而具有可控的、持续的和可调的降解速率,而单独使用壳聚糖可形成具有固有的较差的机械和再吸收性能的凝胶或海绵体,并且单独使用CMC可形成不具有杀菌性能的凝胶或海绵体。
示例性可水合聚氨酯类包括美国专利4,137,200中描述的那些、HYPOLTM亲水性聚氨酯预聚物(Dow化学公司,MidlandMI)和NASOPORETM鼻敷料(nasaldressing)(来自PolyganicsBV,Rozenburglaan,荷兰)。聚合物(一种或多种)在包装和发送至最终用户之前任选地交联。例如,可以采用与本申请同日提交的共同未决的PCT申请(代理案号P0027228.02和151-P-27228WO01)中描述的脱水热交联(dehydrothermalcrosslinking)工艺进行交联。对于公开的可再水合凝胶,这优选地通过将自由流动的可再水合聚合物颗粒脱水热交联以形成自由流动的可再水合交联聚合物颗粒来完成。换句话说,颗粒优选地是本身单独地被交联,而仍然是自由流动的并且能够以后快速地溶解和再水合。对于本发明的海绵体,交联优选地通过将成形的多孔物品脱水热交联来完成,所述物品已经通过将所需聚合物的溶液放置在合适的模具中并且将所述溶液冻干以形成具有与所需的非压缩的海绵体形状相对应的形状的多孔固体而制成。换句话说,海绵体优选地在交联之前成形和制备成多孔的。
交联也可以利用缩合反应(例如,导致失去水的脱水反应,导致失去诸如氯化氢、甲醇或乙酸等另外小分子的反应)、加聚合反应(例如,乙烯基的)、离子反应,或涉及硫化物或胺基团的反应进行。
当使用两种或更多种聚合物的组合时,在掺合聚合物之前交联可以对一种或多于一种的聚合物进行。这容许对下述的性质进行定制,所述性质诸如胶凝行为、胶凝时间和植入后的降解时间。如果需要,得到的共混物可以进行额外的脱水热交联反应,例如脱水热交联反应。聚合物还可以保持分开的状态,并且以后由终端用户混合,尽管这与在制造场所形成共混物相比通常会不太便利。
利用冷电离辐射灭菌法,使公开的形成可水合凝胶的聚合物从未灭菌形式转变成无菌形式。术语“冷”在这个上下文中是指利用电离辐射给在周围温度以下冷冻的聚合物灭菌,而不是指利用电离辐射给周围温度下的聚合物灭菌。应当注意,周围温度下聚合物的电子束灭菌在多种出版物中有时称为“冷”电子束灭菌,从而区分此种灭菌与升高温度的灭菌处理,如利用蒸汽或环氧乙烷。代替地,对于本申请,术语“冷电子束灭菌”是指利用电子束辐射给在周围温度以下冷冻的聚合物灭菌。
聚合物可以以各种方式冷冻,包括储存在冷藏箱中、与冷板接触、暴露到冷的干燥空气中、暴露到干冰中或暴露到液化的无水气体(例如,液体二氧化碳或液氮)中。例如,聚合物可以冷冻到15℃、10℃、5℃、0℃、-5℃、-10℃、-15℃、-20℃,或甚至更冷的温度或冷冻到这些温度之下(如在电子束暴露之前在聚合物样品内部中测得的),例如通过冷冻到接近或达到干冰大气压升华点(-79℃)或液氮大气压沸点(-196℃)的温度可以达到的。无菌聚合物可以比当在周围温度下时利用电离辐射灭菌的其它方面相似的聚合物经历更少的聚合物断链。一般地,当冷冻聚合物温度降低时,由电离辐射灭菌引起的聚合物断链程度可以同样地降低。根据所选的灭菌技术,冷冻可以在灭菌之前和灭菌过程中进行,或仅在灭菌之前进行。对于诸如γ辐射灭菌之类较缓慢的灭菌技术,在灭菌之前和灭菌过程中都需要冷冻。对于诸如电子束处理之类的较快速的灭菌技术,仅在灭菌之前进行冷冻就可能足够。
可以采用多种电离辐射灭菌源,包括γ辐射、紫外线、X-射线和电子束辐射。电子束辐射是特别期望的,这部分是因为它可进行的速度快,其中典型的灭菌循环通常以几分钟的方式完成(例如,两个五分钟循环)。X-射线对于需要比电子束辐射提供的穿透能力更大的应用可能是优选的。也可以采用紫外辐射和γ辐射,但在一些情况下是禁忌的,这部分是因为紫外辐射和γ辐射可以导致聚合物降解程度更高,并且在γ辐射的情况下是禁忌的,这是因为可能需要长得多的灭菌循环(例如,数个小时或更多)。
冷电子束灭菌如上所述是特别期望的,并将在下面更详细地讨论。应当理解,灭菌领域技术人员通过适当改变下面陈述的电子束讨论可以用其它冷电离辐射方法代替冷电子束灭菌。
公开的冷电子束灭菌方法似乎降低了聚合物重均和数均分子量值,但是所降低的程度比当该聚合物在周围温度下时利用电子束辐射灭菌聚合物的情况下所观察到的更少。公开的方法可以提供降低的降解或改进的聚合物分子量的保留以及各种其它物理性能,例如,保存期、可喷洒性、粘性强度、粘附强度,或安置在治疗部位之后的停留或保留时间。例如,经受传统(周围温度)电子束灭菌的形成凝胶的聚合物在喷射时可能不再形成凝胶,但当用冷电子束灭菌代替传统电子束灭菌时该聚合物形成凝胶的能力可被保持。对任何给定物理性能观察到的变化程度可以取决于多种因素,包括选择的聚合物和其分子量和多分散指数。冷电子束灭菌之后的重均或数均分子量可以为,例如相应未灭菌聚合物的重均或数均分子量的至少50%、至少60%、至少70%或至少80%。冷电子束灭菌增大的多分散指数也可以在未灭菌聚合物增大的多分散指数之上,而相比于未经灭菌的聚合物的多发性指数,传统电子束灭菌可能不会改变或可能降低多发性指数。例如,在冷电子束灭菌之后,灭菌的聚合物的多分散指数比未灭菌的聚合物的多分散指数大至少2%、至少4%或至少8%。合适的电子束设备或服务可以从多个供应商获得,包括BeamOneLLC(圣地亚哥SanDiego,CA)、电子束Services,Inc.(坎布雷Cranbury,NJ)、Isotron(UK)、L-3CommunicationPulseSciences(圣利恩乔SanLeandro,CA)、NUTEK公司(黑沃德Hayward,CA)和Sterigenics国际公司(圣地亚哥SanDiego,CA)。期望的电子束辐射剂量水平可以根据选择的聚合物(一种或多种)、选择的产品形式(例如,液体、凝胶、颗粒或海绵体)以及是否存在包装而变化,并且一般可以经验地确定。应当采用充分的电子束辐射从而确保无菌产品,同时避免可能引起过度断链和聚合物降解的水平。选择的剂量可以,例如相当于约10到约100千戈瑞(kGy)、约15到约50kGy或约20到约35kGy的沉积辐射能。
对于某些聚合物(例如,易于氧化的那些),在惰性气氛(例如,在氮气或氩气)下进行灭菌可进一步减少断链或降解。无论是否采用惰性气氛,在干燥条件(例如,在干燥空气、氮气或氩气)下进行灭菌也都是期望的,因为这样做有助于阻止过早的聚合物水合。干燥条件也可以通过在0℃下或0℃以下灭菌来促成,以便杂散的水蒸汽或湿气倾向于在邻近冷表面上凝结和冻结,而不引起过早的聚合物水合。
在灭菌之前或之后,公开的医疗设备可以放置在合适的密封包装(例如,由合适材料制成的注射器、小瓶或袋子)中,并按需要储存或运送给经销商或最终用户(例如,外科医生、内科医师、牙科医生或其他医疗专业人员)。在优选的实施方式中,该医疗设备在冷冻之前或在灭菌之前密封在合适的包装中,以便当运送给经销商或最终用户时该设备及其包装都是无菌形式的。根据所期望的最终用途,选择的包装可以包括多种特征,例如,灭菌维护、保存期指示、保存期保藏、干扰预防(tamperprevention)、标记或警告用的空间、以便可以观察或检查内容物的充足清晰度、干扰指示、无菌度丧失的指示,等等。
公开的医疗设备在安置或插入到治疗部位中之前可以再水合,或者在干燥状态时安置并然后原位再水合(例如,通过加入外部提供的再水合流体、通过吸收内源性流体(endogenousfluid),或两者)。再水合海绵体通常是相对简单的(straightforward),并可以通过将海绵体用水或含有任何其他所需成分的水溶液浸泡或饱和来进行。例如,生理盐溶液可以是优选的并且是容易获得的再水合溶液,如果需要可以使用其他的物质诸如磷酸缓冲盐水(PBS)。由于与水结合时一些干燥粉状材料倾向于形成团块,所以使可再水合凝胶颗粒再水合有些更加困难。但是,可以利用上述共同未决的PCT申请(代理案号NoP0027228.02和151-P-27228WO01)中描述的再水合过程来避免团块,其中将可再水合凝胶颗粒分散在生物相容性水溶性极性分散剂(例如,乙醇、异丙醇或丙酮)中,接着使该分散体与充足的含水颗粒溶剂(即,颗粒的水基溶剂)混合从而将颗粒转化成粘性水凝胶。极性分散剂是颗粒的足够差的溶剂,使得颗粒和分散剂的混合物将不会形成真溶液。在颗粒和分散剂已经通过例如将它们漩涡在一起而搅拌后,所述分散体中的颗粒理想地为充分地小,使得该分散体是稳定的或准稳定的(例如,胶态分散体或适度持久的悬浮液)。不受理论的限制,含水颗粒溶剂的加入被认为容许在每个悬浮的颗粒的表面处经由周围的分散剂溶解至该含水颗粒溶剂相中而几乎同时地发生再水合,从而容许形成粘性水凝胶,而不形成可见的未水合聚合物的团块。以此方式,分散的聚合物(例如分散的多糖)可以与水或水溶液组合以形成无团块的水凝胶,即使干粉状聚合物通常不会那样。在许多情况下,公开的方法可以用来使用两个注射器之间的通道、温和的搅动或其他简单的混合技术而不需要使用机械搅拌器,制备令人满意的无团块的凝胶。公开的混合方法还可以容许形成非常浓缩的水凝胶,其不能通过仅将粉末状可水合聚合物与水或与加入酸或碱的水混合来获得。当粘性水凝胶从粉末状可水合聚合物制备时,聚合物浓度典型地取决于选择的聚合物分子量,并且例如可以是再水合凝胶的约1到约20%,约1到约10%或约1到约5%。凝胶可以理想地在小于30分钟、小于20分钟、小于10分钟、小于5分钟、小于1分钟内或甚至在再水合后基本上立即形成。对于没有立即再水合的聚合物,可以期望地在聚合物已经变得太粘而不能喷洒或另外通过小的孔口分配——例如通过No.SA-3668FIBRIJETTM360°气体辅助内向施药器(GasAssistedEndoscopicApplicator,Micromedics公司.,圣保罗St.Paul,MN)——之前将粉末饱和并将其注射。
公开的医疗设备可以在再水合之前或之后任选地包括多种其他成分。示例性的其他成分包括溶剂、酸、碱、缓冲剂、抗微生物剂、治疗剂和其他辅剂。酸、碱或缓冲剂可以例如将凝胶保持在用于接触人类组织的适当pH,例如,大于5的pH,接近中性的pH,或小于8.5的pH。示例性的缓冲剂包括巴比妥钠、甘氨酰胺、甘氨酸、氯化钾、磷酸钾、邻苯二甲酸氢钾、乙酸钠、柠檬酸钠、磷酸钠和它们的共轭酸。
公开的医疗设备期望地是固有的抗微生物剂,而不需要加入单独的抗微生物剂。如果需要可以采用单独的抗微生物剂。所述抗微生物剂的有用的列举可以参见,例如,美国专利申请公开号US2007/0264296A1。
可用在公开的医疗设备中的示例性治疗剂包括适合用于目标治疗部位处的任何物质,包括止痛剂、抗胆碱能药、抗真菌剂、抗组胺剂、甾体或非甾体抗炎剂、抗寄生虫剂、抗病毒剂、生物抑菌组合物(biostaticcompositions)、化疗/抗肿瘤剂、细胞因子、减充血剂、止血剂(例如凝血酶)、免疫抑制剂、粘液溶解剂(mucolytics)、核酸、肽类、蛋白质、类固醇、血管收缩剂、维生素、它们的混合物和本领域技术人员已知的其他治疗性物质。所述治疗剂的有用的列举可以参见,例如,上面提到的美国专利申请公开号US2007/0264296A1中。
可包括在公开的医疗设备中的其他辅剂包括染料、颜料或其他着色剂(例如,FD&C3号红、FD&C20号红、FD&C6号黄、FD&C2号蓝、D&C5号绿、D&C4号橙、D&C8号红、焦糖、二氧化钛、水果或蔬菜着色剂诸如甜菜粉或β-胡萝卜素、姜黄根、红辣椒和本领域技术人员已知的其他物质);指示剂;调味剂或甜味剂包括但不限于茴香油、樱桃、肉桂油、柠檬油(例如,柠檬油、黎莓油或橙油)、可可、桉树、草药芳香剂(例如丁香油、鼠尾草油或肉桂油)、乳糖、麦芽糖、薄荷醇、薄荷油、糖精、环己基氨基磺酸钠、留兰香油、山梨醇、蔗糖、香草醛、冬青油、木糖醇和它们的混合物;抗氧化剂;消泡剂;和流变学改性剂包括增稠剂和触变胶(thixotrope)。公开的医疗设备期望地不含有可能潜在地损害患者组织或结构例如鼻腔或窦腔中的粘膜组织的成分。
在期望从组织中去除水,例如,从息肉或水肿组织中去除流体的那些情况下,高渗剂可以用于公开的医疗设备中。示例性的高渗剂包括呋塞米、氯化钠凝胶和可以从组织或物质中抽出水的其他盐制剂,它们直接或间接地改变粘膜层的渗透压量(osmolarcontent)。当期望治疗剂的持续释放或延迟释放时,还可以包括释放剂改性剂。
施用的可再水合凝胶可以填充治疗部位(例如,鼻腔或窦腔,或一部分肢体或脊柱中的开口、隐窝、通道或关节),在此情况下,公开的凝胶可以形成非常厚且不暴露于空气或其他附近的气体的层,并且在整个层上具有不同的厚度。公开的可再水合凝胶还可以作为薄膜或其他保形涂层施用,在此情况下本发明的凝胶层可以形成相对薄且暴露于空气或其他附近的气体的层,并且在整个层上具有基本上均一的厚度。可再水合凝胶组合物提供保护层,该保护层可以是粘性的、弹性的或粘弹性的。该保护层期望地粘附于治疗部位处的粘膜或其他天然组织(例如,软骨或骨)并且抵抗分离或其他破坏直至凝胶层发生天然的降解或吸收,例如,在1天至几天(例如,2、3、或4天)、几周或几个月的体内停留时间后。同时细菌再建群(recolonization)或再感染可以被显著地减少或避免,并且可以发生改善的愈合和纤毛再生。保护性凝胶层可以提供多种治疗优势,包括但不限于抵抗细菌粘附、抗感染特性、局部免疫调节、组织保护、减少或消除疼痛或出血、减少炎症、优化纤毛再生环境、减少与重要解剖结构的粘附等等。这些优势可以由多种机制引起,包括a)杀死细菌,b)抑制细菌建群,c)抑制细菌与组织的粘附,d)减少组织发病或脓肿形成,e)减少或防止疾病复发(例如,特别是减少与细菌生物膜中的细菌毒素和被囊多糖(encapsulatedpolysaccharide)相关的慢性炎症),f)在愈合期间包被和保护组织,诸如通过保持促进血小板聚集的湿润伤口,或通过闭合干性伤口而不会形成过度粗糙的结构,g)止血,h)优化粘膜纤毛再生的环境,i)加速纤毛的生长或再生和j)将治疗剂(一种或多种)递送至治疗部位。期望地保护性凝胶层将粘附于一部分粘膜,而使未粘附部分中的纤毛自由进行自然的有节律的纤毛运动(即,纤毛摆动),如果需要也将递送抗微生物剂或其他的治疗剂,并且期望地将阻碍或阻止细菌粘附于治疗部位。
公开的医疗设备可以期望地用作多步骤治疗方案的一部分,其破坏细菌生物膜并且阻碍其恢复。例如,可以进行一系列步骤,其可以广义地分类为清洁/破坏、杀死、充气、保护/包被和愈合。清洗/破坏步骤可以通过施用如上述美国专利申请公开号US2007/0264296A1中讨论的溶剂化系统来进行。杀死步骤可以通过将适当的抗微生物剂应用于治疗部位来进行。这可以例如通过将抗微生物剂包含在溶剂化系统中作为单独应用的组合物,或包含在溶剂化系统和单独应用的组合物两者中来实现。抗微生物剂还可以在操作后应用或施用。充气步骤可以通过开放闭塞的或部分闭塞的通道,例如,对于鼻部应用的窦或窦口,从而向被治疗组织提供空气通道或改善空气通道来进行。这可以例如通过手术去除阻塞性组织结构或手工地将所述结构移位来实现。保护/包被步骤可以通过用公开的凝胶组合物包被由此治疗的组织的至少一部分,或通过用公开的海绵体覆盖由此治疗的组织的至少一部分来进行。愈合步骤可以通过允许清洗的、保护的和封闭的组织表面经历至正常状态的恢复来进行,例如,通过一种或多种愈合机制诸如炎性应答的调节、吞噬作用、粘膜重塑、纤毛再生或正常功能的完全或部分恢复。多步骤治疗方案可以包括或紧接着清除步骤,在该步骤中凝胶组合物或海绵体是充分生物可降解的或生物可再吸收的,从而在所需的时间期限内从治疗部位消失,所述时间期限,例如,超过1天、超过3天,或约4到约7天,并且期望地不脱落大的固体块。公开的方法可以有利地在无需手术的条件下实现,例如,通过普通的吸入/吸出技术应用和去除任选的溶剂化系统,或通过简单地冲洗受感染组织然后应用公开的凝胶组合物或海绵体。等同的一系列步骤可以在一部分中耳或内耳中以多步骤治疗方案进行。关于所述治疗方案的更多细节可以参见美国专利申请公开号2007/0264310A1。
在下面非限制性实施例中进一步说明本发明。
实施例1
将低分子量形成可水合凝胶的多糖聚合物(来自FMCBioPolymerAS的NovaMatrixunit的PROTASANTMG113170,000kDa壳聚糖谷氨酸盐)和中分子量形成可水合凝胶的多糖聚合物(来自FMCBioPolymerAS的NovaMatrixunit的PROTASANG213350,000kDa壳聚糖谷氨酸盐)的样品在PBS中溶解为5wt.%的聚合物浓度,然后将它们冻干以形成干燥粉末。经由SEC-MALS,利用Tosoh公司(日本)的TSK-GELTMG6000PWXL、G5000PWXL和G3000PWXL尺寸排阻色谱柱,Waters公司(Milford,MA)的WATERSTM2695SeparationModule,Waters公司的WATERS2414DRIDetector(检测器),WyattTechnology公司(圣芭芭拉SantaBarbara,CA)的DAWNHELEOSTM多角度光散射检测器和WyattTechnology公司的ASTRATMVSP高分子表征软件,对每个样品的未灭菌部分进行评估以确定Mw、Mn和多分散指数。在25kGy的剂量下利用电子束辐射给储存在约24℃下的每个样品部分和利用冷藏箱冷冻至-20到-25℃下的部分进行灭菌,并对其进行评估以确定Mw、Mn和多分散指数。这些结果在下面表1中示出:
表1
表1中的结果表明:在电子束灭菌之前冷冻聚合物引起比该聚合物在周围温度下时利用电子束灭菌所观察到的明显更好的分子量保留。
也评估了表1中的样品,从而确定它们的喷洒特性。将每个样品以5%的浓度溶解在水中。使用上述No.SA-3668FIBRIJETTM360°气体辅助内向施药器,将所得溶液连同5wt.%的氧化淀粉溶液一起喷洒到水平表面上。未灭菌材料(即,试验序号1和试验序号4)形成了非滴落凝胶(non-drippinggel),其中试验序号1的未灭菌G113样品比试验序号4的G213样品提供了更好的胶凝和喷洒性能。在周围温度或冷电子束灭菌之后,G113样品(即,试验序号2和试验序号3)形成了凝胶,该凝胶的粘性比利用试验序号1的未灭菌G113样品获得的那些凝胶粘性小,并且还表现出更长的胶凝时间。试验序号2和试验序号3样品也表现出滴落的倾向。利用试验序号3的冷电子束灭菌样品制得的凝胶比利用试验序号2的周围温度电子束灭菌样品制得的凝胶表现出更大的粘度和更小的滴落倾向。
周围温度或冷电子束灭菌G213样品(即,试验序号5和试验序号6)形成了凝胶,该凝胶比利用试验序号4的未灭菌G213样品获得的那些凝胶粘性小。试验序号4和试验序号5样品不滴落,但试验序号5样品具有缓慢的胶凝时间。在所评估的灭菌产品样品当中,利用试验序号6的冷电子束灭菌样品制得的凝胶表现出喷洒性能、凝胶形成、缺少滴落和胶凝时间的最佳平衡。
实施例2
采用实施例1的方法,评估了由冻干羧甲基壳聚糖制得的凝胶,从而确定在周围温度或冷电子束灭菌之后它们的喷射、滴落和胶凝特性。在周围温度电子束灭菌之后,该凝胶显著变厚并且喷洒时变现不佳。在冷电子束灭菌之后,该凝胶具有稍微较小的粘度并且在喷洒时表现得可接受。
尽管在本文中已经阐明并且描述了具体的实施方式,用于说明优选的实施方式,但本领域普通技术人员要理解的是预期达到相同目的的大量可替代的或等价的实现方式可以代替所示和所述的具体实施方式,而不背离本发明的范围。本申请意在涵盖本文所讨论的优选实施方式的任何改变或变型。因此,显然,本发明旨在仅由权利要求及其等同物来限制。
Claims (21)
1.一种聚合物灭菌的方法,所述方法包含:
a)提供在周围温度以下冷冻的基本上不含胶原的颗粒或海绵状多孔的形成可水合凝胶的聚合物;和
b)在将所述聚合物冷冻至低于0℃的温度时利用电离辐射对所述冷冻聚合物灭菌,从而提供无菌聚合物,该电离辐射灭菌使所述聚合物的分子量降低,但是降低的程度比所述聚合物在周围温度下利用电子束辐射灭菌时的降低的程度低。
2.根据权利要求1所述的方法,其中所述无菌聚合物比在周围温度下利用电离辐射灭菌的其它方面相似的聚合物具有更少的聚合物断链。
3.根据权利要求1所述的方法,其中所述无菌聚合物比未经灭菌的其它方面相似的聚合物具有更高的多分散性。
4.根据权利要求1所述的方法,其中所述无菌聚合物利用电子束辐射在低于-10℃的温度下灭菌,并且比在周围温度下利用电子束辐射灭菌的其它方面相似的聚合物具有更高的多分散性。
5.根据权利要求1所述的方法,其中所述无菌聚合物利用电子束辐射在低于-10℃的温度下灭菌,并且比在周围温度下利用电子束辐射灭菌的其它方面相似的聚合物具有更高的重均分子量。
6.根据权利要求1所述的方法,其中所述无菌聚合物的重均分子量或数均分子量是相应的灭菌之前的重均分子量或数均分子量的至少60%。
7.根据权利要求1所述的方法,其中所述无菌聚合物的重均分子量或数均分子量是相应的灭菌之前的重均分子量或数均分子量的至少70%。
8.根据权利要求1所述的方法,其中所述无菌聚合物的重均分子量或数均分子量是相应的灭菌之前的重均或数均分子量的至少80%。
9.根据权利要求1所述的方法,其中所述无菌聚合物的多分散指数比灭菌之前的所述聚合物的多分散指数大至少2%。
10.根据权利要求1所述的方法,其中所述无菌聚合物的多分散指数比灭菌之前的所述聚合物的多分散指数大至少4%。
11.根据权利要求1所述的方法,其中所述无菌聚合物的多分散指数比灭菌之前的所述聚合物的多分散指数大至少8%。
12.根据权利要求1所述的方法,其中所述无菌聚合物是颗粒。
13.根据权利要求1所述的方法,其中所述无菌聚合物是非粉碎的。
14.根据权利要求1所述的方法,其中利用所述无菌聚合物制备的水凝胶是可喷洒的并且喷洒时将形成凝胶。
15.根据权利要求1所述的方法,其中所述无菌聚合物是海绵体。
16.根据权利要求1所述的方法,其中所述聚合物包含多糖。
17.根据权利要求1所述的方法,其中所述聚合物包含壳聚糖。
18.根据权利要求1所述的方法,其中所述聚合物包含壳聚糖和另一多糖的混合物。
19.根据权利要求1所述的方法,其中所述聚合物包含壳聚糖和羧甲基纤维素的混合物。
20.根据权利要求1所述的方法,其中所述聚合物包含聚乙二醇。
21.一种包含无菌粘性聚合水凝胶的医疗设备,所述聚合水凝胶的分子量经电离辐射灭菌而降低,但是降低的程度比所述聚合水凝胶在周围温度下利用电子束辐射灭菌时的降低的程度低,所述聚合水凝胶的多分散指数比所述聚合水凝胶在未灭菌时的多分散指数高,或者所述聚合水凝胶的重均分子量或数均分子量比所述聚合水凝胶在周围温度下利用电离辐射灭菌时的各自重均分子量或数均分子量高。
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