CN105828844B - 包含挤出增强剂的干组合物 - Google Patents
包含挤出增强剂的干组合物 Download PDFInfo
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Abstract
公开了一种包含一种或多种多元醇的干组合物,其一在加入水性介质后就形成适合用于止血程序中的基本上均匀的糊剂。所述糊剂一在加入所述液体后就自发地复水;因此形成所述糊剂不需要机械混合。所述组合物可以进一步包含挤出增强剂例如白蛋白。还公开了制备所述干组合物的方法、从所述干组合物获得的糊剂和所述干组合物或糊剂用于医学和外科目的的用途。
Description
技术领域
本公开涉及一种适合用于止血和/或伤口愈合中的干组合物,其中所述干组合物包含一种或多种多元醇并且一在加入水性介质后就自发地形成糊剂。所述组合物进一步包含挤出增强剂例如白蛋白。本公开还涉及制备所述干组合物的方法和所述组合物的用途。
背景技术
例如胶原蛋白和明胶等基于蛋白质的止血材料可以固体海绵和松散或未包装的粉末形式从市面购得,用于外科程序中。取决于混合条件和材料的相对比率,将松散或未包装的粉末与例如盐水或凝血酶等流体混合可以形成糊剂或浆料,所述糊剂或浆料可以作为止血组合物在弥漫性出血的情况下,尤其在从不平坦表面或难以到达的区域弥漫性出血的情况下使用。
常规的止血糊剂在使用时通过机械搅动和混合松散粉末与液体以提供组合物的均匀性来制备。粉末与流体的混合可以在例如烧杯等容器中进行。所述混合需要将粉末从其原始容器转移到烧杯中,将流体加入到装有粉末的烧杯中,然后揉捏所述混合物以形成糊剂。只有在如此形成糊剂之后,才可以将糊剂置于递送构件或施药器(例如注射器)中并且施用到伤口上。
WO 03/055531涉及一种包括固定量的粉末形式的止血剂(例如明胶粉末)的容器。一在加入适量的液体后,就通过盖上盖并且振荡容器来进行容器内的机械混合。然后可以从容器中移出得到的腻子状止血糊剂并将其施用给患者以促进止血。
或者,已经尝试对一个注射器(注射器I)预加载松散的明胶粉末,并且对另一注射器(注射器II)预加载液体。当制备糊剂时,经由鲁尔锁(luer lock)连接注射器I和注射器II并且将注射器II中的溶液推入注射器I中。通过尝试使溶液和粉末在注射器I与注射器II之间反复地来回传递,可能形成或者可能不形成均匀糊剂。通常在外科情形下无法获得具有最佳粉末:液体比的止血糊剂,因为粉末和液体在注射器中的混合不充分。即使所述混合方法成功形成糊剂,形成所述糊剂所必需的时间和机械力也是不合需要的或甚至不可接受的。此外,所述混合可以影响糊剂的最终密度(太强烈的混合可能导致较低密度的糊剂),并且因此时常影响糊剂的不一致的稠度。
Floseal Haemostatic Matrix(Baxter)是一种用于制造止血明胶糊剂的试剂盒。明胶糊剂通过以下方式制造:首先制备凝血酶溶液并且然后在两个连接的注射器之间来回地转移明胶基质-凝血酶溶液混合物持续共计至少20轮。所述糊剂然后可以从注射器直接施用给患者以促进止血。
同样,Haemostatic Matrix(Ethicon)是一种用于制造包含凝血酶的止血明胶糊剂的试剂盒,所述止血明胶糊剂通过在两个连接的注射器之间来回地转移明胶基质-凝血酶溶液混合物持续共计至少6轮来制备。
US 2005/0284809涉及一种用于制备止血糊剂的方法,所述止血糊剂较容易吸收水性液体,使得需要较小的机械力和较短的时间来形成可流动的止血糊剂。US 2005/0284809的糊剂是从压缩的止血粉末粒子制备的,并且为了制备所述糊剂,所述止血粉末粒子必须在连接的注射器之间来回地转移持续共计至少5轮。
WO 2011/151400涉及一种用于制备包含例如凝血酶等凝血诱导剂和例如明胶等生物相容性聚合物的干止血组合物的方法。混合凝血诱导剂和生物相容性聚合物以形成糊剂并且对糊剂进行冻干。得到的干组合物通过如先前所描述的在两个连接的注射器之间来回地转移组合物和稀释剂持续共计至少20轮来进行复水。
混合程序和操作是耗时的并且可能会损害止血糊剂的无菌性。如果可以提供将会消除对于所述不合需要的混合要求的需要的止血组合物,那么将是合乎需要的。
WO 2013/185776公开了一种适合用于伤口愈合和止血应用的干糊剂组合物,其一在加入水性介质后就自发地复水形成可流动糊剂,即不需要任何混合。所述干组合物是通过混合交联的生物相容性聚合物、一种或多种多元醇和水性介质以制备糊剂,然后冻干所述糊剂以获得所述干组合物来制备的。
WO 2013/060770公开了一种明胶糊剂组合物,其中所述组合物包含挤出增强剂。已知提供适量的挤出增强剂例如白蛋白能够促成使用更高的明胶浓度,这又会改进此类产品的止血特性。WO 2013/060770以全文引用的方式并入。
提供比常规可流动糊剂产品更容易从注射器挤出的自发复水型干糊剂组合物将是合乎需要的。提供相比常规可流动糊剂具有更高浓度的聚合物(例如明胶)的自发复水型干糊剂组合物也是合乎需要的,所述自发复水型干糊剂组合物保留有容易从注射器挤出的能力。
发明内容
本公开涉及一种改良的干组合物,其一在加入适量的水性介质后就形成适合用于止血和伤口愈合程序中的基本上均匀的糊剂。糊剂一在加入液体后就自发地形成,即形成所述糊剂不需要机械混合。
本公开进一步涉及一种制备所述干组合物的方法,其包括以下步骤:
a.提供粉末形式的生物相容性聚合物、一种或多种多元醇、挤出增强剂和水性介质,
b.混合所述生物相容性聚合物、所述一种或多种多元醇、所述挤出增强剂和所述水性介质以获得糊剂,和
c.干燥所述糊剂。
生物相容性聚合物优选地适合用于止血和/或伤口愈合中。
优选地,挤出增强剂是白蛋白,更优选地是人血清白蛋白。
本公开同样涵盖从干组合物形成的糊剂的用途。
附图说明
图1.水的相图。所述相图显示在压力-温度空间中固相、液相和气相这三个相之间的平衡线或相界。
图2.实施例6的包含不同多元醇的被冷冻干燥的明胶糊剂的平均复水时间+/-标准差。
具体实施方式
定义
“生物活性剂”是提供可以在体内或体外被证实的一定药理学(通常是有利的)作用的任何试剂、药物、化合物、物质的组合物(composition of matter)或混合物。因此,如果试剂与人体或动物体内的细胞组织具有相互作用或对所述细胞组织具有作用,那么将所述试剂视为生物活性的。如本文所用,这个术语还包括在个体内产生局部或全身作用的任何生理学或药理学活性物质。生物活性剂可以是蛋白质,例如酶。生物活性剂的其它实例包括但不限于包含以下各项的试剂或由以下各项组成的试剂:寡糖、多糖、任选地被糖基化的肽、任选地被糖基化的多肽、寡核苷酸、聚核苷酸、脂质、脂肪酸、脂肪酸酯和次级代谢物。所述生物活性剂可在预防上或在治疗上结合例如人或任何其它动物等个体的治疗使用。
“生物相容性”是指材料执行其预期功能而不会在宿主中引起任何不合需要的局部或全身作用的能力。
“生物可吸收性”是在本上下文中用于描述制备所述粉末的材料可以在体内降解成更小分子的术语,所述更小分子的大小允许它们被输送到血流中。通过所述降解和吸收,所述粉末材料将逐渐从施用部位去除。举例来说,明胶可以通过蛋白水解组织酶降解成可吸收的更小分子,由此明胶在施用于组织中时通常在约4-6周内被吸收,并且当施用于出血表面和粘膜上时通常在3-5天内被吸收。
根据本公开的“挤出增强剂”涵盖能够促进糊剂从注射器挤出的任何生物相容性化合物。
“凝胶”是可以具有柔软和脆弱到坚硬和强韧范围内的性质的固体胶状材料。凝胶被定义为在稳态下不展现流动的基本上稀薄的交联体系。以重量计,凝胶主要是液体,但是它们因为液体内的三维交联网络而表现得像固体。正是流体内的交联赋予了凝胶其结构(硬度)并且促成了粘度(粘性)。这样,凝胶是液体分子在固体内的分散体,其中固体是连续相并且液体是不连续相。凝胶不是糊剂或浆料。
“止血”是一个使出血减少或停止的过程。止血在血液存在于身体或血管外部时发生并且是身体停止出血和失血的本能反应。在止血期间,以快速次序发生三个步骤。血管痉挛是第一个反应,此时血管发生收缩从而允许损失较少的血液。在第二个步骤——血小板栓形成中,血小板粘附在一起以形成暂时性密封物,从而覆盖血管壁中的破裂处。第三个并且也是最后一个步骤被称为凝血或血液凝结。凝血利用充当“分子胶”的纤维蛋白丝强化血小板栓。
根据本公开的“止血剂”是生物可吸收性材料。合适的生物可吸收性材料的实例包括但不限于明胶、胶原蛋白、几丁质、壳聚糖、海藻酸盐、纤维素、聚乙醇酸、聚乙酸和其混合物。
“国际单位(IU)”。在药理学中,国际单位是基于生物活性或作用的针对物质的量的测量单位。其缩写成IU、UI或IE。其用于定量维生素、激素、一些药物、疫苗、血液制品和类似的生物活性物质。
根据本公开的“糊剂”具有可塑的类似腻子的稠度,例如牙膏。糊剂是粉碎固体/粉末状固体与液体的浓稠流体混合物。糊剂是如下的物质:其表现为固体,直到施加足够大的负荷或应力,此时其像流体一样流动,即糊剂是可流动的。糊剂通常由粒状材料在背景流体中的悬浮物组成。单个的颗粒像沙滩上的沙子一样挤在一起,从而形成了无序的、玻璃状或无定形结构,并且赋予了糊剂其类似固体的特性。正是这“挤在一起”赋予了糊剂其最不寻常的性质中的一些;这使糊剂表现易碎物的性质。糊剂不是凝胶/胶状物。“浆料”是粉末状/粉碎固体与液体(通常是水)的流体混合物。浆料在某些方面表现得像浓稠流体,在重力下流动并且在不太浓稠的情况下能够泵送。浆料可以被视为稀糊,即浆料一般比糊剂含有更多的水。
“百分比”。如果没有其它指示,那么百分比是重量/重量(w/w)。
“自发”。术语“自发”用于描述由内力或内因引起的现象,所述现象与外部介质或刺激无关并且在短时期内发生,即优选在少于约30秒内、更优选在少于约20秒内、甚至更优选在少于约10秒内或在少于约5秒内发生。
具体实施方式
本公开涉及一种干组合物,其一在加入适量的水性介质后就形成适合用于止血程序中的基本上均匀的糊剂。糊剂一在加入液体组分后就自发地形成,即形成所述糊剂不需要机械混合。
所述干组合物可以通过包括以下顺序步骤的方法制备:
a.提供粉末形式的生物相容性聚合物、一种或多种多元醇、挤出增强剂和水性介质,
b.混合所述生物相容性聚合物、所述一种或多种多元醇、所述挤出增强剂和所述水性介质以获得糊剂,和
c.干燥所述糊剂。
本公开进一步涉及一种适合用于止血和/或伤口愈合程序中的糊剂,所述糊剂通过将水性介质加入到干组合物中来制备,并且涉及所述糊剂用于促进止血和/或伤口愈合的用途。
还公开了本文所述的干组合物在制备用于止血和伤口愈合程序中的糊剂中的用途。
本文中公开的干组合物的优势有很多并且包括:
·制备糊剂所花的时间较少,例如出血可以更快地止住。
·在制备期间损害糊剂的无菌性的风险降低,因为处置步骤较少。
·在制备期间出错的风险降低,因为糊剂的制备得到简化。
·每次获得的糊剂的稠度都是最佳的。
·糊剂容易挤出(从例如注射器排出止血糊剂所需要的力较小)并且因此止血糊剂的施用精准度更高。
·在溶液中不稳定的生物活性剂可以在干燥前加入到糊剂中并且因此将存在于本公开的干组合物中。举例来说,凝血酶可以在干燥前加入到糊剂中,从而避免耗时且易于出错的凝血酶稀释步骤。
所有以上因素都导致患者安全性的提高。
生物相容性聚合物
本公开涉及一种粉末形式的生物相容性试剂,其用于产生糊剂。然后干燥糊剂以获得适合用于止血和伤口愈合程序中的干组合物。
本公开的生物相容性聚合物可以是生物聚合物或非生物聚合物。合适的生物聚合物包括蛋白质,例如明胶、可溶性胶原蛋白、白蛋白、血红蛋白、酪蛋白、纤维蛋白原、纤维蛋白、纤维粘连蛋白(fibronectin)、弹性蛋白、角蛋白和层粘连蛋白(laminin)或其衍生物或组合。尤其优选使用明胶或可溶性非纤维状胶原蛋白,更优选使用明胶。其它合适的生物聚合物包括多糖,例如糖胺聚糖、淀粉衍生物、木聚糖、纤维素衍生物、半纤维素衍生物、琼脂糖、海藻酸盐和壳聚糖;或其衍生物或组合。合适的非生物聚合物将被选定为可通过以下两种机制中的任一种降解,即(1)聚合物骨架的瓦解,或(2)产生水溶性的侧链的降解。示例性非生物聚合物包括合成物,例如聚丙烯酸酯、聚甲基丙烯酸酯、聚丙烯酰胺、聚乙烯树脂、聚丙交酯-乙交酯、聚已酸内酯和聚氧乙烯;或其衍生物或组合。不同种类的聚合物的组合也是可能的。
本公开的糊剂可以包含单一生物相容性聚合物或两种或更多种生物相容性聚合物的混合物。
在一个实施方案中,生物相容性聚合物是生物可吸收的。合适的生物可吸收性材料的实例包括明胶、胶原蛋白、几丁质、壳聚糖、海藻酸盐、纤维素、氧化纤维素、聚乙醇酸、聚乙酸和其组合。应了解本公开还涵盖其各种形式,例如线性或交联形式、盐、酯等。
在本公开的一优选实施方案中,生物可吸收性材料是明胶。明胶是优选的,因为明胶具有高生物可吸收性。此外,明胶具有高生物相容性,意味着当/如果进入血流或与人组织长期接触时,明胶对动物例如人无毒。
明胶通常来源于猪来源,但也可以来源于其它动物来源,例如来自于牛或鱼来源。明胶还可以合成制得,即通过重组方式制得。
在一优选实施方案中,聚合物是交联的。
可以使用所属领域技术人员已知的任何合适的交联方法,包括化学和物理交联方法。
在本公开的一个实施方案中,已经通过物理方法(例如通过干热)使聚合物交联。干热处理通常在100℃到250℃(例如约110℃到约200℃)的温度下进行。具体来说,温度范围可以是110-160℃,例如110-140℃,或120-180℃,或130-170℃,或130-160℃,或120-150℃。交联的时间段可以由所属领域技术人员优化并且通常是如下的时间段:约10分钟到约12小时,例如约1小时到约10小时,例如约2小时到约10小时,例如约4小时到约8小时,例如约5小时到约7小时,例如约6小时。
合适的化学交联剂的实例包括但不限于醛类(尤其是戊二醛和甲醛)、酰基叠氮、碳化二亚胺、六亚甲基二异氰酸酯、聚醚氧化物、1,4-丁二醇二缩水甘油醚、鞣酸、醛糖(例如D-果糖)、京尼平(genipin)和染料介导的光氧化。具体化合物包括但不限于1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDC)、二硫代双(丙酸二酰肼)(DTP)、1-乙基-3-(3-二甲基氨基-丙基)-碳化二亚胺(EDAC)。
在一个实施方案中,粉末形式的生物相容性聚合物从交联海绵获得。生物相容性聚合物可以例如从明胶或胶原蛋白的交联海绵、尤其明胶的交联海绵(例如市售的海绵和海绵)获得。交联海绵通过所属领域中已知的方法微粉化以获得粉末形式的交联生物相容性聚合物,例如通过旋转床、挤出、粒化和在强力混合器中处理,或研磨(例如通过使用锤式磨机或离心式磨机)来微粉化。
从Ethicon购得的是基于明胶的交联可吸收性止血海绵。其每克吸收>35g血液并且其在4-6周内被完全吸收于人体内。
在一个实施方案中,交联粉末粒子的大小小于大约1000微米,即使得它们能够通过1×1mm筛子。
在一个实施方案中,糊剂在干燥前包含约10%到约60%的生物相容性聚合物,例如约10%到约50%的生物相容性聚合物,例如约10%到约40%的生物相容性聚合物,例如约10%到约30%的生物相容性聚合物,例如约12%到约25%的生物相容性聚合物,例如约14%到约25%的生物相容性聚合物,例如约15%到约25%的生物相容性聚合物,例如约16%到约20%的生物相容性聚合物,例如约17%到约20%的生物相容性聚合物,例如约18%到约20%的生物相容性聚合物。
在一个实施方案中,糊剂在干燥前包含超过10%的生物相容性聚合物,例如超过15%的生物相容性聚合物,例如超过16%的生物相容性聚合物,例如超过17%的生物相容性聚合物,例如超过18%的生物相容性聚合物,例如超过19%的生物相容性聚合物,例如超过20%的生物相容性聚合物。
在一个实施方案中,糊剂在干燥前包含少于40%的生物相容性聚合物,例如少于30%的生物相容性聚合物,例如少于25%的生物相容性聚合物,例如少于20%的生物相容性聚合物。
在一优选实施方案中,糊剂在干燥前包含约10%到约30%的生物相容性聚合物,更优选约15%到约25%的生物相容性聚合物,例如约20%的生物相容性聚合物。
在一个实施方案中,糊剂在干燥前包含约15%到约20%的生物相容性聚合物,例如约16%到约20%的生物相容性聚合物,例如约17%到约20%的生物相容性聚合物,例如约18%到约20%的生物相容性聚合物。
在一个实施方案中,糊剂在干燥前包含约20%到约25%的生物相容性聚合物,例如约21%到约25%的生物相容性聚合物,例如约22%到约25%的生物相容性聚合物,例如约23%到约25%的生物相容性聚合物。
干燥之后,组合物包含约40%到80%的生物相容性聚合物,例如约45%到80%的生物相容性聚合物,例如约50%到80%的生物相容性聚合物,例如约55%到80%的生物相容性聚合物。
在一个实施方案中,干燥之后的组合物包含约40%到80%的生物相容性聚合物,例如约45%到75%的生物相容性聚合物,例如约50%到70%的生物相容性聚合物。
在一个实施方案中,本公开的干组合物包含超过约30%的生物相容性聚合物,例如超过约40%的生物相容性聚合物,例如超过约45%的生物相容性聚合物,例如超过约50%的生物相容性聚合物,例如超过约55%的生物相容性聚合物,例如超过约60%的生物相容性聚合物,例如超过约65%的生物相容性聚合物,例如超过约70%的生物相容性聚合物,例如超过约75%的生物相容性聚合物,例如超过约80%的生物相容性聚合物。
在一个实施方案中,本公开的干组合物包含少于约80%的生物相容性聚合物,例如少于约70%的生物相容性聚合物,例如少于约65%的生物相容性聚合物,例如少于约60%的生物相容性聚合物,例如少于约55%的生物相容性聚合物,例如少于约50%的生物相容性聚合物。
水性介质
本公开的水性介质可以是适合用于制备适合于所属领域技术人员已知的止血用途的糊剂的任何水性介质,例如水、盐水、氯化钙溶液或缓冲水性介质。水可以是WFI(注射用水)。对水性介质进行选择,使得复水后的糊剂产物的张力适合用于人或动物受试者。
在一个实施方案中,本公开的水性介质是盐水溶液。
在一个实施方案中,本公开的水性介质是氯化钙溶液。
在其它实施方案中,水性介质是水。
水性介质还可以是适用于止血糊剂中的缓冲水性介质。可以使用所属领域技术人员已知的任何合适的缓冲剂,例如一种或多种选自由以下各项组成的组的缓冲剂:柠檬酸钠;柠檬酸、柠檬酸钠;乙酸、乙酸钠;K2HPO4、KH2PO4;Na2HPO4、NaH2PO4;CHES;硼砂、氢氧化钠;TAPS;N,N-二羟乙基甘氨酸(Bicine);Tris;三(羟甲基)甲基甘氨酸(Tricine);TAPSO;HEPES;TES;MOPS;PIPES;甲次砷酸盐(Cacodylate);SSC;MES或其它。缓冲水性介质的pH应当适合于产生打算用于人类用途的止血糊剂并且可以由所属领域技术人员确定。
根据生物相容性聚合物的量调节水性介质的量,使得形成具有合适稠度的糊剂。为了优化制造,在一些情况下理想的是在干燥前向糊剂中加入比最终的复水糊剂组合物中所需的水更少的水,使得糊剂占据尽可能小的空间并且在干燥步骤中去除水所需的能量更少。干燥前的糊剂因此可以具有比最终复水糊剂更低的水含量。“丢失的”水可以在复水期间加入以获得具有期望的水:生物相容性聚合物比率的可流动糊剂。
本公开的糊剂在干燥前包含约50%到约90%的水,例如约55%到约85%的水,例如约60%到约80%的水,例如约70%的水。
优选地,本公开的糊剂在干燥前包含约60%到约80%的水,更优选约70%到约75%的水。
在干燥后,干组合物包含少于约5%的水,例如少于约3%的水,优选少于约2%的水,更优选少于约1.5%的水,甚至更优选少于约1%的水或甚至更少。因此,在一个实施方案中,干组合物包含约0.1%到约5%的水,例如约0.1%到约2%的水。
在一个实施方案中,干组合物中的残余水含量是约0.5%或更少。例如用工业冷冻干燥装置可以实现所述低残余水含量。
干燥之后组合物中的低残余水含量是合乎需要的,因为其降低了干组合物中微生物生长的风险。此外,如果组合物包含在水性条件下不稳定的生物活性剂,例如凝血酶,那么低残余水含量是必需的。如果本公开的组合物中存在凝血酶,那么干组合物中的残余水含量优选少于约3%水,更优选少于约2%水。
多元醇
根据本公开,在干燥组合物之前将一种或多种多元醇加入到组合物中。一种或多种多元醇在获得干组合物中起作用,所述干组合物一在加入水性介质形式的液体例如水时后就自发地复水,以形成具有用于止血目的的最佳稠度的糊剂,而无需使用任何类型的机械混合或搅拌。
如本文所定义的多元醇是具有多个羟基官能团的化合物。如本文所定义的多元醇包括糖(单糖、二糖和多糖)和糖醇和其衍生物。
单糖包括但不限于葡萄糖、果糖、半乳糖、木糖和核糖。
二糖包括但不限于蔗糖(sucrose/saccharose)、乳果糖、乳糖、麦芽糖、海藻糖和纤维二糖。
多糖包括但不限于淀粉、糖原、纤维素和几丁质。
糖醇也被称为多元醇,是碳水化合物的氢化形式,其羰基(醛或酮、还原糖)已被还原成伯羟基或仲羟基(因此是醇)。糖醇具有通式H(HCHO)n+1H,而糖具有H(HCHO)nHCO。可用于本公开的方法中的一些常见的糖醇包括但不限于:二醇(2-碳)、甘油(3-碳)、赤藓糖醇(4-碳)、苏糖醇(4-碳)、阿拉伯糖醇(5-碳)、木糖醇(5-碳)、核糖醇(5-碳)、甘露糖醇(6-碳)、山梨糖醇(6-碳)、半乳糖醇(6-碳)、岩藻糖醇(6-碳)、艾杜糖醇(6-碳)、肌醇(6-碳;一种环状糖醇)、庚七醇(7-碳)、异麦芽酮糖醇(isomalt,12-碳)、麦芽糖醇(12-碳)、乳糖醇(12-碳)、聚葡糖醇(Polyglycitol)。
在一个实施方案中,组合物包含单一多元醇。
在本公开的一个实施方案中,组合物包含一种以上多元醇,例如两种、三种、四种、五种、六种或甚至更多种不同的多元醇。
在本公开的一个实施方案中,组合物包含两种多元醇,例如甘露糖醇与甘油或海藻糖与二醇。
在本公开的一个实施方案中,组合物包含一种或多种糖醇,例如一种或多种选自由以下各项组成的组的糖醇:二醇、甘油、赤藓糖醇、苏糖醇、阿拉伯糖醇、木糖醇、核糖醇、甘露糖醇、山梨糖醇、半乳糖醇、岩藻糖醇、艾杜糖醇、肌醇、庚七醇、异麦芽酮糖醇、麦芽糖醇、乳糖醇和聚葡糖醇。
在一个实施方案中,组合物包含一种或多种糖醇和一种或多种糖,例如一种糖醇和一种糖。
在一个实施方案中,组合物包含一种糖醇和任选的一种或多种额外的多元醇,所述多元醇可以是糖醇或糖。
在一个实施方案中,组合物不包含糖作为唯一的多元醇。
在本公开的一个实施方案中,组合物包含甘露糖醇。
在本公开的一个实施方案中,组合物包含山梨糖醇。
在本公开的一个实施方案中,组合物包含甘油。
在本公开的一个实施方案中,组合物包含海藻糖。
在本公开的一个实施方案中,组合物包含二醇,例如丙二醇。
在本公开的一个实施方案中,组合物包含木糖醇。
在本公开的一个实施方案中,组合物包含麦芽糖醇。
在本公开的一个实施方案中,组合物包含山梨糖醇。
在一个实施方案中,糊剂在干燥前包含约1%到约40%的一种或多种多元醇,例如约1%到约30%的一种或多种多元醇,例如约1%到约25%的一种或多种多元醇,例如约1%到约20%的一种或多种多元醇,例如约1%到约15%的一种或多种多元醇,例如约1%到约14%的一种或多种多元醇,例如约1%到约13%的一种或多种多元醇,例如约1%到约12%的一种或多种多元醇,例如约1%到约11%的一种或多种多元醇,例如约1%到约10%的一种或多种多元醇。
在一个实施方案中,糊剂在干燥前包含约2%到约40%的一种或多种多元醇,例如约2%到约30%的一种或多种多元醇,例如约2%到约25%的一种或多种多元醇,例如约2%到约20%的一种或多种多元醇,例如约2%到约18%的一种或多种多元醇,例如约2%到约17%的一种或多种多元醇,例如约2%到约16%的一种或多种多元醇,例如约2%到约15%的一种或多种多元醇,例如约2%到约14%的一种或多种多元醇,例如约2%到约13%的一种或多种多元醇,例如约2%到约12%的一种或多种多元醇,例如约2%到约11%的一种或多种多元醇,例如约2%到约10%的一种或多种多元醇。
在一个实施方案中,糊剂在干燥前包含约3%到约40%的一种或多种多元醇,例如约3%到约30%的一种或多种多元醇,例如约3%到约25%的一种或多种多元醇,例如约3%到约20%的一种或多种多元醇,例如约3%到约18%的一种或多种多元醇,例如约3%到约17%的一种或多种多元醇,例如约3%到约16%的一种或多种多元醇,例如约3%到约15%的一种或多种多元醇,例如约3%到约14%的一种或多种多元醇,例如约3%到约13%的一种或多种多元醇,例如约3%到约12%的一种或多种多元醇,例如约3%到约11%的一种或多种多元醇,例如约3%到约10%的一种或多种多元醇。
在一个实施方案中,糊剂在干燥前包含超过约5%的一种或多种多元醇,因此在一个实施方案中糊剂在干燥前包含约5%到约40%的一种或多种多元醇,例如约5%到约30%的一种或多种多元醇,例如约5%到约25%的一种或多种多元醇,例如约5%到约20%的一种或多种多元醇,例如约5%到约18%的一种或多种多元醇,例如约5%到约17%的一种或多种多元醇,例如约5%到约16%的一种或多种多元醇,例如约5%到约15%的一种或多种多元醇,例如约5%到约14%的一种或多种多元醇,例如约5%到约13%的一种或多种多元醇,例如约5%到约12%的一种或多种多元醇,例如约5%到约11%的一种或多种多元醇,例如约5%到约10%的一种或多种多元醇。
在一个实施方案中,糊剂在干燥前包含约6%到约40%的一种或多种多元醇,例如约6%到约30%的一种或多种多元醇,例如约6%到约25%的一种或多种多元醇,例如约6%到约20%的一种或多种多元醇,例如约6%到约18%的一种或多种多元醇,例如约6%到约17%的一种或多种多元醇,例如约6%到约16%的一种或多种多元醇,例如约6%到约15%的一种或多种多元醇,例如约6%到约14%的一种或多种多元醇,例如约6%到约13%的一种或多种多元醇,例如约6%到约12%的一种或多种多元醇,例如约6%到约11%的一种或多种多元醇,例如约6%到约10%的一种或多种多元醇。
在一个实施方案中,糊剂在干燥前包含约10%到约40%的一种或多种多元醇,例如约10%到约30%的一种或多种多元醇,例如约10%到约25%的一种或多种多元醇,例如约10%到约20%的一种或多种多元醇,例如约10%到约18%的一种或多种多元醇,例如约10%到约17%的一种或多种多元醇,例如约10%到约16%的一种或多种多元醇,例如约10%到约15%的一种或多种多元醇。
在一个实施方案中,糊剂在干燥前包含超过约1%的一种或多种多元醇,例如超过约2%的一种或多种多元醇,例如超过约3%的一种或多种多元醇,例如超过约4%的一种或多种多元醇,例如超过约5%的一种或多种多元醇,例如超过约6%的一种或多种多元醇,例如超过约7%的一种或多种多元醇,例如超过约8%的一种或多种多元醇,例如超过约9%的一种或多种多元醇,例如超过约10%的一种或多种多元醇。
在一个实施方案中,糊剂在干燥前包含少于约20%的一种或多种多元醇,例如少于约18%的一种或多种多元醇,例如少于约17%的一种或多种多元醇,例如少于约16%的一种或多种多元醇,例如少于约15%的一种或多种多元醇,例如少于约14%的一种或多种多元醇,例如少于约13%的一种或多种多元醇,例如少于约12%的一种或多种多元醇,例如少于约11%的一种或多种多元醇,例如少于约10%的一种或多种多元醇。
在干燥后,干组合物包含约10%到约60%的一种或多种多元醇,例如约20%到约50%的一种或多种多元醇,例如约20%到约45%的一种或多种多元醇,例如约20%到约40%、例如约20%到约35%的一种或多种多元醇,例如约20%到约30%的一种或多种多元醇。
在一个实施方案中,干组合物包含约20%到约60%的一种或多种多元醇,例如约20%到约50%的一种或多种多元醇,例如约20%到约50%、例如约20%到约45%的一种或多种多元醇,例如约20%到约40%、例如约20%到约30%的一种或多种多元醇。
在一个实施方案中,干组合物包含约25%到约60%的一种或多种多元醇,例如约25%到约50%的一种或多种多元醇,例如约25%到约45%的一种或多种多元醇,例如约25%到约40%的一种或多种多元醇,例如约25%到约35%的一种或多种多元醇,例如约25%到约30%的一种或多种多元醇。
在一个实施方案中,干组合物包含约27%到约60%的一种或多种多元醇,例如约27%到约50%的一种或多种多元醇,例如约27%到约45%的一种或多种多元醇,例如约27%到约40%的一种或多种多元醇,例如约27%到约35%的一种或多种多元醇,例如约27%到约30%的一种或多种多元醇。
在一个实施方案中,干组合物包含约30%到约60%的一种或多种多元醇,例如约30%到约50%的一种或多种多元醇,例如约30%到约45%的一种或多种多元醇,例如约30%到约40%的一种或多种多元醇,例如约30%到约35%的一种或多种多元醇。
在一个实施方案中,干组合物包含比生物相容性聚合物少的多元醇,即多元醇:生物相容性聚合物的比率小于1:1,例如小于或约0.9:1,例如小于或约0.8:1,例如小于或约0.7:1,例如小于或约0.6:1,例如小于或约0.5:1,例如小于或约0.4:1,例如小于或约0.3:1,例如小于或约0.2:1,例如小于或约0.1:1。多元醇:生物相容性聚合物的比率在干燥前的糊剂中是相同的。
在一个实施方案中,多元醇:生物相容性聚合物的比率为约0.1:1到1:1,例如约0.2:1到1:1,例如约0.3:1到1:1,例如约0.4:1到1:1。
在一优选实施方案中,多元醇:生物相容性聚合物的比率为约0.2:1到0.8:1,例如约0.2:1到0.7:1,例如约0.2:1到0.6:1,例如约0.2:1到0.5:1。甚至更优选地,多元醇:生物相容性聚合物的比率为约0.3:1到0.8:1,例如约0.3:1到0.7:1,例如约0.3:1到0.6:1,例如约0.3:1到0.5:1,例如约0.35:1到0.5:1,例如约0.35:1到0.45:1。
在一个实施方案中,多元醇不是聚乙二醇。
挤出增强剂
先前已经显示,提供适量的特定挤出增强剂例如白蛋白能够促成使用更高的明胶浓度,因为挤出增强剂降低从例如注射器挤出明胶糊剂组合物所需的力的量。使用更高的明胶浓度又可以改进此类产品的止血特性。提供适量的挤出增强剂是必需的。这些量应该足够高,以便获得挤出效果,即甚至在相对较高的量的生物相容性聚合物例如交联明胶的情况下也能获得可流动糊剂,使得止血糊剂组合物可以由外科医生使用例如包括施药器尖端(applicator tip)的注射器精准地施用;另一方面,这些量应当低至能够防止止血组合物的负面功能特性。
在一优选实施方案中,挤出增强剂是白蛋白,特别是人血清白蛋白。
在干燥前的湿糊剂组合物中,挤出增强剂例如白蛋白优选以约0.1%到约10%的量存在,例如约0.2%到约8%,例如约0.3%到约7%,优选地约0.5%到约5%,更优选地约1%到约4%。
在干组合物中,挤出增强剂例如白蛋白优选以约0.3%到约30%的量存在,例如约0.5%到约25%,例如约1%到约20%,优选地约2%到约15%。
在一个实施方案中,挤出增强剂不存在于干组合物中,而是在复水期间被引入到糊剂组合物中。举例来说,挤出增强剂可以存在于用于使糊剂复水的水性介质中,从而获得包含挤出增强剂的湿糊剂组合物。
在一个实施方案中,存在于适合用于分配糊剂形式的组合物的施药器装置例如注射器中的复水后的湿糊剂组合物具有40N或更低,优选地低于35N,特别优选地低于30N或甚至低于20N的平均挤出力。挤出力可以通过本领域已知的能够测量从注射器挤出糊剂产品所需的力的合适方法来测试。
在一个实施方案中,复水后的湿糊剂组合物具有40N或更低,优选地低于35N,特别优选地低于30N或甚至低于20N的平均挤出力(使用WO2013/060770的实施例1中所描述的测试方法)。
根据本公开的另一类挤出增强剂是磷脂例如磷脂酰胆碱和磷脂酰丝氨酸,或复杂混合物例如卵磷脂或大豆油。
生物活性剂
在本公开的一个实施方案中,干组合物包含一种或多种生物活性剂。必要的是生物活性剂保留其生物活性,即在干组合物复水之后,生物活性剂在糊剂中具有生物活性。许多生物活性剂在溶液中不稳定,尤其是当存在水时可能降解或丧失二级结构的酶和其它蛋白质。
在一个实施方案中,生物活性剂刺激伤口愈合和/或止血,例如凝血酶。
常规地,在需要止血糊剂时,将凝血酶溶液加入到明胶粉末中以直接在手术部位制备止血糊剂,例如通过使用市售的止血试剂盒(例如Floseal和)进行。凝血酶溶液必须正好在制备糊剂之前制备,因为溶液中的凝血酶非常不稳定并且将快速地自身降解。在手术部位制备凝血酶溶液是耗时的并且就正确稀释凝血酶来说存在出错的风险。
本公开的方法允许在干燥前将凝血酶加入到糊剂中,从而产生包含凝血酶的干组合物,所述干组合物一在用合适水性介质例如水复水后就将包含所需量的凝血酶,而无需耗时且易于出错的凝血酶稀释步骤和在手术部位加入。凝血酶可以包含在干组合物中,构成优于制备止血糊剂的常规方法的明显优势。
发明人先前已经显示凝血酶可以包含在糊剂中并且通过冷冻干燥进行干燥,同时在复水后的糊剂中测量的凝血酶活性基本上没有损失。
可以在干燥前以约100IU/ml糊剂到约500IU/ml糊剂(例如约150IU/ml糊剂到约450IU/ml糊剂,例如约200IU/ml糊剂到约400IU/ml糊剂,例如约250IU/ml糊剂到约350IU/ml糊剂)范围内的浓度将凝血酶加入到糊剂中。
在一个实施方案中,所述一种或多种生物活性剂可以是例如凝血酶或凝血酶与纤维蛋白原的组合,或者凝血酶和纤维蛋白原与因子XIII的组合,或者凝血酶和纤维蛋白原和因子XIII与氨甲环酸的组合。
凝血酶是在人类中由F2基因编码的“胰蛋白酶类”丝氨酸蛋白酶蛋白。凝血酶原(凝血因子II)在凝血级联中经过蛋白水解裂解以形成凝血酶,最终遏制血液损失。凝血酶进而充当将可溶性纤维蛋白原转化为不溶性的纤维蛋白链并且催化许多其它凝血相关反应的丝氨酸蛋白酶。在血液凝固途径中,凝血酶用于将因子XI转化为XIa,将VIII转化为VIIIa,将V转化为Va并且将纤维蛋白原转化为纤维蛋白。
一种优选的生物活性剂是凝血酶。在一个实施方案中,凝血酶作为凝血酶原加入。
在一个实施方案中,干组合物包含一种或多种刺激骨头和/或肌腱愈合的生物活性剂,例如一种或多种选自由基质金属蛋白酶(MMP)、胰岛素类生长因子1(IGF-I)、血小板源性生长因子(PDGF)、血管内皮生长因子(VEGF)、碱性成纤维细胞生长因子(bFGF)和转化生长因子β(TGF-β)组成的组的生长因子。
在一个实施方案中,干组合物包含一种或多种骨形态生成蛋白(BMP)。骨形态生成蛋白(BMP)是TGF-β超家族的子群。骨形态生成蛋白(BMP)是一组也被称为细胞因子和代谢物原(metabologen)的生长因子。最初通过诱导骨头和软骨形成的能力发现的BMP现在被认为构成了一组关键的形态生成信号,从而精心安排整个体内的组织架构。
在一个实施方案中,干组合物包含一种或多种基质金属蛋白酶(MMP)。MMP是依赖于锌的肽链内切酶。MMP在损伤之后的愈合过程期间在细胞外基质(ECM)的降解和重塑中具有非常重要的作用。包括MMP-1、MMP-2、MMP-8、MMP-13和MMP-14在内的某些MMP具有胶原酶活性,意味着不同于许多其它酶,所述MMP能够降解胶原蛋白I原纤维。
这些生长因子在愈合过程期间都具有不同的作用。IGF-1在炎症的第一阶段期间增加胶原蛋白和蛋白聚糖的产生,并且PDGF也存在于损伤后的早期阶段期间并促进其它生长因子的合成以及DNA的合成和细胞的增殖。已知TGF-β的三种同种型(TGF-β1、TGF-β2、TGF-β3)在伤口愈合和瘢痕形成中起作用。众所周知VEGF可以促进血管生成并且诱导内皮细胞增殖和迁移。
在一个实施方案中,干组合物包含细胞外基质(ECM)薄片或粒子。ECM是动物组织的细胞外部分,其通常对动物细胞提供结构支撑,此外还执行各种其它重要功能。已显示ECM在愈合中具有非常有利的作用,因为其促进功能组织再生。
可结合本公开的糊剂使用的生物制剂的种类是庞大的。一般来说,可经由本文中公开的组合物施用的生物制剂包括但不限于:抗感染剂,例如抗生素和抗病毒剂;止痛药和止痛药组合;驱虫药;抗关节炎药;抗惊厥药;抗抑郁药;抗组胺剂;消炎药;抗偏头痛制剂;抗肿瘤药;抗帕金森病药(antiparkinsonism drug);抗精神病药;退烧药、镇痉药;抗胆碱能药;拟交感神经药;黄嘌呤衍生物;心血管制剂,包括钙通道阻滞剂和β-阻滞剂,例如吲哚洛尔(pindolol)和抗心律失常药;抗高血压药;利尿剂;血管舒张药,包括全身冠状动脉、外周和脑;中枢神经系统兴奋剂;激素,例如雌二醇和其它类固醇,包括皮质类固醇;免疫抑制剂;肌肉松弛剂;副交感神经阻断药;精神兴奋剂;天然衍生或遗传改造的蛋白质、多糖、糖蛋白或脂蛋白;寡核苷酸、抗体、抗原、胆碱能药、化疗药、放射性试剂、骨诱导剂、细胞抑制剂、肝素中和剂、促凝血剂和止血剂,例如凝血酶原、凝血酶、纤维蛋白原、纤维蛋白、纤维粘连蛋白、肝素酶、因子X/Xa、因子VII/VIIa、因子VIII/VIIIa、因子IX/IXa、因子XI/XIa、因子XII/XIIa、因子XIII/XIIIa、组织因子、巴曲酶(batroxobin)、安克洛酶(ancrod)、蛇静脉酶(ecarin)、血管性血友病因子(von Willebrand Factor)、胶原蛋白、弹性蛋白、白蛋白、明胶、血小板表面糖蛋白、加压素、加压素类似物、肾上腺素、选择素、促凝血毒液、血纤维蛋白溶酶原活化因子抑制剂、血小板活化剂和具有止血活性的合成肽。
其它化合物
本公开的干组合物还可以包含一种或多种以下物质:DMSO(二甲亚砜)、2-甲基-2,4-戊二醇(MPD)和/或下表中所提到的一种或多种化合物。
在一个实施方案中,本公开的干组合物包含一种或多种抗微生物剂,例如一种或多种抗细菌剂。
在一个实施方案中,本公开的干组合物包含苯扎氯铵(BAC)。
在一个实施方案中,本公开的干组合物不包含抗微生物剂。
制备糊剂
根据本公开的方法,将生物相容性聚合物、挤出增强剂和一种或多种多元醇与合适的水性介质混合以获得糊剂。混合可以用所属领域技术人员已知的任何合适方式进行,例如通过手动混合内容物或通过使用电动混合装置(例如手动混合器、厨房混合器或工业混合器)进行。
糊剂的混合一般可以在室温(20-25℃)下进行。然而,如果糊剂中包含凝血酶或其它酶,那么明智的做法是在寒冷温度下和/或在短时期内进行糊剂的混合以避免或降低凝血酶的蛋白水解活性,因为众所周知凝血酶在溶液中容易发生自身降解。因此,当糊剂中打算包含凝血酶或其它蛋白水解酶时,糊剂的混合可以在室温以下的温度下(例如在约2℃到约20℃下,例如在约2℃到约15℃下,优选在约4℃下)进行。
保持糊剂中的凝血酶生物活性的另一种或额外方式是使凝血酶在湿润状态下所处的时间(即混合时间)最短。因此,当糊剂中打算包含凝血酶或其它蛋白水解酶时,糊剂的混合通常在约5分钟到约10小时(例如约5分钟到约5小时,例如约5分钟到约2小时,优选地约5分钟到约1小时)内进行。
本发明人先前已经发现,在低温下进行糊剂的混合以避免凝血酶活性损失并不是必需的,因为当在环境温度下进行糊剂的混合时没有发现凝血酶活性的降低。
容器
所属领域技术人员已知的任何合适容器都可以用于制备糊剂并且在干燥时容纳糊剂,例如小瓶、罐、管、托盘、料筒或注射器。
在一个实施方案中,在一个容器中制备糊剂,并将所述糊剂转移到另一容器中用于干燥,其中所述另一容器可以选自小瓶、罐、管、托盘、料筒和注射器。
根据本公开的“罐”是具有广口开口的刚性的、大致圆柱形的容器。罐可以包括施加在罐口上的可再封闭的封闭单元/盖。
容器可以由任何合适的材料制成,例如玻璃、陶瓷、塑料或金属,例如不锈钢。
合适塑料材料的实例包括但不限于聚乙烯、聚丙烯、聚苯乙烯、聚氯乙烯和聚四氟乙烯(PTFE)。
在一个实施方案中,将糊剂填充到注射器或适合于分配可流动的止血组合物的其它已知施药器中并在其中干燥。
在一个实施方案中,糊剂在适合用于分配糊剂形式的组合物的施药器例如注射器中被干燥。因此,在一个实施方案中,本公开涉及一种施药器例如注射器,包括容纳在其中的干组合物。
取决于所用容器的形状,本公开的干组合物可以各种形状、形式和大小制备。它们例如可以呈塞状物、圆盘状物、杆状物、管状物、锥形筒、片、球体、半球体、片剂、丸粒、颗粒或甚至细微粒或细粉(粉碎)的形式。
止血片
在一个实施方案中,干组合物呈片的形式,即基本上平坦的组合物。
片形式的干组合物可以通过将糊剂薄且均匀地铺在表面上、随后干燥所述糊剂以获得基本上平坦的干片组合物来获得。片形式的干组合物一在与液体接触后就将自发地复水而形成糊剂。因此,片形式的干组合物既具有传统使用的外科海绵的优点,因其可以覆盖相对大的区域,还具有糊剂的优点,因其在湿润时一在湿润后就容易贴合不平坦表面。
片形式的干组合物是柔软的和柔性的。
在一个实施方案中,本公开涉及一种用于止血和/或伤口愈合的片形式的干组合物。
在一个实施方案中,所述片在使用前、即在施用到伤口前没有经过预先湿润。
在一个实施方案中,干片组合物的高度是约0.5mm到约10mm,优选地约1mm到5mm,更优选地约1mm到3mm,例如约2mm。
干片组合物的大小(宽度和深度)取决于片的预期用途并且可以由所属领域技术人员选择。干片材料可以是例如矩形、方形或圆形。举例来说,干片组合物可以例如呈大约5cm×10cm、2cm×6cm、6cm×8cm或8cm×12cm的矩形形式。
在一个实施方案中,在使用前将干片组合物切割成期望的形状。
干燥糊剂
根据本公开,干燥糊剂以获得干组合物。糊剂可以通过所属领域技术人员已知的任何合适方法干燥。合适干燥方法的实例包括冷冻干燥和喷雾干燥。
在一个实施方案中,在干燥步骤之前冷冻糊剂。
在一优选实施方案中,对糊剂冷冻干燥。可以使用所属领域技术人员已知的任何合适的冷冻干燥技术和设备。
冷冻干燥(也称为冻干和低温干燥)是通常用于保存易腐烂材料或使得所述材料更便于运输的脱水方法。冷冻干燥通过冷冻所述材料,然后降低周围压力以允许所述材料中的冷冻水直接从固相升华成气相来实现。
基本上存在三种类别的冷冻干燥器:歧管式冷冻干燥器、旋转式冷冻干燥器和托盘式冷冻干燥器。所有类型的冷冻干燥器都具有以下两个组件:真空泵,其用于降低容纳待干燥物质的容器内的环境气压;和冷凝器,其用于通过在被冷却到-40℃到-80℃的表面上冷凝来去除水分。歧管式冷冻干燥器、旋转式冷冻干燥器和托盘式冷冻干燥器的不同之处在于使被干燥物质与冷凝器接合的方法。在歧管式冷冻干燥器中,使用通常圆形的短管将具有干燥产物的多个容器连接到冷凝器。旋转式冷冻干燥器和托盘式冷冻干燥器具有单个大的储集器以用于被干燥物质。
旋转式冷冻干燥器通常用于干燥丸粒、小方块和其它可倾倒的物质。旋转式干燥器具有圆柱形储集器,所述储集器在干燥期间旋转以实现整个物质中的较均匀干燥。托盘式冷冻干燥器通常具有矩形储集器,所述矩形储集器具有搁板,所述搁板上的例如医药溶液和组织提取物等产物可以被放置于托盘、小瓶和其它容器中。
歧管式冷冻干燥器通常用于当干燥小容器中的液体物质时和当产物将在短时期内使用时的实验室环境中。歧管式干燥器将产物干燥到小于5%的水分含量。如果不使用热,那么只能实现初级干燥(去除未结合的水)。必须增加加热器以实现二级干燥,这将去除结合水并且将产生更低的水分含量。
托盘式冷冻干燥器通常大于歧管式干燥器并且更复杂。托盘式冷冻干燥器用于干燥各种材料。托盘式冷冻干燥器用于产生最干燥的产物以供长期储存。托盘式冷冻干燥器允许在适当位置冷冻产物并且进行初级(去除未结合的水)和二级(去除结合水)冷冻干燥,从而产生最干燥的可能终产物。托盘式冷冻干燥器可以干燥散装的或在小瓶或其它容器中的产物。当在小瓶中干燥时,冷冻干燥器配备有加塞机构,所述加塞机构允许塞子被按压到位,从而在小瓶暴露于大气之前将其密封。这用于长期储存,例如疫苗。
正在开发改进的冷冻干燥技术以扩展可冷冻干燥的产物的范围、改进产物质量并且以较少的人力较快地生产产物。
从1930年代开始,工业冷冻干燥就已经依赖于单一类型的设备:托盘式冷冻干燥器。在2005年,对于大宗材料开发了更快速且更低劳动强度的冷冻干燥方法。这一冷冻干燥过程被证明能够从单个容器产生自由流动的粉末。被称为“主动冷冻干燥”AFD技术的新颖方法使用连续移动来改进质量转移并且因此缩短加工时间,同时还消除了来回转移干燥托盘和下游大小缩减器件的需求。
在完整的冷冻干燥过程中存在四个阶段:预处理、冷冻、初级干燥和二级干燥。
预处理包括在冷冻前处理产物的任何方法。这可以包括浓缩产物、配方修正(即加入用于增加稳定性和/或改进加工的组分)、减少高蒸气压溶剂或增加表面积。在许多情况下,预处理产物的决定是基于关于冷冻干燥和其需求的理论知识,或者根据循环时间或产物质量考量的需要。预处理方法包括:冷冻浓缩、溶液相浓缩、进行配制以保持产物外观、进行配制以使反应性产物稳定、进行配制以增加表面积和减少高蒸气压溶剂。
在实验室中,通常通过将材料置于冷冻干燥烧瓶中并在被称为壳式冷冻器(shellfreezer)的浴中旋转所述烧瓶来进行冷冻,所述浴通过机械制冷、干冰和甲醇、或液氮进行冷却。在更大规模上,通常使用冷冻干燥机器进行冷冻。在这个步骤中,重要的是将材料冷却到低于其三相点,即材料的固相和液相可以共存的最低温度。这确保了在随后步骤中将发生升华而不是熔化。较大的晶体较易于冷冻干燥。为了产生较大的晶体,应当缓慢冷冻产物,或者可以使产物的温度上下地循环。这个循环过程被称作退火。在其它情况下,更好的是快速进行冷冻,目的是使材料迅速降到其低共熔点以下,从而避免形成冰晶。冷冻温度通常为-40℃到-80℃。冷冻阶段在整个冷冻干燥过程中是最关键的,因为如果操作不当,则可能损坏产物。
非晶材料不具有低共熔点,但是它们具有临界点,必须将产物维持在临界点以下以防止初级干燥和二级干燥期间的回熔或塌陷。
在初级干燥阶段期间,将压力降低(到几毫巴或更低的范围),并且对材料供应足够的热以使水升华。可以使用升华分子的升华潜热来计算必需的热量。在这个初始干燥阶段中,材料中约95%的水被升华。这个阶段可能很缓慢(在工业上可以是数天),因为如果施加太多热,则可能改变材料的结构。
在这个阶段中,通过施加部分真空来控制压力。真空加速升华,使其可用作有意的干燥过程。此外,冷的冷凝器腔室和/或冷凝器板提供了供水蒸气在上面再凝固的表面。这个冷凝器在保持材料冷冻方面不起作用;相反,其防止水蒸气到达真空泵,水蒸气到达真空泵可使泵的性能降格。冷凝器温度通常低于-50℃。
重要的是应注意到,在这个压力范围内,热主要通过传导或辐射来产生;因为空气密度很低,所以对流作用可以忽略不计。
水的蒸气压是水蒸气饱和时所处的压力。在更高压力下水将会冷凝。水的蒸气压是在经水饱和的任何气体混合物中的水蒸气的分压力。水的蒸气压决定进行冷冻干燥所必需的温度和压力。
水的蒸气压(mTorr=毫托;mB=毫巴)
温度(℃) | 毫托 | mB |
0 | 4579 | 6.104 |
-4 | 3280 | 4.372 |
-8 | 2326 | 3.097 |
-12 | 1632 | 2.172 |
-16 | 1132 | 1.506 |
-20 | 930 | 1.032 |
-24 | 526 | 0.6985 |
-28 | 351 | 0.4669 |
-32 | 231 | 0.3079 |
-36 | 150 | 0.2020 |
-40 | 96.6 | 0.1238 |
-44 | 60.9 | 0.0809 |
-48 | 37.8 | 0.0502 |
-52 | 23.0 | 0.0300 |
-56 | 13.8 | 0.0183 |
-60 | 8.0 | 0.0107 |
-64 | 4.6 | 0.0061 |
-68 | 2.6 | 0.0034 |
-72 | 1.4 | 0.0018 |
二级干燥阶段旨在去除未冷冻的水分子,因为在初级干燥阶段中去除了冰。冷冻干燥过程的这个部分由材料的吸附等温线控制。在这个阶段中,温度被升高到高于初级干燥阶段中的温度,并且甚至可以高于0℃,以破坏在水分子与冷冻材料之间已经形成的任何物理-化学相互作用。通常还在这个阶段中降低压力以促进解吸附(通常在微巴范围内)。然而,也存在受益于压力升高的产物。
在冷冻干燥过程完成之后,可以用惰性气体例如氮气破坏真空,随后密封材料。
在操作结束时,冷冻干燥产物中的最终残余水含量通常极低,例如大约2%或更低。
冷冻干燥过程将糊剂转化成硬的“蛋糕状”组合物,一在加入适量的水性介质例如水后,所述组合物就将自发地形成即用型糊剂,即形成所述糊剂不需要机械混合/复水。
在一个实施方案中,在加入水性介质之前,粉碎通过冷冻干燥糊剂获得的硬蛋糕状结构。
在一替代性实施方案中,通过喷雾干燥获得本公开的干组合物。可以应用所属领域技术人员已知的任何喷雾干燥技术和设备。
喷雾干燥是通过用热气体快速干燥而从液体或浆料产生干粉的方法。空气通常是经过加热的干燥介质;然而,如果液体是易燃溶剂例如乙醇或者产物对氧敏感时,那么使用氮。
所有的喷雾干燥器都使用某种类型的雾化器或喷雾喷嘴以将液体或浆料分散成受控的液滴大小的喷雾。其中最常见的是旋转盘和单一流体高压旋流喷嘴。或者,对于一些应用来说,使用双流体喷嘴或超声波喷嘴。取决于过程需要,可以经过适当选择而实现10μm到500μm的液滴大小。最常见的应用在100μm到200μm直径范围内。获得的干粉通常是自由流动的。
与其它干燥方法相比,喷雾干燥器可以非常快速地干燥产物。它们还在单个步骤中将溶液或浆料转化成干燥粉末,这可有利于利润最大化和过程简化。
外包装
在一个实施方案中,在例如注射器或另一容纳单元内所容纳的干组合物被进一步容纳在外包装中,使得干燥产物在使用前一直保持无菌。这将允许使用者去除外包装并将干组合物转移到无菌区中。这时可以加入适量的水性介质,随后即用型糊剂在数秒内自发地形成而无需机械搅动、搅拌或混合。
外包装通常由柔性的、半刚性的或刚性的材料制成并且通常由例如塑料、铝箔和/或塑料压层等材料组成,其中塑料可选自由PET、PETG、PE、LLDPE、CPP、PA、PETP、METPET、Tyvek组成的组并且任选地用粘合剂例如聚氨基甲酸酯粘结或经过共挤出。
在一个实施方案中,外包装是铝箔外包装。
外包装优选地形成针对水分的完全屏障。
外包装优选地能够耐受灭菌处理,例如辐射灭菌处理。
灭菌
本公开的干组合物优选是无菌的。可以利用所属领域中已知的任何合适的灭菌技术。灭菌优选地在包装步骤之后,即当干组合物容纳在外包装中时进行。因此,在一优选实施方案中,灭菌是终末灭菌。
灭菌是指有效地杀死或灭除传染性病原(例如真菌、细菌、病毒、朊病毒和孢子形式等)的任何过程。干组合物的灭菌可以通过例如施加热、化学品和辐照来实现。热灭菌包括高压灭菌(使用高温蒸汽)和干热;辐射灭菌包括X射线、γ射线和β射线、UV光和亚原子粒子;化学灭菌包括使用环氧乙烷气体、臭氧、含氯漂白剂、戊二醛、甲醛、邻苯二甲醛、过氧化氢和过乙酸。
在一个实施方案中,通过辐照(例如电离辐照)对干组合物进行灭菌,以便使组合物无菌。所述辐照可以包括电子束(β辐照)或γ辐照。辐照水平和灭菌条件(包括辐照组合物的时间)是提供无菌组合物的那些。灭菌条件与当前用于制备当前可用的止血松散粉末的那些条件类似。一旦获悉本公开书的优点,所属领域技术人员就能够容易地确定提供无菌组合物所必需的辐照水平。
当干燥产物中存在凝血酶和/或其它敏感生物活性剂时,通过利用约25kGy或更低的β辐照或γ辐照以终末灭菌形式进行灭菌。
在一个实施方案中,用环氧乙烷进行灭菌。
利用干热进行的灭菌通常可以通过将干组合物加热到100℃到250℃(例如约110℃到约200℃)的温度来进行。具体来说,温度可以在110-160℃范围内,例如在110-140℃范围内,或在120-180℃范围内,或在130-170℃范围内,或在130-160℃范围内,或在120-150℃范围内。
在一个实施方案中,干组合物在包装后不经过灭菌。当干组合物通过无菌生产技术制造时,产物在置入外包装中时已经是无菌的并且不需要进一步灭菌。因此,在一个实施方案中,本公开涉及由无菌技术生产的组合物。
干组合物的复水
本公开的干组合物可以通过加入适量的水性介质来复水。用于使糊剂复水的水性介质可以例如选自水、盐水、CaCl2溶液或缓冲水溶液。
在一个实施方案中,用于使干组合物复水的水性介质是水。在一个实施方案中,对水性介质的张力进行选择,使得复水后的糊剂的张力与在外科程序中在人受试者上使用是相容的。
在一个实施方案中,用于使干组合物复水的水性介质是盐水。
在一个实施方案中,用于使干组合物复水的水性介质包含挤出增强剂例如白蛋白。在这种情况下,干组合物优选地不含挤出增强剂。
一在加入水性介质后,即用型可流动糊剂就自发地、即在几秒内形成。重要的是,形成糊剂不需要混合。
在一个实施方案中,复水后的糊剂相比干燥前的糊剂含有更低浓度的生物相容性聚合物,因为加入的水多于在干燥步骤期间从糊剂去除的水。
在一个实施方案中,本公开涉及一种用于使干组合物复水的方法,其包括以下步骤:
a.提供如本文所述的干组合物,所述干组合物任选地包含挤出增强剂,和
b.将水性介质加入到干组合物中。
水性介质可以任选地包含挤出增强剂例如白蛋白。
挤出增强剂可以存在于干组合物中和/或复水液体(即水性介质)中。
在一些实施方案中,复水后的糊剂包含与常规使用的可流动糊剂组合物类似浓度的聚合物例如明胶,但是由于存在挤出增强剂,本公开的复水后的糊剂相对更容易从施药器例如注射器挤出。
在一个实施方案中,复水后的糊剂相比常规使用的可流动糊剂制剂包含更高量的生物相容性聚合物。增加量的聚合物可以产生改进的止血效果,同时仍然允许糊剂容易从例如注射器挤出。
在一个实施方案中,本公开的复水后的糊剂包含约10%到约25%的生物相容性聚合物,例如约10%到约20%的生物相容性聚合物,例如约12%到约18%的生物相容性聚合物,例如约14%到约16%的生物相容性聚合物,例如约15%的生物相容性聚合物。
在一个实施方案中,本公开的复水后的糊剂包含小于约15%的生物相容性聚合物,例如约10%到约15%的生物相容性聚合物,例如约11%到约15%的生物相容性聚合物,例如约12%到约15%的生物相容性聚合物,例如约13%到约15%的生物相容性聚合物,例如约14%到约15%的生物相容性聚合物。
在一个实施方案中,本公开的复水后的糊剂包含超过约15%的生物相容性聚合物,例如约15%到约25%的生物相容性聚合物,例如约15%到约20%的生物相容性聚合物,例如约16%到约20%的生物相容性聚合物,例如约17%到约20%的生物相容性聚合物,例如约18%到约20%的生物相容性聚合物。
医学用途
本公开进一步涉及干组合物或从干组合物获得的糊剂用于促进止血和/或伤口愈合的用途。
本公开的糊剂例如可用于其中需要出血控制的一系列外科程序中。糊剂贴合到不规则表面上以迅速终止出血,并且其因此可用于在止血海绵无效的粗糙或不平坦表面上提供快速止血。
止血糊剂在需要时由医护人员、即医生或护士直接在手术部位制备。因此,糊剂通常在极其紧张的情况下制备,所以用于制备糊剂的过程必需简单并且快速,以确保尽可能快地遏制出血并且在制备糊剂时不会出错。另外重要的是,糊剂的稠度适合用作止血糊剂,糊剂导致有效且快速的止血,以及糊剂容易从施药器装置挤出,使得施用糊剂的外科医生不用太大力就可以将糊剂精准地施予出血部位。
本公开的糊剂由于以下事实而优于例如Floseal和Surgiflo等当前可用的糊剂:本公开的糊剂可以通过向干组合物中加入一定量的水性介质,随后自发地(即在少于约30秒内,优选地在少于约20秒内,更优选地在少于约10秒内,甚至更优选地在少于约5秒内)形成即用型止血糊剂来简单地制备。
待加入到干组合物中的液体的数量可以由所属领域技术人员调节。当加入正确量的液体时,如此形成的糊剂总是具有最佳稠度。对于常规糊剂来说情况并非总是如此,其中糊剂的稠度可以依赖于所施加的力和耗时的混合。不需要机械混合还意味着制备糊剂所花的时间更少,这进而提高了患者安全性,这两者都是因为可以更快速地将止血糊剂施加给患者并且简单的制备方法降低了止血糊剂制备期间出错的可能性。
当干组合物内包含凝血酶时,本公开还具有优于常规糊剂的优点,因为本公开避免了当前制备止血糊剂的方法中所涉及的耗时且易于出错的凝血酶稀释和加入步骤。
在一个实施方案中,本公开涉及通过将本文中公开的干组合物或复水后的糊剂施用到出血部位而在有需要的个体中遏制出血/促进止血的方法。
本公开的糊剂可用于任何类型的外科,包括普通外科、心胸外科、血管外科、整形外科、儿科外科、结肠直肠外科、移植外科、肿瘤外科、创伤外科、内分泌外科、乳腺外科、皮肤外科、耳鼻喉科、妇科、口腔颌面外科、牙科外科、矫形外科、神经外科、眼科、足部外科、泌尿科。
在一个实施方案中,本公开涉及通过将本公开的干组合物或糊剂施用到伤口处而在有需要的个体中促进伤口愈合的方法。
“伤口”泛指以不同方式引发且具有不同特征的皮肤和/或深部(皮下)组织的损伤(例如因为长期卧床导致的褥疮和由外伤诱发的伤口)。取决于伤口深度,可将伤口分类为四个等级中的一个:i)第I级:仅限于上皮的伤口;ii)第II级:延伸到真皮中的伤口;iii)第III级:延伸到皮下组织中的伤口;和iv)第IV级(或全厚度伤口):暴露骨头(例如骨头压力点,例如大转子,或骶骨)的伤口。本公开涉及使用本发明的干组合物或复水后的糊剂治疗以上提到的任何类型的伤口。
伤口的治疗原则上可以导致伤口愈合或伤口愈合加速。加速愈合可以是由于例如施用促进伤口愈合的物质所致。或者,伤口愈合可以通过预防细菌或病毒感染,或通过降低原本会延长伤口治疗过程的此类感染的风险来促进。
在一个实施方案中,本公开涉及通过将本公开的干组合物或糊剂施用到受伤骨头、肌腱或组织处而在有需要的个体中促进骨头和/或肌腱和/或组织愈合的方法。
本文提到的“个体”可以是任何哺乳动物,包括但不限于啮齿目(Rodentia)的哺乳动物(例如小鼠和仓鼠)和兔型目(Logomorpha)的哺乳动物(例如兔)。哺乳动物优选来自食肉目(Carnivora),包括猫科(猫)和犬科(狗)。哺乳动物更优选来自偶蹄目(Artiodactyla)(包括牛科(母牛)和猪科(猪))或奇蹄目(Perssodactyla)(包括马科(马))。哺乳动物最优选来自灵长目(Primate)、阔鼻小目(Ceboid)或Simoid(猴)或类人猿目(Anthropoid)(人和猿)。特别优选的哺乳动物是人。
试剂盒
本公开进一步涉及一种试剂盒,其包含干组合物和与所述干组合物的量匹配的一定量的水性介质,使得一在加入所述水性介质后,具有合适稠度的糊剂就将自发地、即在几秒内形成。优选地,所述试剂盒是用于在有需要的个体中促进止血或用于伤口、骨头、肌腱和/或组织愈合中。
因此,在一个实施方案中,本公开涉及一种试剂盒,其包括:
a)包含通过本公开的方法获得的干组合物的容器,
b)包含水性介质的容器,和
c)任选的外包装。
用于使糊剂复水的水性介质可以例如选自水、盐水、CaCl2溶液或缓冲水溶液。
在一个实施方案中,用于使干组合物复水的水性介质是水。在一个实施方案中,对水性介质的张力进行选择,以使得一在向干组合物中加入水性介质后就将形成基本上等渗的糊剂。通常对糊剂的张力进行选择,使得其与外科应用是相容的。
在一个实施方案中,用于使干组合物复水的水性介质是盐水。
在一个实施方案中,干组合物包含凝血酶。
在一个实施方案中,用于使干组合物复水的水性介质包含挤出增强剂例如白蛋白。在这种情况下,干组合物优选地不含挤出增强剂。
实施例
实施例1.包含不同量的甘露糖醇和甘油的止血糊剂
材料
50g明胶粉末(研磨的交联明胶海绵)
200ml缓冲液
多元醇
50%苯扎氯铵(BAC)
0.9%盐水溶液
根据以下方案的x g甘露糖醇和y g甘油:
设备
冷冻干燥器:Leybold-Heraus,Lyovac GT2或Christ Alpha 1-4LSC
混合器:Kenwood,Major KM616
方法
缓冲溶液:
将2.0g±0.1g BAC(50%)加入到250mL蓝盖瓶中。
将98.0g±0.5g盐水溶液加入到BAC中
使用磁力搅拌混合2分钟—这是BAC储备溶液
将123.0g±0.5g甘油加入到2000mL量瓶中
加入10g±0.5g BAC储备溶液
加入盐水达到2000mL标记
给量瓶塞上塞子并上下倒置几次
通过磁力搅拌混合5±1分钟
糊剂:
在混合器中在搅拌下将x g多元醇溶解于200ml缓冲溶液中。加入50g明胶粉末并且与溶解的多元醇混合直到大约5分钟获得均匀糊剂。在大约20℃的室温下进行糊剂的混合。
冷冻干燥:
将获得的糊剂装入10ml一次性塑料注射器(每个注射器5.5ml)中并且在-30℃下放置最少4小时。将冷冻的糊剂转移到冷冻干燥器中并且冷冻干燥15小时直到干燥。
复水:
通过向每个注射器中加入8ml液体、即加入在冷冻干燥过程中从组合物去除的水量来使干组合物复水。不使用机械混合或搅拌。仅仅向干组合物中加入水并且保持组合物不被触碰直到再形成糊剂。
结果
测试不同配方的复水时间,即在不使用任何种类的机械搅动的情况下适用于止血目的的糊剂自发形成所需的时间。*一式三份测定
配方11是阴性对照。配方11糊剂的稠度明显逊于含有不同量的甘露糖醇和甘油的糊剂的稠度。
配方5
配方5的自发复水时间是5秒。下表分别说明糊剂(湿润)和经干燥组合物(干燥)中的配方5的内容物。
配方5中的甘油的总百分比在糊剂中因此是6.29%并且在经干燥的组合物中是19.61%。
总多元醇浓度(即甘露糖醇和甘油)在糊剂中是13.56%并且在干燥后是42.27%。
干组合物中的多元醇:明胶比率是大约0.75:1。
实施例2.甘露糖醇和甘油
根据实施例1所描述的方法制备糊剂,干燥并复水。下表显示糊剂的内容物。
根据上表制备的糊剂的自发复水时间是6秒。
总多元醇浓度(即甘露糖醇和甘油)在糊剂中是11.97%并且在干燥后是38.79%。
干组合物中的多元醇:明胶比率是大约0.65:1。
实施例3.甘露糖醇
除了使用水代替实施例1的缓冲溶液以外,根据实施例1所描述的方法制备糊剂,干燥并复水。下表显示糊剂的内容物。
根据上表制备的糊剂的自发复水时间是7秒。
本实施例的结果显示用于止血目的的具有合适稠度的糊剂可以从只包含明胶、水和单一多元醇(在这种情况下是甘露糖醇)的冷冻干燥糊剂获得。
干组合物中的多元醇:明胶比率是大约0.4:1。
实施例4.海藻糖和甘油
根据实施例1所描述的方法制备糊剂,干燥并复水。下表显示糊剂的内容物。
根据上表制备的糊剂的自发复水时间是8秒。
总多元醇浓度(即海藻糖和甘油)在糊剂中是11.97%并且在干燥后是38.79%。
干组合物中的多元醇:明胶比率是大约0.65:1。
实施例5.凝血酶
凝血酶以2500IU/产物(8ml)的理论浓度包含在实施例1的配方5糊剂中。如实施例1所描述在室温(大约20℃)下制备糊剂并混合。
如实施例1所描述通过冷冻干燥来干燥得到的糊剂并复水。测量复水后的糊剂中的凝血酶活性。结果显示于下表中。
没有测量到复水后的糊剂中的凝血酶活性损失。
这些结果进一步显示,在低温下进行糊剂的混合以避免凝血酶活性损失并不是严格必需的,因为当在环境温度下进行混合时没有发现凝血酶活性的降低。
实施例6.不同多元醇
除了使用含BAC的H2O代替实施例1的缓冲液以外,基本上如实施例1所描述来制备包含不同多元醇的糊剂,干燥并复水。下表显示糊剂的内容物。
干组合物中的多元醇:明胶比率是大约0.4:1。
下表和图2中显示根据上表制备的包含不同多元醇的糊剂的自发复水时间。对于每种多元醇,实验重复5次。
以秒计的复水时间:
甘露糖醇 | 木糖醇 | 海藻糖 | 麦芽糖醇 | 山梨糖醇 | |
1 | 7 | 14 | 11 | 14 | 29 |
2 | 9 | 31 | 28 | 14 | 28 |
3 | 9 | 20 | 16 | 23 | 29 |
4 | 10 | 30 | 29 | 16 | 35 |
5 | 9 | 31 | 23 | 22 | 32 |
平均值 | 8.8 | 25.2 | 21.4 | 17.8 | 30.6 |
标准差 | 1.1 | 7.8 | 7.8 | 4.4 | 2.9 |
实验显示不同种类的多元醇都可用于制备冷冻干燥的明胶糊剂,所述明胶糊剂一在加入水后就将自发地复水。复水后的糊剂具有适合直接作为止血糊剂使用的稠度。
Claims (40)
1.一种制备适合用于止血和伤口愈合中的干组合物的方法,其包括以下顺序步骤:
a.提供粉末形式的生物相容性聚合物、一种或多种多元醇、选自由白蛋白、磷脂酰胆碱、磷脂酰丝氨酸、卵磷脂和大豆油组成的组的挤出增强剂和水性介质,
b.混合所述生物相容性聚合物、所述一种或多种多元醇、所述挤出增强剂和所述水性介质,以获得糊剂,和
c.干燥所述糊剂;
其中所述干组合物包含10%w/w到60%w/w的一种或多种多元醇;
其中所述干组合物在加入水性介质后复水形成糊剂,而无需机械混合。
2.根据权利要求1所述的方法,其中所述挤出增强剂是白蛋白。
3.根据权利要求2所述的方法,其中所述白蛋白是人血清白蛋白。
4.根据权利要求1所述的方法,其中所述糊剂在干燥前包含0.1%w/w到10%w/w的量的所述挤出增强剂。
5.根据权利要求4所述的方法,其中所述糊剂在干燥前包含0.5%w/w到5.0%w/w的量的所述挤出增强剂。
6.根据权利要求1所述的方法,其中所述干组合物包含20%w/w到50%w/w的一种或多种多元醇。
7.根据权利要求1所述的方法,其中所述干组合物包含20%w/w到40%w/w的一种或多种多元醇。
8.根据权利要求1所述的方法,其中所述干组合物包含20%w/w到30%w/w的一种或多种多元醇。
9.根据权利要求1-8任一项所述的方法,其中所述糊剂在干燥前包含3%w/w到20%w/w的一种或多种多元醇。
10.根据权利要求1-8任一项所述的方法,其中所述生物相容性聚合物是交联的。
11.根据权利要求1-8任一项所述的方法,其中所述生物相容性聚合物从交联海绵获得。
12.根据权利要求1-8任一项所述的方法,其中所述生物相容性聚合物是明胶。
13.根据权利要求1-8任一项所述的方法,其中所述干燥是冷冻干燥。
14.根据权利要求1-8任一项所述的方法,其中所述糊剂在干燥前包含:
a.5%w/w到20%w/w的一种或多种多元醇,
b.0.5%w/w到5%w/w的挤出增强剂,
c.15%w/w到25%w/w的生物相容性聚合物,和
d.60%w/w到80%w/w的水。
15.根据权利要求1-8任一项所述的方法,其中所述干组合物包含少于5%w/w的水。
16.根据权利要求1-8任一项所述的方法,其中所述干组合物包含少于3%w/w的水。
17.根据权利要求1-8任一项所述的方法,其中所述干组合物包含少于2%w/w的水。
18.根据权利要求1-8任一项所述的方法,其中所述干组合物包含少于1%w/w的水。
19.根据权利要求1-8任一项所述的方法,其中所述一种或多种多元醇选自糖和/或它们的衍生物。
20.根据权利要求19所述的方法,其中所述一种或多种多元醇是糖醇和/或它们的衍生物。
21.根据权利要求20所述的方法,其中所述糖醇选自由二醇、甘油、赤藓糖醇、苏糖醇、阿拉伯糖醇、木糖醇、核糖醇、甘露糖醇、山梨糖醇、半乳糖醇、岩藻糖醇、艾杜糖醇、肌醇、庚七醇、异麦芽酮糖醇、麦芽糖醇、乳糖醇和聚葡糖醇组成的组。
22.根据权利要求21所述的方法,其中所述一种或多种多元醇是甘露糖醇。
23.根据权利要求22所述的方法,其中所述干组合物包含一种或多种其它多元醇。
24.根据权利要求1-8任一项所述的方法,其中所述干组合物进一步包含一种或多种刺激止血或伤口、骨头、肌腱和/或组织愈合的生物活性剂。
25.根据权利要求24所述的方法,其中所述生物活性剂是凝血酶。
26.根据权利要求1-8任一项所述的方法,其中所述水性介质选自由水、盐水、氯化钙溶液和缓冲水性介质组成的组。
27.根据权利要求1-8任一项所述的方法,其中所述方法包括将所述干组合物置于外包装中的另一步骤。
28.根据权利要求27所述的方法,其中所述外包装是铝箔包装。
29.根据权利要求1-8任一项所述的方法,其中所述方法包括对所述干组合物灭菌的另一步骤。
30.根据权利要求1-8任一项所述的方法,其中所述糊剂被填充到适合用于分配糊剂形式的组合物的施药器中并在其中被干燥。
31.根据权利要求30所述的方法,其中所述施药器是注射器。
32.根据权利要求1-8任一项所述的方法,其中所述干组合物在少于30秒内在无机械混合的情况下复水以形成糊剂。
33.一种干组合物,其由根据权利要求1-32中任一权利要求所述的方法获得。
34.根据权利要求33所述的干组合物,其中所述干组合物存在于适合用于分配糊剂形式的组合物的施药器中。
35.根据权利要求33所述的干组合物,其中所述干组合物呈片的形式。
36.由根据权利要求1到32中任一权利要求所述的方法获得的干组合物或根据权利要求33或34所述的干组合物在制备糊剂中的用途。
37.由根据权利要求1到32中任一权利要求所述的方法获得的干组合物或根据权利要求33到35中任一权利要求所述的干组合物,其用于在有需要的个体中促进止血和/或伤口、骨头、肌腱和/或组织愈合。
38.一种试剂盒,其包括:
a.包含由根据权利要求1到32中任一权利要求所述的方法获得的干组合物或根据权利要求33到34中任一权利要求所述的干组合物的容器,和
b.包含水性介质的容器。
39.根据权利要求38所述的试剂盒,其还包括:c.外包装。
40.一种用于使干组合物复水的方法,其包括以下步骤:
a.提供根据权利要求1到32中任一权利要求所述的方法获得的干组合物或根据权利要求33到34中任一权利要求所述的干组合物,
b.将水性介质加入到所述干组合物中。
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CA2928963A1 (en) | 2015-06-18 |
EP3079731B1 (en) | 2018-08-08 |
AU2014361291A1 (en) | 2016-06-02 |
US10111980B2 (en) | 2018-10-30 |
BR112016013322B1 (pt) | 2020-07-21 |
EP3470094B1 (en) | 2020-07-22 |
RU2678592C1 (ru) | 2019-01-30 |
CA2928963C (en) | 2020-10-27 |
EP3470094A1 (en) | 2019-04-17 |
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