CN1555249A - 干燥止血组合物及其制备方法 - Google Patents

干燥止血组合物及其制备方法 Download PDF

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CN1555249A
CN1555249A CNA028182073A CN02818207A CN1555249A CN 1555249 A CN1555249 A CN 1555249A CN A028182073 A CNA028182073 A CN A028182073A CN 02818207 A CN02818207 A CN 02818207A CN 1555249 A CN1555249 A CN 1555249A
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Z��Ǯ
Z·钱
E·A·奥萨瓦
C·J·赖克
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    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
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Abstract

制备干燥交联明胶组合物,这种组合物能迅速再水化以生成宜作止血密封剂用的明胶水凝胶。明胶要在某种再水化助剂如聚乙二醇、聚乙烯吡咯烷酮和葡聚糖存在下进行交联,目的是形成一种干燥的交联明胶粉。已经发现,使用再水化助剂能在再水化水性介质,典型的是含凝血酶的盐水存在下,大幅度提高再水化率。

Description

干燥止血组合物及其制备方法
发明背景
1.发明领域
本发明一般地涉及胶原与胶原-衍生的组合物以及它们的制备方法。特别是,本发明涉及一种生产能以更高速率吸水的干燥交联明胶或其它胶原或胶原-衍生的组合物的方法。
本申请的受让人Fusion Medical Technologies公司生产一种止血组合物,商品名为FloSeal。FloSeal产品以包括2个注射器的包装出售。第一个注射器装满用一种缓冲溶液预水化的交联牛明胶颗粒。该明胶水凝胶含约85%(重量/重量)水,其形式是一种可流动水凝胶。在即将用于手术室之前,要将盐水中的凝血酶与明胶水凝胶混合。凝血酶要在盐水中制备并吸入第二注射器内,两个注射器互连在一起,以便凝血酶与明胶混合。
业已发现,所得明胶水凝胶颗粒与凝血酶的混合物涂在出血处时是一种非常有效的止血密封剂。一般,该密封剂要用它在其中已混合好的注射器施涂到出血处。血液将渗透过所形成的水凝胶颗粒床,凝血酶与血液中的血纤维蛋白原反应,在明胶周围形成血纤维蛋白凝块,从而封住出血处。
现有的FloSeal产品虽然非常有效,但其储存寿命有限。相信明胶的稳定性因包装水凝胶的水解而降低。为抑制可能的水解降解,FloSeal产品通常要在保温包装中运输。
为此,希望提供组合了胶原、明胶或其它胶原-衍生的水凝胶与含凝血酶的水溶液的这类更好的止血密封组合物。尤其希望提供抗水解降解并因此而具有更长储存寿命的这类组合物。特别希望提供其止血活性与现有FloSeal产品相当而储存寿命又更长的改进组合物。这类组合物如果能为随后的使用而迅速再水化,从而使它们能通过注射器挤出,那是非常有利的。下文所述的本发明将至少部分满足上述目的。
2.背景技术描述
Fusion Medical Technologies公司出售的FloSeal产品在Hood等于1999年9月以Efficacy of Topical Hemostat FloSealTM inVascular Surgery为题公开发表在Fusion Medical Techmologies公司资助的文摘中已有所述。有关FloSeal产品的专利包括美国专利号6,063,061和6,066,325。适合于混合并输送FloSeal产品中一个胶原、明胶或其它胶原衍生的组分和一个凝血酶组分的双注射器系统已描述在美国专利5,908,054中。所有上述专利的全部公开内容都包括于此供参考。
发明概述
本发明提供改进的止血密封组合物、制备这类改进组合物的方法及包含这类改进组合物的试剂盒。这些方法与组合物特别适用于包括手术出血处、外伤出血处等在内的出血处的止血。这类组合物的典型用途可以用于密封在血管导管插入术形成的血管穿透之上的组织系统。
这类组合物包含一种已制成能迅速再水化的干燥交联明胶粉。该明胶粉优选包含较大的颗粒,也称为碎片或次单元,如美国专利6,063,061和6,066,325所述,该专利的全部公开内容已包括在前面供参考。优选的颗粒尺寸范围为150μm-750μm,但在很多情况下也可以用该优选范围之外的颗粒尺寸。这类干燥组合物在暴露于再水化水性介质中时也将表现出大的“平衡溶胀比”。优选溶胀比在400%-1000%范围内,但也可以落在该范围之外,如上述参考专利所述。“平衡溶胀比”可通过将明胶水凝胶粉末完全水化从而完全溶胀时的重量减去其干燥重量确定。然后将差值除以干燥重量并乘以100,以给出溶胀比值。干燥重量应将该物质在高温下处理足够长时间以基本除去所有的残留水份,例如在120℃下处理2小时后测定。实现物质平衡水化的方法可以如下:将干燥物质在适当的再水化介质如盐水中浸泡足够长时间,使水含量达到恒定,一般要在室温下浸泡18-24小时。
本发明的干燥交联明胶粉通常含有一些残留水份,但须足够干燥以达到所要求的稳定性和更长的储存寿命。一般干燥组合物的含湿量低于20重量%或更低,优选含湿量在5重量%-15重量%范围内。为保持其干燥度,组合物一般以适合于防湿气侵入的方式包装,如结合本发明的试剂盒所详述。
在本发明的一个具体方面,组合物将包含含湿量为20%(重量/重量)或更低的交联明胶粉,其中所述粉末要在有再水化助剂存在下交联,以使粉末的再水化率较之不用再水化助剂时所制成的类似粉末的再水化率至少高5%。这里“再水化率”定义为1g粉末(以干燥重量为基准计算)在30秒内吸收的浓度一般为0.9%(重量/重量)盐水的量,以gm/gm表示。测定该速率的具体技术在下文实验部分描述。本发明优选组合物的再水化率至少为3gm/gm,优选至少3.5gm/gm,通常为3.75gm/gm或更高。不用再水化助剂所制成的类似粉末的再水化率一般低于3,再水化率的增加通常至少为5%,优选至少10%,更优选至少25%或更高。
本发明的再水化率更高的干燥交联明胶粉优选通过在有某种再水化助剂存在下制备粉末而获得。这类再水化助剂将在粉末制备期间存在,但通常要从最终产品中除去。例如,以总固体量约20%存在的再水化助剂在最终产品中一般要降到1重量%以下,通常低于0.5重量%。再水化助剂的实例包括聚乙二醇(PEG),优选分子量约1000;聚乙烯吡咯烷酮(PVP),优选平均分子量约50,000;和葡聚糖,一般平均分子量约40,000。在制备本发明的组合物时,优选使用上述再水化助剂中的至少2种,更优选使用所有这3种。
因此,本发明的方法包含提供一种未交联明胶与再水化助剂组合的水溶液。未交联明胶在水溶液中的存在量一般为5%(重量/重量)-15%(重量/重量),再水化助剂的存在量一般为水溶液中明胶重量的5%-30%(重量/重量)。优选再水化助剂包含明胶重量2.5%-20%(重量/重量)的PEG,1.25%-20%(重量/重量)的PVP和1.25%-20%(重量/重量)的葡聚糖。
然后将未交联明胶与再水化助剂一起以任何适合于形成水凝胶的方法进行交联。例如,聚合物分子可以用双-或多-官能度交联剂进行交联,交联剂以共价键连接在两个或多个聚合物分子链上。典型的双官能度交联剂包括醛、环氧化物、琥珀酰亚胺、碳二亚胺、马来酰亚胺、叠氮化物、碳酸酯、异氰酸酯、二乙烯基砜、醇、胺、亚胺酯、酸酐、卤化物、硅烷、重氮基乙酸酯、氮丙啶等等。或者也可以用氧化剂和其它试剂如高碘酸盐实现交联,这类试剂能活化聚合物上的侧链或部分,使它们与其它侧链或部分反应,形成交联键。交联的另一种方法包含将聚合物暴露于γ射线之类的射线中以活化聚合物链,以允许发生交联反应。脱氢热交联法也适用。交联明胶分子的优选方法如下所述。
生成交联明胶的典型方法如下。获得明胶并将其悬浮在水溶液中,形成未交联水凝胶,固体含量一般为1重量%-70重量%,通常为3重量%-10重量%。明胶的交联一般是暴露在戊二醛(例如,浓度为0.01%-0.05%重量/重量,在0℃-15℃缓冲水溶液中过夜)、高碘酸钠(例如,浓度为0.05M,在0℃-15℃保持48小时)或1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(“EDC”)中(例如,浓度为0.5%-1.5%重量/重量,在室温下过夜),或暴露在约0.3-3兆拉德γ或电子束辐照中。或者,也可以通过将明胶颗粒悬浮在醇中,优选甲醇或乙醇,固体含量一般为1重量%-70重量%,通常为3重量%-10重量%,然后通过暴露于交联剂中进行交联,交联剂一般是戊二醛(例如,浓度为0.01%-0.1%重量/重量,在室温下过夜)。在戊二醛的情况下,pH值应保持约6-11,优选7-10。用戊二醛交联时,交联是通过Schiff碱形成的,然后可以通过随后的还原如用氢硼化钠处理而稳定化。交联后,所得颗粒可用水清洗,任选地在醇中漂洗,并烘干。然后可将所得干燥粉末装进本发明的涂布器,如下文更详细的描述。
交联后,要从所得水凝胶中除去至少50%(重量/重量)再水化助剂。通常,除去再水化助剂的方法是过滤水凝胶,接着清洗所得的滤饼。为了将产品清洗到所需的水平并除去至少50%,优选至少90%(重量/重量)起始存在的再水化助剂,这样的过滤/清洗步骤可重复一次或多次。
过滤后,明胶要烘干,典型的方法是烘干所得到的最终滤饼。烘干的滤饼随后要经破碎或研磨,以形成颗粒尺寸在上述所需范围内的交联粉末。
按照本发明的试剂盒将包含一个容纳如前所述本发明干燥交联明胶粉末的第一容器。该试剂盒还包含一个容纳再水化水性介质的第二容器,再水化水性介质一般是拟在明胶再水化时与明胶混合的包含凝血酶的盐水或其它水溶液。两个容器可具有任何形式,但优选允许干明胶与再水化介质混合的注射器形式。
附图简述
图1示意一个按照本发明原理构成的试剂盒。
具体实施方案详述
下列实例仅为说明而给出,无意限制本发明。
实施例1:明胶粉的制备
将牛皮条悬浮在浓度为1M-2M的氢氧化钠溶液中,在室温下保持1小时,用磷酸中和之,然后清洗之。然后将处理过的条再悬浮在去离子水中,将pH值调到7-8,并加热到70℃。用均化器进一步减小条的尺寸。在70℃放置1小时后,皮大多溶解成明胶。皮量的选择要使所得明胶溶液中的固体含量为约3-10%(重量/重量),典型值为7-10%。然后将溶液在涂有Teflon的金属盘上浇铸成薄层,经干燥并研磨成明胶粉末。
实施例2:“改性明胶粉”的制备
将再水化助剂(表1)溶解在500mL 50℃去离子水中,然后在该溶液中加入一定量如实施例1那样制备的牛皮衍生明胶粉。明胶在溶液中的最终浓度要选为约8%(重量/重量,以本体明胶粉为基准),再水化助剂在溶液中的总量要如实施例9-44(表1和2)所选。在明胶溶解之后,将溶液倒进带Teflon涂层的金属盘内并干燥之。将干燥的明胶片研磨成“改性明胶粉”。
或者也可以将牛皮条悬浮在浓度为1M-2M的氢氧化钠溶液中,在室温下保持1小时,用磷酸中和之,然后清洗之。然后将处理过的条再悬浮在去离子水中,将pH值调到7-8,并加热到70℃。用均化器进一步减小条的尺寸。在70℃放置1小时后,皮大多溶解成明胶。皮量的选择要使所得明胶溶液中的固体含量约为3-10%(重量/重量),典型值为7-10%。再水化助剂的用量要如实施例9-44那样选择(表1和2)并以固体形式或溶于少量水的形式加进明胶溶液。然后将溶液在带Teflon涂层的金属盘上浇铸成薄层,经干燥并研磨成“改性明胶粉”。改性明胶粉的一些配方实施例列在表1与2中。
实施例3:从“改性明胶粉”制备交联明胶粉
将600mL 0.2M磷酸盐缓冲液(pH值9.2±0.2)冷却到低于12℃的温度。在该缓冲液中加入0.32mL戊二醛(25%),然后再加入20g改性明胶粉,使戊二醛的浓度为4000ppm(戊二醛与改性明胶本体重量之比)。用搅拌棒使明胶悬浮在戊二醛溶液中。将各悬浮液的pH值调到9.2±0.2范围内,然后在9-12℃的温度和9.2±0.2的pH值下保持19小时。
过滤该悬浮液并用去离子水清洗滤饼3次,方法是用去离子水完全浸没滤饼,然后使用真空将清洗水吸过滤饼。每次清洗期间,滤饼留在漏斗内。
在烧杯内将0.2g NaBH4溶于600mL浓度为25mM的磷酸盐缓冲液中,pH值为7.4±0.2。在室温(约22℃)下将上述滤饼悬浮在NaBH4溶液中3小时,然后过滤去除液体。
然后在室温(约22℃)下将滤饼悬浮在600mL缓冲液中30min,再过滤。缓冲液由磷酸钠(二元酸酐和一元一水合物)和抗坏血酸钠组成。重复上述步骤2次,以确保盐与明胶以适当比例存在,从而在重构时形成所需的缓冲组合物。干燥该滤饼,然后用Waring Blender研磨成“交联明胶粉”。
本方法也用来从未改性明胶粉制备交联明胶粉;即在制备期间不加再水化助剂的明胶。
实施例4:从交联明胶粉制备辐照产品
在几支5ml注射器的每一支内放进约800mg(本体重量)如实施例2那样制备的交联明胶粉。在室温下用γ射线消毒含粉末注射器。
实施例5:用产品作为止血剂
从改性明胶粉末制备一支注射器内含约0.8g辐照交联明胶粉末的产品。改性明胶粉如实施例2那样制备。改性明胶粉经进一步交联并辐照,如实施例3和4那样。将产品与4mL盐水溶液混合,每ml盐水溶液含约1000单位牛血清凝血酶。混合是通过在由阴-阴直通Luer连接器连接的两个注射器之间往返通过而实现的。当注射器中的粉末与凝血酶溶液混合时粉末就被水化了,形成水凝胶颗粒。
在农庄级猪的肝上产生一片约1cm×1cm×0.2cm深的伤口。该头猪已用肝素抗凝过,因此其活化血凝时间(ACT)是其基础值的3-5倍,该伤口在处理以前不断流血。从混合开始约30秒钟后,将约2mL水化粉末从注射器中挤到伤口上并压住2分钟。除去压力后,分别在涂抹后3min、10min和50min观察处理伤口的流血情况。3min和10min观察,未见处理伤口流血。10min后用盐水溶液冲洗处理过的伤口。除去过量物质后,仍未见再流血。在涂抹后50min时,再观察伤口,也未见流血。
实施例6:测定粉末的再水化率
粉末的“再水化率”测定如下。装在5mL注射器中的粉末与含一定体积水溶液的第二注射器通过在两个注射器之间由Luer接头连接的通道混合30秒钟。选择的水溶液体积要超过预期在30秒钟内吸收的量。一般是将0.8g(本体重量)粉末与3mL 0.9%氯化钠水溶液混合。然后立即过滤所得混合物,以除去所有未被吸收的液体。称重湿过滤物,然后在120℃烘箱内烘2小时,再称重。这一测量给出从湿物质中除去的总水量以及干粉重量。然后在对原来残留在粉末中的水份作过微小校正后计算出被粉末吸收的水量。“再水化率”以每克干粉末在30秒间隔内吸收的盐水质量给出。
在下面的计算中,本体粉末的固体分数(“S”)是独立地通过将本体粉末在120℃烘2小时并对干燥前后的粉末称重测得的。S值由下式计算:
Figure A0281820700101
再水化率计算:
A:盘和滤纸的起始重量
B:盘、滤纸和水化粉末的重量
C:盘、滤纸和样品在烘箱内烘干后的重量
S:注射器内起始本体粉末的固体分数
M:混合期间每克粉末(干重)吸收的盐水克数(“吸收率”)
M = ( B - A ) - ( C - A ) / S ( C - A )
实施例7:对几批粉末产品测定的再水化率与物理性能
表1和2示意了对几批粉末产品(实施例9-23)中每批测定的再水化率结果。这些批次的粉末分别如实施例1、2、3和4那样的方法制备。除实施例9与17之外,都从改性明胶按不同比例的明胶与下列再水化助剂制备:平均分子量为1000的聚乙二醇(PEG);牌号为“k-30”对应于平均分子量约50,000的聚乙烯吡咯烷酮(PVP);和平均分子量40,000的葡聚糖。
可以看到,使用不同比例组合的明胶和再水化助剂,能使粉末产品的每克粉末在30秒内吸收的盐水溶液多于用无再水化助剂的明胶制成的粉末产品。还可以看到,用明胶、PEG、PVP和葡聚糖以本体重量比为80∶10∶5∶5的组合(实施例10)的改性明胶所生成的粉末产品,每克在30秒内吸收的盐水溶液比从未改性明胶制成的粉末多约33%。
表1还给出了对这些粉末产品批次测定的其它物理性能值。“固体百分含量”由称取粉末在120℃烘2小时以除去残余水份前后的重量测定。“DSC峰温”是指从1℃-70℃进行的差示扫描量热法测定的温度谱上出现峰的温度。“平衡溶胀比”的测定方法如下:在室温下让粉末悬浮在过量盐水溶液中至少18小时。对该水化粉末称重以确定其“平衡湿重”,然后在120℃烘2小时,再称重,以确定其“干重”。平衡溶胀比计算如下:
“平均颗粒尺寸”值用光散射法在Coulter LS颗粒尺寸分析仪上测定。
从表1给出的数据中显然可看到,适当使用再水化助剂能改变粉末产品的再水化率而不会明显改变其它物理性能。
实施例8:测定聚乙二醇、聚乙烯吡咯烷酮和葡聚糖在改性明胶粉末和交联粉末中的含量
将约50mg改性明胶或250mg交联辐照粉末产品悬浮在10mL去离子水中并在65℃加热3小时。然后将样品以2000rpm离心处理15min。将所得悬浮液滤过一个0.45μm Gelman Acrodisc漏斗,弃去第一mL。所得样品然后用3种不同的高效液相色谱法(HPLC)进行评估,以定量给出样品中聚乙二醇(PEG)、聚乙烯吡咯烷酮(PVP)和葡聚糖的含量。对于PEG,将100μl样品注射到Waters Ultrahydrogel 120柱上,柱子尺寸7.8×300mm,带保护柱和预过滤漏斗,用去离子水作为移动相。用折光指数测定仪监测流出物。对于PVP,将100μl样品注射到Phenomenex Kingsorb C18 5μm柱上,柱子尺寸4.6×150mm,带保护柱和预过滤漏斗,用梯度甲醇与磷酸钠水溶液作为移动相。用紫外吸收测定仪监测流出物。对于葡聚糖,将100μl样品注射到WatersUltrahydrogel线柱上,柱子尺寸7.8×300mm,带保护柱和预过滤漏斗,用0.1M pH7磷酸钠与乙腈按90∶10作为移动相。用折光指数测定仪监测流出物。为进行分析,所有柱子都加热到40℃。定量极限对PEG和PVP约为0.1%(重量/重量样品),对于葡聚糖,为0.2%(重量/重量样品)。
改性明胶如实施例2那样制备。按上述方法分析改性明胶的PEG、PVP和葡聚糖。结果表明,PEG、PVP和葡聚糖的存在量分别为16%、8%和3%(重量/重量本体)。让改性明胶依次经交联、氢硼化物处理和清洗,如实施例3那样,以形成交联改性明胶粉。当以上述方法用HPLC分析这种粉末的PEG、PVP和葡聚糖时,发现这三种再水化助剂中每一种的含量都低于定量极限。
实施例9:不加再水化助剂制成的粉末产品
按实施例1那样从牛皮条制备未改性明胶-即不加加工助剂的明胶并按实施例3那样进行交联。如实施例4那样将交联未改性明胶装入注射器并进行γ辐照。如实施例6和7那样测定所得产物的物理性能,结果示于表1。
实施例10-23:用再水化助剂制成的粉末产品
如实施例2那样从明胶粉或皮条和1、2或3种再水化助剂制备改性明胶批料。表1给出了所用本体明胶与再水化助剂的比例。然后如实施例3那样交联该改性明胶。除实施例17之外,所用的再水化助剂如下所示:平均分子量约1000的聚乙二醇(PEG);牌号为“k-30”、平均分子量约50,000的聚乙烯吡咯烷酮;和平均分子量约40,000的葡聚糖。在实施例17中,用平均分子量约400的PEG。然后如实施例4那样将该交联改性明胶装进注射器并进行γ辐照。如实施例6和7那样测定从每一种制备方法得到的粉末产品的物理性能,结果示于表1。用实施例10的配方得到的数据是按照该配方制备的9批样品的平均值与标准偏差。
实施例24-44:用各种再水化助剂制成的粉末产品
如实施例2那样从明胶粉或皮条和几种再水化助剂之一制备几批改性明胶。表2给出了每批所用再水化助剂的名称与浓度,浓度以本体明胶与再水化助剂的重量比和制备改性明胶所用的本体溶质的总百分数表示。然后如实施例3那样交联该改性明胶。然后如实施例4那样将交联改性明胶装进注射器并进行γ辐照。如实施例6和7那样测定从每一种制备方法得到的粉末产品的物理性能,结果示于表2。表2中给出了实施例9的配方的结果作为比较。
                                           表1
批次 改性明胶的目标本体百分数明胶    PEG     PVP      葡聚糖(本体   MW=    MW~     MW=重量)   1000D   50000D   40000D          交联与γ辐照后粉末产品的性能(大部分再水化助剂已除去)DSC                  平均峰温    平衡溶胀比   颗粒尺寸  再水化固体%  (℃)    (%)         (μm)     率*
未加再水化助剂实施例9优选组成(四路混合物)实施例10三路混合物实施例11实施例12实施例13明胶-PEG混合物实施例14实施例15实施例16实施例17明胶-PVP混合物实施例18实施例19实施例20明胶-葡聚糖混合物实施例21实施例22实施例23 208-329批的平均化与标准偏差228-69-1228-69-2228-78212-39-2228-42-3228-42-1214-62-1228-38-3228-38-2228-38-1228-35-3228-35-2228-35-1 100     0       0        080      10      5        580      10      10       080      10      0        1080      0       10       1094      6       0        089      11      0        080      20      0        089      11**   0        094      0       6        089      0       11       080      0       20       094      0       0        689      0       0        1180      0       0        20 88.6    41.3    551          440       2.8587.6    42.1    595          423       3.791.0     1.4     43           65        0.1588.1    40.8    667          387       3.5188.4    40.6    670          367       3.1486.7    41.1    632          414       3.2086.2    44.4    502          372       2.6888.6    42.8    594          428       3.1688.9    42.4    575          312       3.4787.1    40.7    599          406       3.1188.2    42.2    567          399       3.2688.3    41.0    605          422       3.4488.6    42.4    596          401       3.5288.1    40.5    631          395       3.1888.3    41.4    598          345       3.0388.5    41.9    624          392       3.01
*-再水化速定义为每克粉末产品(干重)在30秒内吸收的盐水克数
**-用Mw=400的PEG代替Mw=1000的PEG
                                           表2
批次               再水化助剂改性明胶中加工助剂的Mw或      本体明胶    浓度类型    其它牌号  重量:助剂  (本体wt%)                 物理性能DSC                 平均峰温    平衡溶胀比  颗粒尺寸固体%  (℃)    (%)        (μm) 再水化率*
实施例9   208-32               无再水化助剂 88.6    41.3    551         440   2.85
实施例24实施例25实施例26   214-11-1214-11-2214-11-3 甘油    n/a       4           20%甘油    n/a       8           11%甘油    n/a       16          6% 85.5    43.4    483         65386.4    43.4    529         42186.5    43.0    543         398   2.192.622.35
实施例27实施例28实施例29实施例30   214-44-1214-44-2214-44-3214-44-4 葡聚糖  148000D   4           20%葡聚糖  148000D   8           11%葡聚糖  148000D   16          6%葡聚糖  148000D   32          3% 85.5    nr      634         43385.4    nr      607         45385.5    nr      603         52785.7    nr      531         491   2.622.572.332.37
实施例31   228-35-4 葡聚糖  40000D    32          3% 84.5    41.4    633         380   2.59
实施例32实施例33实施例34实施例35   214-50-1214-50-2214-50-3214-50-4 PVP     k-90      4           20%PVP     k-90      8           11%PVP     k-90      16          6%PVP     k-90      32          3% 85.3    44.0    612         66485.6    44.3    538         58185.6    44.1    527         59386.1    43.0    597         538   2.412.712.782.76
实施例36   214-53-4 PVP     k-30      32          3% 87.3    41.1    580         447   2.72
实施例37实施例38实施例39   214-59-1214-66-1212-39-1 PEG     400       4           20%PEG     400       6           14%PEG     400       16          6% 86.7    42.0    595         40786.5    40.8    603         50186.2    43.8    513         403   2.182.632.11
实施例40   212-39-2 PEG     1000      16          6% 86.2    44.4    502         372   2.68
实施例41实施例42实施例43实施例44   214-59-3214-66-3214-62-3212-39-3 PEG     8000      4           20%PEG     8000      6           14%PEG     8000      8           11%PEG     8000      16          6% 87.4    41.5    548         42986.9    41.4    581         42686.8    42.0    631         51186.4    44.6    546         518   2.873.802.782.72
nr=未报告    *-再水化率定义为每克粉末产品(干重)在30秒内吸收的盐水克数
虽然以上是本发明优选实施方案的完整描述,但可以用各种变化、改变和等代体。因此不应将以上的描述当作限制由所附权利要求规定的本发明范围。

Claims (20)

1.一种制造基本干燥的交联明胶粉的方法,所述方法包含:
提供一种包含交联明胶与至少一种再水化助剂组合的水溶液;
烘干该明胶与再水化助剂的溶液以形成固体;
研磨该固体以形成粉末;
交联该粉末;
除去至少50%(重量/重量)再水化助剂;以及
烘干该交联明胶以形成一种含湿量低于20%(重量/重量)的粉末。
2.如权利要求1的方法,其中再水化助剂包含1、2或3种选自下列一组的物质:聚乙二醇(PEG)、聚乙烯基吡咯烷酮(PVP)和葡聚糖。
3.如权利要求1或2的方法,其中再水化助剂以水溶液中所存在明胶重量的5%-30%的浓度存在。
4.如权利要求3的方法,其中再水化助剂包含的PEG浓度为2.5重量%-20重量%,PVP浓度为1.25重量%-20重量%,以及葡聚糖浓度为1.25重量%-20重量%。
5.如前述权利要求中任何一项的方法,其中交联包括在明胶溶液中加入一种交联剂。
6.如权利要求5的方法,其中交联剂包含戊二醛。
7.如前述权利要求中任何一项的方法,其中除去至少50%再水化助剂包括过滤交联粉末在溶剂中的悬浮液,接着过滤明胶以形成滤饼,然后清洗滤饼以除去再水化助剂。
8.如权利要求7的方法,其中清洗滤饼除去至少90%(重量/重量)起始存在于明胶中的再水化助剂。
9.如前述权利要求中任何一项的方法,其中烘干包括烘干清洗后的滤饼,其中该方法还包含烘干经研磨的滤饼,以形成干燥研磨明胶粉。
10.一种包含含湿量为20%(重量/重量)或更低的交联明胶粉的组合物,其中所述粉末是在再水化助剂存在下进行交联的,以使该粉末的再水化率比不用再水化助剂时所制备的类似粉末的再水化率高至少5%。
11.如权利要求10中的组合物,其中所述粉末的再水化率比不用再水化助剂时所制备的类似粉末的再水化率高至少10%,任选地,高至少25%。
12.如权利要求10或11的组合物,其中再水化助剂包含1、2或3种选自下列一组的物质:聚乙二醇(PEG)、聚乙烯基吡咯烷酮(PVP)和葡聚糖。
13.如前述权利要求中任何一项的组合物,其中所述粉末的平均颗粒尺寸为150μm-750μm。
14.如前述权利要求中任何一项的组合物,其中所述粉末的平衡溶胀比为400%-1000%。
15.一种包含下列部分的试剂盒:
一个容纳权利要求12-19任何一项的交联明胶粉的第一容器;和
一个容纳再水化水性介质的第二容器。
16.如权利要求15的试剂盒,其中第一容器是一个注射器。
17.如权利要求16的试剂盒,其中第二容器是一个注射器。
18.如前述权利要求中任何一项的试剂盒,其中再水化水性介质包含凝血酶。
19.如前述权利要求中任何一项的试剂盒,还包含使用说明书,指出组合交联明胶粉与再水化介质以形成含凝血酶的明胶水凝胶碎片和在伤口上涂布该水凝胶的方法。
20.如前述权利要求中任何一项的试剂盒,还包含一个容纳第一容器与第二容器的包装。
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