CN106061518A - 生物降解性医疗用粘结剂或密封剂组合物 - Google Patents
生物降解性医疗用粘结剂或密封剂组合物 Download PDFInfo
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- CN106061518A CN106061518A CN201480067775.9A CN201480067775A CN106061518A CN 106061518 A CN106061518 A CN 106061518A CN 201480067775 A CN201480067775 A CN 201480067775A CN 106061518 A CN106061518 A CN 106061518A
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Abstract
本发明提供包含氧化糖胺聚糖和聚胺的生物降解性医疗用粘结剂或密封剂组合物。本发明的组合物在生物降解性、涂敷性、凝胶化时间,止血功能、粘结力及水分吸收力等方面呈现改善的效果,从而可用于生物组织的粘结、填充、涂敷、防止粘连、伤口覆盖、防止露出及止血等可使用医疗用粘结剂或密封剂的多种医疗用途。
Description
技术领域
本发明涉及包含具有甲酰基的氧化糖胺聚糖和聚胺的生物降解性医疗用粘结剂或密封剂组合物。
背景技术
生物粘结剂(bioadhesive)及密封剂为在进行手术时用于缝合组织或涂敷在组织上,或者用作防出血剂(止血)、体液和血液阻断剂等,因生物粘结剂及密封剂与皮肤相接触,因此要求具有生物相容性,并且应在生物体内不产生毒性和危害性,而且还应具有生物降解性,且不得妨碍生物体治愈。
目前,已投入实际使用的医疗用粘结材料为氰基丙烯酸酯类、纤维蛋白胶类、动物胶类、聚氨酯类等,美国Closure Medical公司推出称作多抹棒(Dermabond)的氰基丙烯酸辛酯的医疗用组织粘结剂,并在1997年8月获得欧洲经济共同体的销售许可,且在1998年获得美国食品药品监督管理局(FDA)的许可。但是,在氰基丙烯酸酯类粘结剂中,因固化物缺乏柔韧性且坚硬,因此存在妨碍创伤治愈的情况,并且,很难在生物体内降解,因此,存在因粘结剂被包化而容易变成异物等问题。并且,由于纤维蛋白胶的粘结力相当低,因此存在所生成的纤维蛋白块从组织脱落的情况,且由于上述纤维蛋白胶为血液制剂,因此存在病毒感染等隐患。
除上述医疗用粘结剂之外,在韩国公开专利第10-2009-0083484号中公开了包含冷冻干燥之后进行机械粉碎而制备的葡聚糖醛粉末和ε-聚-L-赖氨酸粉末的医疗用双组分型粘结剂(商品名称:LYDEX)。上述双组分型粘结剂的特征在于上述双组分型粘结剂为粉末状的医疗用粘结剂,但是,存在用于降解凝胶的时间较长,且在水分吸收力方面无法获得期待效果的问题。因此,对具有改善降解时间、粘结力及水分吸收力等特征的新医疗用粘结剂的需求变高。
在整个说明书中,参照并引用了多个论文及专利文献。整个被引用的论文及专利文献的公开内容作为参照插入于本说明书中,从而使本发明所属技术领域的水平及本发明的内容更加明确地得到说明。
发明内容
技术问题
为了开发即使在存在体液及血液的体内部位中也可充分执行粘结、覆盖及止血,尤其,与其他生物降解性高分子相比,可吸收大量水分,可在体内自行降解的生物降解性医疗用粘结及密封剂,本发明人员进行了研究及努力。最终确认到,通过一同使用导入甲酰基来氧化的氧化糖胺聚糖和聚胺,从而可有效执行生物组织的粘结、填充、涂敷、防止粘连、伤口覆盖及止血等作用,由此完成了本发明。
因此,本发明的目的在于,提供医疗用粘结剂或密封剂(或医疗用粘结剂或密封剂组合物)。
本发明的另一目的在于,提供生物组织的粘结、填充、涂敷、防止粘连、伤口覆盖或止血方法。
通过下述的针对发明的详细说明、发明要求保护范围及附图,使得本发明的其他目的及优点变得更加明确。
解决问题的方案
根据本发明的一实施方式,本发明提供如下的生物降解性医疗用粘结剂或密封剂(或医疗用粘结剂或密封剂组合物),上述生物降解性医疗用粘结剂或密封剂包含:第一成分a,包含导入甲酰基来氧化的氧化糖胺聚糖;以及第二成分b,包含具有两个以上氨基的聚胺,上述第二成分在水溶液状态下的pH为8.5至11.0。
根据本发明的再一实施方式,本发明提供如下的生物降解性医疗用粘结剂或密封剂(或医疗用粘结剂或密封剂组合物),上述生物降解性医疗用粘结剂或密封剂包含:第一成分a,包含导入甲酰基来氧化的氧化糖胺聚糖;以及第二成分b,包含具有两个以上氨基的聚胺,上述第二成分在水溶液状态下的pH为8.5至11.0。
在混合上述第一成分及第二成分的情况下,甲酰基/氨基的摩尔比为0.1至500。
根据本发明的另一实施方式,本发明提供包括将上述生物降解性医疗用粘结剂或密封剂组合物(或医疗用粘结剂或密封剂组合物)适用于需要粘结、填充、涂敷、防止粘连、伤口覆盖或止血的生物组织的步骤,上述步骤包含在生物组织的粘结、填充、涂敷、防止粘连、伤口覆盖或止血的方法中。
为了开发即使在存在体液及血液的体内部位中也可充分执行粘结、覆盖及止血,尤其,与其他生物降解性高分子相比,可吸收大量水分,可在体内自行降解的生物降解性医疗用粘结及密封剂,本发明人员进行了研究及努力。最终确认到,通过一同使用导入甲酰基来氧化的氧化糖胺聚糖和聚胺,从而可有效执行生物组织的粘结、填充、涂敷、防止粘连、伤口覆盖及止血等作用。
在本说明书中,互换使用医疗用粘结剂或密封剂和它们的组合物。
如下述实施例所确认,与以往的医疗用双组分型粘结剂(LYDEX)相比,本发明的组合物在凝胶化形成时间、粘结力及水分吸收力方面呈现出得到改善的效果(参照表5至表7),且在止血效果方面也比以往的止血剂(AristaTMAH)呈现出更加优秀的效果(参照图12)。上述结果表示,作为第一成分和第二成分的组合的本发明的组合物对生物组织的粘结、填充、涂敷、防止粘连、伤口覆盖及止血等医疗用途方面呈现优秀的物性,从而可将本发明的组合物用作上述医药用途。
本发明的组合物包含作为第一成分的氧化糖胺聚糖。上述术语“氧化糖胺聚糖”表示通过导入甲酰基(-CHO)来使糖胺聚糖被氧化。上述糖胺聚糖为呈包含己醣胺的双糖重复结构的多糖,在这一点上与作为单糖的O-糖苷组合的葡聚糖不同。
可通过高碘酸氧化法实施上述甲酰基的导入。例如,利用高碘酸或高碘酸盐来使糖胺聚糖氧化,从而可获得每无水葡萄糖单元(糖基)中导入有适当数量(例如,0.01至0.95个)的甲酰基的氧化糖胺聚糖。
根据本发明的一实例,根据计算的上述氧化糖胺聚糖的氧化度为10至99.5%。当与第二成分组合使用时,具有上述氧化度的氧化糖胺聚糖可通过迅速吸收体内的血液和体液,从而可在短时间内实施凝胶化。
根据一特定例,上述氧化糖胺聚糖的氧化度为10至60%,在再一特定例中,上述氧化糖胺聚糖的氧化度为10至55%,在另一特定例中,上述氧化糖胺聚糖的氧化度为10至50%,在又一特定例中,上述氧化糖胺聚糖的氧化度为10至45%,在又一特定例中,上述氧化糖胺聚糖的氧化度为10至40%。作为一例,上述第一成分包含一种以上的氧化糖胺聚糖,在上述氧化糖胺聚糖为氧化透明质酸的情况下,上述氧化透明质酸的氧化度为10~20%。
可通过NaOH滴定法实施上述糖胺聚糖的氧化度测定。例如,将17.5g的盐酸羟胺和6ml的0.05%甲基橙与994ml的蒸馏水进行混合来制备0.25mol/l的盐酸羟胺溶液,并通过滴定方法将上述盐酸羟胺溶液的pH滴定为4之后,使0.1g的氧化糖胺聚糖溶解于25ml的上述溶液,并利用0.1mol/l氢氧化钠来重新将上述溶液的pH值滴定为4之后,代入来计算氧化度(%)。
根据本发明的一实例,在上述氧化糖胺聚糖中,每无水葡萄糖单元(糖基)具有0.01至0.95个甲酰基。
根据本发明的一实例,上述氧化糖胺聚糖选自由氧化透明质酸、氧化硫酸软骨素、氧化软骨素、氧化硫酸皮肤素、氧化硫酸乙酰肝素、氧化肝素及氧化硫酸角质素组成的组。
根据本发明,通过使用特定分子量的糖胺聚糖,从而可适当调整粘结剂/密封剂组合物的凝胶化性能、凝胶化状态维持时间、凝胶的弹性等。
根据本发明的一实例,用于获得上述氧化糖胺聚糖的糖胺聚糖的分子量为1000至500万。作为一例,用于获得上述氧化糖胺聚糖的糖胺聚糖的分子量可以为1万至400万、5万至350万、10万至350万、10万至300万、10万至250万、10万至200万或10万至160万。
根据本发明的一实例,上述第一成分包含具有10万至200万分子量的透明质酸。根据一特定例,上述氧化透明质酸的分子量为10万至160万。
根据本发明的一实例,上述第一成分包含两种以上的氧化糖胺聚糖。
根据本发明的一实例,上述氧化糖胺聚糖的重量百分比为1:0.5~5。根据一特定例,上述氧化糖胺聚糖的重量百分比为1:0.5~4,根据再一特定例,上述氧化糖胺聚糖的重量百分比为1:0.5~3.5,根据另一特定例,上述氧化糖胺聚糖的重量百分比为1:0.5~3,根据又一特定例,上述氧化糖胺聚糖的重量百分比为1:0.5~2.5,根据又一特定例,上述氧化糖胺聚糖的重量百分比为1:0.5~2,根据又一特定例,上述氧化糖胺聚糖的重量百分比为1:0.5~1.5。
根据本发明的一实例,上述两种以上的氧化糖胺聚糖为氧化透明质酸及氧化硫酸软骨素。上述氧化透明质酸和上述氧化硫酸软骨素的重量百分比可以为1:0.5~5、1:0.5~4、1:0.5~3.5、1:0.5~3、1:0.5~2.5、1:0.5~2、1:0.5~1.5或1:0.8~1.2。
根据本发明的一实例,上述氧化透明质酸的氧化度为10~40%。根据一特定例,上述氧化透明质酸的氧化度为12~40%,根据再一特定例,上述氧化透明质酸的氧化度为12~38%,根据另一特定例,上述氧化透明质酸的氧化度为13~37%。
根据本发明的一实例,上述氧化硫酸软骨素的氧化度为10~55%。根据一特定例,上述氧化硫酸软骨素的氧化度为10~50%,在再一特定例中,上述氧化硫酸软骨素的氧化度为10~45%,在另一特定例中,上述氧化硫酸软骨素的氧化度为10~40%,在又一特定例中,上述氧化硫酸软骨素的氧化度为10~35%。
根据本发明的一实例,上述第一成分呈粉末状、液状或固体状(例如,颗粒形态)。作为一例,粉末状的第一成分可通过对含有氧化糖胺聚糖的溶液进行干燥(例如,喷雾干燥、冷冻干燥等)之后对其进行粉碎(例如,机械粉碎)来获得。
作为活性成分,本发明的组合物除了第一成分之外,还包含第二成分,上述第二成分包含具有两个以上氨基的聚胺。上述第二成分在水溶液状态下的pH为8.5~11.0。如以下实施例所确认,在上述第二成分的水溶液状态下的pH为8.5~11.0情况下,可在数秒内实现凝胶化(参照图7)。
根据一特定例,上述第二成分在水溶液状态下的pH为9.0~11.0。
根据本发明的一实例,上述聚胺还可包含二氨基和/或三氨基。
根据本发明的一实例,包含上述聚胺的第二成分呈粉末状、液状或固体状(例如,颗粒)。作为一例,粉末状的第二成分可通过对包含聚胺溶液进行干燥之后对其进行粉碎来获得。此时,上述含有聚胺溶液还可包含pH调节剂,使得第二成分在水溶液状态下的pH范围为8.5~11.0。作为一例,上述pH调节剂可以为乙酸、柠檬酸、琥珀酸、戊二酸、苹果酸、富马酸及马来酸等单价或多价羧酸化合物或其无水物等。
根据本发明的一实例,上述聚胺选自由聚赖氨酸、壳聚糖、白蛋白、腐胺(putrescine)、尸胺(cadaverine)、亚精胺(spermidine)、精胺(spermine)、精蛋白及聚乙烯亚胺(Polyethylenimine)组成的组。
根据本发明的一实例,上述聚胺具有100以上的分子量。作为一例,上述聚胺的分子量可以为1000至20万。
根据本发明的一实例,上述聚胺为聚-L-赖氨酸。上述聚-L-赖氨酸可以为使用微生物(例如,链霉菌)或酶来生成的聚ε-聚-L-赖氨酸。
根据本发明的一实例,除了聚胺之外,上述第二成分还可包含pH调节剂。
根据本发明的一实例,本发明的组合物还可包含药物。作为一例,第二成分可包含上述药物。上述药物可具有一个以上的胺基,作为一例,上述药物可以为蒽环类药物、吉西他滨、万古霉素、多粘菌素、甲氨蝶呤、蛋白质药物及肽药物等。在此情况下,当第一成分和第二成分被凝胶化时,上述药物的胺基也与第一成分的甲酰基一同起到作用,从而三种成分可一同形成凝胶,随着所形成的凝胶崩溃,逐渐放出药物,从而可呈现药理活性。
根据本发明的一实例,本发明的组合物能够以多种形态剂型化,例如,可包含呈粉末状、液状或固体状(例如,颗粒形态)的第一成分和呈粉末状、液状或固体状的第二成分的组合。
根据本发明的一实例,本发明的组合物包含0.5~10:1重量百分比的第一成分和第二成分。
根据一特定例,上述第一成分与第二成分的重量百分比为0.5~8:1,在再一特定例中,上述第一成分与第二成分的重量百分比为0.5~6:1,在另一特定例中,上述第一成分与第二成分的重量百分比为0.5~4:1,在又一特定例中,上述第一成分与第二成分的重量百分比为0.5~3:1,在又一特定例中,上述第一成分与第二成分的重量百分比为0.5~2:1,在又一特定例中,上述第一成分与第二成分的重量百分比为0.5~1.5:1,在又一特定例中,上述第一成分与第二成分的重量百分比为0.8~1.5:1,在又一特定例中,上述第一成分与第二成分的重量百分比为0.8~1.2:1。
根据本发明,可通过调整上述第一成分的甲酰基与第二成分的氨基的比例来调整凝胶形成时间、生成凝胶的降解时间等。
根据本发明的一实例,在混合上述第一成分及第二成分的情况下,甲酰基/氨基的摩尔比为0.1~500。
根据一特定例,在混合上述第一成分及第二成分的情况下,甲酰基/氨基的摩尔比为1~400,在再一特定例中,甲酰基/氨基的摩尔比为1~350,在另一特定例中,甲酰基/氨基的摩尔比为1~300,在又一特定例中,甲酰基/氨基的摩尔比为10~300。
为了获得医疗效果(医疗用途),上述第一成分和第二成分可同时或依次被涂敷于粘附体(生物体内部及外部的皮肤面)。此时,根据情况,为了实施上述第一及第二成分的凝胶化,可喷射生理盐水或蒸馏水。
根据本发明的一实例,上述医疗用途选自由生物组织的粘结、填充、涂敷、防止粘连、伤口覆盖及止血用途构成的组。
本发明的组合物以将第一成分和第二成分盛在相同容器的状态提供,或者以将上述第一成分和第二成分盛在不同容器的状态来提供。
发明的效果
概括本发明的特征及优点如下:
(ⅰ)本发明提供包含氧化糖胺聚糖和聚胺的生物降解性医疗用粘结剂或密封剂组合物。
(ⅱ)本发明的组合物在生物降解性、涂敷性、凝胶化时间、止血功能、粘结力及水分吸收力等方面呈现出改善的效果。
(ⅲ)本发明的组合物可用作能够用于生物组织的粘结、填充、涂敷、防止粘连、伤口覆盖、防止露出及止血等可使用医疗用粘结剂或密封剂的多种医疗用途。
附图说明
图1示出利用傅立叶红外(FT-IR)分光计来分析氧化透明质酸的结果。
图2为示出利用具有氨基的第二成分的混合物的凝胶化状态和凝胶化时间的照片。
图3为示出按照互不相同的重量百分比混合的第一成分和第二成分混合物的凝胶化评价结果的照片。
图4为对本发明的粘结剂及密封剂组合物的凝胶化时间与以往的粘结剂组合物(医疗用双组分型粘结剂)的凝胶化时间相比较来示出的照片。
图5为对本发明的粘结剂及密封剂组合物的粘结力与以往的粘结剂组合物(医疗用双组分型粘结剂)的粘结力相比较来示出的图表。
图6为示出在切除胃粘膜后,在出血部位涂敷本发明的粘结剂及密封剂组合物或以往的粘结剂组合物(医疗用双组分型粘结剂)之后的结果(年膜附着能力和止血能力)的照片。
图7为示出氧化糖胺聚糖和聚胺混合物的凝胶化状态和凝胶化时间以及是否基于pH实现凝胶化的照片。
图8至图11示出以肝叶切除术模型、肾脏切除术模型、胃粘膜切除术模型及血管应用模型为对象来实施的本发明的粘结剂及密封剂组合物和以往的止血剂(AristaTMAH)之间的比较实验结果。
图12为定量示出图8至图11的结果的图表。
具体实施方式
以下,通过实施例,更加详细说明本发明。以下实施例仅用于更加详细说明本发明,根据本发明主旨,本发明所属技术领域的普通技术人员知晓本发明的范围并不局限于以下实施例。
实施例
实施例1.制备医疗用粘结剂①
(1)制备氧化透明质酸(CHO-HA:第一成分)
将分子量为7kDa、150kDa、400kDa或3000kDa的透明质酸(HA)1g或3g溶解在溶解有高碘酸钠(NaIO4)的150ml的水中。此时,如下表1至表4所示,通过改变高碘酸钠的浓度和反应条件来使氧化度(取代度(DS),%)发生改变。在15~70℃的温度下,对反应烧瓶进行3~48小时的反应,并利用分子量筛截为1~100kDa的渗析膜,以蒸馏水对反应物进行了24小时的渗析之后对所获得的氧化透明质酸进行4日以上的冷冻干燥,之后将其粉碎来使被粉碎的氧化透明质酸通过500μm大小的网眼,从而获得直径约为500μm以下的氧化透明质酸。
氧化透明质酸
利用傅立叶红外分光计(Cary 640,Agilent Technologies,USA)分析氧化透明质酸,最终在4000~400cm-1(resolution 4cm-1)中确认出取代基(图1)。
为了确认透明质酸的氧化度,将17.5g的盐酸羟胺和6ml的0.05%甲基橙与994ml的蒸馏水进行混合来制备出0.25M盐酸羟胺溶液,并将其pH滴定为4。将0.1g的氧化透明质酸溶解在25ml的上述溶液,并利用0.1mM氢氧化铝,重新将其pH滴定为4。利用以下算式计算氧化度(%),计算结果如表1至表4。
数学式1
表1
表2
表3
表4
(2)具有两个以上的氨基的第二成分
在含有氨基的多种聚胺中,代表性地将壳聚糖、精蛋白、聚乙烯亚胺、聚赖氨酸、精胺、亚精胺及白蛋白等用作第二成分,利用pH调节剂(酸、酸盐、碱、碱盐等)来将5重量百分比以上的聚胺水溶液的pH调整成8.5、9.0、9.5及10之后,与上述氧化透明质酸/氧化硫酸软骨素的情况相同地使用了经过冷冻干燥之后所获得的粉末。
对上述分类的含氨基的聚胺的凝胶化度和凝胶化时间进行了评价。最终,白蛋白、碱性聚赖氨酸(BPL)、聚乙烯亚胺呈现出优秀的凝胶化速度和凝胶的稳定性(图2)。其中,利用碱性聚赖氨酸进行了以下实验。
实施例2.物性评价
(1)凝胶化评价
以互不相同的重量百分比(1:1、2:1、4:1、8:1)对在实施例1中获得的第一成分及第二成分进行混合,并向混合后的成分进行浇水来确认凝胶化程度。
其结果如下,即,在以8:1的比例混合第一成分和第二成分的情况下,在经过10分钟之后,一部分变成了液体。与以1:1的比例混合第一成分和第二成分的情况相比,在分别以2:1和4:1的比例混合第一成分及第二成分的情况下,凝胶的弹性较为下降(图3)。并且,虽然利用3000kDa分子量的透明质酸的混合制剂被凝胶化,但其弹性下降。在分子量150kDa和1400kDa的透明质酸的情况下,透明质酸与取代度无关地被凝胶化,但是,当取代度为10%(10~19%)时的混合制剂呈现出短的凝胶化时间,且具有优秀的弹性。
基于以上结果,以1:1的重量百分比混合第一成分(向分子量150kDa或1400kDa的透明质酸导入醛基的,取代度为10%的氧化透明质酸)和第二成分来实施以下实验。
(2)对凝胶化时间的评价
按30mg的单位对在2ml管中经过混合的成分进行细分,并将其收集于管盖。在1秒之内向上述管盖喷射120μl的水之后,测定了凝胶化的时间。在LYDEX的情况下,与透明质酸混合制剂相比,尽管使用了更少量(80μl)的水,但获得固化的凝胶所需时间为10秒以上。相反,在氧化透明质酸的混合制剂的情况下,呈现出2~3秒以内的极短的凝胶化时间(图4及表5)。
表5
(3)粘结力评价
向100mg的混合成分喷射800μl的水之后,利用物性测试仪(Texture Analyzer)来测定了粘结力。其结果如下,即,与氧化透明质酸混合制剂相比,尽管LYDEX使用了更少量(500μl)的水,但平均粘结力呈现出约为53.6gf。相反,在氧化透明质酸的混合制剂的情况下,测定出的平均粘结力分别约为65.9及67.5gf(图5及表6)。
表6
(4)吸水力评价
对LYDEX以及与第二成分经过混合的各个CHO-HA 150kDa(DS 10%)、CHO-HA1400kDa(DS 10%)的吸水力进行了评价。将30mg的各个样本放置在皮氏培养皿(60)来测定了其重量。考虑产品的吸水力,添加了样本重量的30倍(30g)的预先加热至37℃的蒸馏水。将样本放置在37℃的恒温器中30分钟之后,将皮氏培养皿倒置30分钟并测定了样本的重量。利用以下的算式计算了吸水力。
数学式2
其结果确认到,与现有LYDEX剂型相比,氧化透明质酸的混合制剂(CHO-HA1400kDa)的吸水力约为LYDEX剂型的五倍左右(表7)。
表7
实施例3.生物体内评价
(1)实验动物
将体重为2至3kg的三只雄性兔(New Zealand White:东方生物(Orient Bio),城南,韩国)用于实验。根据韩国仁荷大学的实验动物研究委员会(Experimental AnimalResearch Committee)的方针,执行了所有动物饲养及试验过程。
(2)引发胃出血的动物模型
以如下方式制作了兔子的粘膜切除术(mucosectomy)-诱导胃出血模型。在手术前24小时,对兔子采取绝食措施,并向兔子的肌内注射氯胺酮(4.2mg/kg)及甲苯噻嗪(11.7mg/kg)的混合物来对兔子进行了麻醉。通过切开兔子的上腹部来使胃露出,并沿着胃大弯(greater curvature)切开约为5~7cm左右。向胃的粘膜下层(submucosal layer)注射200μl的等张生理盐水,并利用手术剪刀切除溶胀的胃粘膜。切除部位的直径约为7~10mm。
(3)粘膜附着能力及止血能力评价
在正在出血的被切除的兔子胃粘膜涂敷约0.5g的混合制剂(1:1重量百分比的第一成分和第二成分的混合物)。其结果如下,即,如图6所示,在涂敷混合制剂的同时,混合制剂和血液就进行反应,从而使混合制剂凝胶化,与非处置组相比,缩短了出血时间。并且,确认到本发明的组合物的粘膜附着能力(图6)。
实施例4.医疗用粘结剂的制备②
(1)氧化透明质酸和氧化硫酸软骨素(第一成分)的制备
将3g的分子量为1400kDa的氧化透明质酸(SHANDONG BLOOMAGE FREDA BIOPHARMCO.,Ltd)溶解在150ml的蒸馏水中。接着,如表1所示,添加高碘酸钠(分子量为213.89),并在40℃的温度下,将反应烧杯搅拌24小时并使其进行反应。而且,用蒸馏水对反应后的溶液进行48小时的渗析(使用分子量筛截为12000~14000的渗析膜)之后进行冷冻干燥。
将3g的分子量为5000~50000之间的硫酸软骨素(YANTAI DONGCHENGBIOCHEMICAL CO.,Ltd)溶解在15ml的蒸馏水中。接着,如表2所示,添加高碘酸钠(分子量为213.89),并在常温下,搅拌18小时并使其进行反应。而且,用蒸馏水对经过反应后的溶液进行48小时的渗析(使用分子量筛截为12000~14000的渗析膜)之后进行冷冻干燥。
在以下的实验中,将氧化透明质酸和氧化硫酸软骨素作为第一成分来使用。
利用NaOH的滴定法确认到透明质酸和硫酸软骨素的取代度(氧化度)。具体地,将17.5g的盐酸羟胺和6ml的0.05%甲基橙与994ml的蒸馏水相混合来制备0.25mol/l的盐酸羟胺溶液,并将其pH滴定为4。将0.1g的氧化透明质酸或硫酸软骨素溶解在25ml的上述溶液中,并利用0.1mol/l氢氧化钠来重新将上述溶液的pH滴定为4。利用以下算式来计算取代度(%),其结果如下述表8及表9。
数学式3
表8
表9
(2)制备具有两个以上的氨基的第二成分
在含有氨基的多种聚胺中,代表性地将壳聚糖、精蛋白、聚乙烯亚胺、聚赖氨酸、精胺、亚精胺及白蛋白等选作第二成分,为了确认第二成分是否基于pH来实现凝胶化,在水溶液状态下,将pH调整为多种范围(5.5~6.4、6.5~7.4、7.5~8.4、8.5~9.4、9.5~10.4、10.5~11)之后,与上述氧化透明质酸/氧化硫酸软骨素的情况相同地使用了经过冷冻干燥之后所获得的粉末。混合上述第一成分的氧化透明质酸/氧化硫酸软骨素。其结果如下,即,与聚胺的种类无关,确认到仅在pH为8.5~11的情况下实现凝胶化。作为一例,在聚-L-赖氨酸的pH为8.5的情况下形成了凝胶,但是在pH为5.6的情况下,未形成凝胶。在本实验中,根据凝胶的透明度来确定凝胶的形成与否(透明:凝胶化,不透明:未被凝胶化)(图7)。
实施例5.确认最佳比例
(1)确立按分子量、比例的最佳条件
根据氧化度,将获得的粉末状的氧化硫酸软骨素和分子量为150~3000kDa的氧化透明质酸(1:1)按照比例与聚胺(PA,选定pH为8.5~9.5的聚赖氨酸来使用)相混合来确认物性。根据氧化度,在按照比例混合的粉末50mg中投入已灭菌处理的蒸馏水200μl来用肉眼确认了吸收已灭菌处理的蒸馏水的程度。分别将在10秒钟内开始吸收粉末已灭菌处理的蒸馏水的情况评价为好(+++),将在30秒钟内开始吸收的情况评价为普通(++),将在60秒钟以上之内开始吸收的情况评价为差(+)来确认了溶解度(solubility)。并且,当投入已灭菌处理的蒸馏水时,确认是否实现凝胶化并确认凝胶化时间。确认上述制备的凝胶是否实现液化并测定液化时间。并在下述表中整理了上述确认的结果(表10及表11)。
如表11所示,在几乎所有的第一成分和第二成分的组合中,导出让人满意的水分吸收力和凝胶化时间,其中,呈现出最佳性能(水分吸收力为+++,凝胶化时间为30秒钟以内)的为将10~50%氧化硫酸软骨素和10~40%氧化透明质酸(分子量为150、1400或3000kDa)与聚胺按照1:1的比例进行混合的混合制剂(样本号:3、4、12、14、17、26、29),基于上述结果,在下述实施例中,使用#14(命名为UI-SAH)来进行了实验。
表10
表11
NO. | 样本 | 水分吸收力 | 凝胶化时间(秒) | 液化时间(分) |
1 | Oxi-CS1+Oxi-HA150K-1+PA | ++ | 50 | — |
2 | Oxi-CS2+Oxi-HA150K-1+PA | ++ | 16 | — |
3 | Oxi-CS4+Oxi-HA150K-1+PA | +++ | 25 | — |
4 | Oxi-CS1+Oxi-HA150K-2+PA | +++ | 25 | — |
5 | Oxi-CS2+Oxi-HA150K-2+PA | ++ | 10 | — |
6 | Oxi-CS4+Oxi-HA150K-2+PA | ++ | 38 | — |
7 | Oxi-CS1+Oxi-HA150K-3+PA | ++ | 20 | — |
7 | Oxi-CS2+Oxi-HA150K-3+PA | ++ | 15 | — |
8 | Oxi-CS4+Oxi-HA150K-3+PA | — | — | — |
9 | Oxi-CS1+Oxi-HA150K-4+PA | ++ | 25 | — |
10 | Oxi-CS2+Oxi-HA150K-4+PA | ++ | 15 | — |
11 | Oxi-CS4+Oxi-HA150K-4+PA | — | — | — |
12 | Oxi-CS1+Oxi-HA1400K-1+PA | +++ | 25 | — |
13 | Oxi-CS2+Oxi-HA1400K-1+PA | ++ | 20 | — |
14 | Oxi-CS4+Oxi-HA1400K-1+PA | +++ | 25 | — |
15 | Oxi-CS1+Oxi-HA1400K-2+PA | ++ | 25 | — |
16 | Oxi-CS2+Oxi-HA1400K-2+PA | ++ | 15 | — |
17 | Oxi-CS4+Oxi-HA1400K-2+PA | +++ | 25 | — |
18 | Oxi-CS1+Oxi-HA1400K-3+PA | ++ | 26 | — |
19 | Oxi-CS2+Oxi-HA1400K-3+PA | ++ | 12 | — |
20 | Oxi-CS4+Oxi-HA1400K-3+PA | ++ | 23 | — |
21 | Oxi-CS1+Oxi-HA1400K-4+PA | +++ | 34 | — |
22 | Oxi-CS2+Oxi-HA1400K-4+PA | ++ | 10 | — |
23 | Oxi-CS4+Oxi-HA1400K-4+PA | +++ | 33 | — |
24 | Oxi-CS1+Oxi-HA3000K-1+PA | +++ | 32 | — |
25 | Oxi-CS2+Oxi-HA3000K-1+PA | ++ | 11 | — |
26 | Oxi-CS4+Oxi-HA3000K-1+PA | +++ | 28 | — |
27 | Oxi-CS1+Oxi-HA3000K-2+PA | ++ | 27 | — |
28 | Oxi-CS2+Oxi-HA3000K-2+PA | ++ | 11 | — |
29 | Oxi-CS4+Oxi-HA3000K-2+PA | +++ | 30 | — |
30 | Oxi-CS1+Oxi-HA3000K-3+PA | ++ | 30 | — |
31 | Oxi-CS2+Oxi-HA3000K-3+PA | ++ | 10 | — |
32 | Oxi-CS4+Oxi-HA3000K-3+PA | +++ | 35 | — |
33 | Oxi-CS1+Oxi-HA3000K-4+PA | +++ | 50 | — |
34 | Oxi-CS2+Oxi-HA3000K-4+PA | ++ | 10 | — |
35 | Oxi-CS4+Oxi-HA3000K-4+PA | +++ | 35 |
实施例6.制作老鼠出血模型及止血作用评价
(1)肝叶切除术模型
向体重200~300g的雄性SD老鼠的腹腔注射氯胺酮和赛拉嗪混合物来对老鼠进行麻醉之后,将中央上腹部向横向或纵向切开约为3~4cm左右。利用湿纱布,从切开的腹部的缝隙露出肝叶,利用血管用夹子对肝门静脉及肝动脉进行结扎。利用手术剪刀切开从肝叶的边缘相距约1cm的位置,在上述位置涂敷了50~100mg的UI~SAH。作为对比组,在上述位置涂敷了阿里斯泰可降解止血粉(AristaTM AH(Medafor Inc.,USA)。在进行涂敷之后,将结扎的夹子去除后确认是否发生出血现象,并利用已被灭菌的纱布测定出血量。
(2)肾脏切除术模型
向体重200~300g的雄性SD老鼠的腹腔注射氯胺酮和赛拉嗪混合物来对老鼠进行麻醉之后,将右侧腹部向纵向切开约3~4cm左右。利用湿纱布,使肾脏从切开的腹部的缝隙露出,利用血管用夹子对肾静脉(renal vein)、肾动脉(renal arteries)进行结扎。利用手术剪刀切开从肾脏的边缘相隔约1cm左右的位置,并在上述位置涂敷了50~100mg的UI~SAH。作为对比组,在上述位置涂敷了AristaTM AH(Medafor Inc.,USA)。在进行涂敷之后,去除结扎的夹子之后确认是否发生出血现象,并利用已灭菌处理的纱布测定出血量。
(3)胃粘膜切除术模型
使体重为200~300g的雄性SD老鼠绝食24小时之后,向上述老鼠的腹腔注射氯胺酮和赛拉嗪混合物来对老鼠进行麻醉,之后,将中央上腹部向纵向或横向切开约为3~4cm左右。利用湿纱布,使胃从切开的腹部的缝隙露出,并将血管少的胃弯曲部分向水平切开约3cm左右来使胃内壁露出。向胃内壁注入注射用生理盐水100μl之后,利用手术剪刀将胃粘膜切除,切除的部分呈直径为约5mm的圆,并向上述部分涂敷50~100mg的UI~SAH。作为对比组,在上述位置涂敷了AristaTM AH(Medafor Inc.,USA)。确认在涂敷部位是否发生出血现象,并利用已灭菌处理的纱布测定出血量。
(4)血管(Portal vein)出血模型
向体重为200~300g的雄性SD老鼠的腹腔注射氯胺酮和赛拉嗪混合物来对老鼠进行麻醉之后,将中央上腹部向横向或纵向切开约5~6cm左右。从切开腹部的缝隙使其他脏器向左侧移动之后,露出门静脉(Portal vein)。利用血管用夹子在对门静脉的上部和下部两处进行结扎。利用18标准尺寸针,在门静脉穿出一个孔之后,在上述孔涂敷50~100g的UI~SAH。作为对比组,在上述位置涂敷了AristaTM AH(Medafor Inc.,USA)。在进行涂敷之后,将结扎的夹子去除,之后确认是否发生出血现象,并利用已灭菌处理的纱布测定出血量。
(5)实验结果
将实验结果在图8至图12中示出。如图12所示,本发明的组合物的止血效果比对比组(AristaTM AH)更优秀。
以上,详细说明了本发明的特定部分,对于本发明所属技术领域的普通技术人员而言,上述具体记述仅属于优选实例,本发明的范围并不局限于上述实例。因此,本发明的实际范围由所附的发明要求保护范围及其等同技术方案所定义。
Claims (10)
1.一种生物降解性医疗用粘结剂或密封剂组合物,其特征在于,包含:
第一成分(a),包含导入甲酰基来氧化的氧化糖胺聚糖;以及
第二成分(b),包含具有两个以上氨基的聚胺,上述第二成分在水溶液状态下的pH为8.5至11.0。
2.根据权利要求1所述的生物降解性医疗用粘结剂或密封剂组合物,其特征在于,上述氧化糖胺聚糖选自由氧化透明质酸、氧化硫酸软骨素、氧化软骨素、氧化硫酸皮肤素、氧化硫酸乙酰肝素、氧化肝素及氧化硫酸角质素组成的组。
3.根据权利要求1所述的生物降解性医疗用粘结剂或密封剂组合物,其特征在于,根据计算的上述氧化糖胺聚糖的氧化度(%)为10至99.5%。
4.根据权利要求1所述的生物降解性医疗用粘结剂或密封剂组合物,其特征在于,上述第一成分包括两种以上的氧化糖胺聚糖。
5.根据权利要求4所述的生物降解性医疗用粘结剂或密封剂组合物,其特征在于,上述两种以上的氧化糖胺聚糖为氧化透明质酸及氧化硫酸软骨素。
6.根据权利要求5所述的生物降解性医疗用粘结剂或密封剂组合物,其特征在于,上述氧化透明质酸的氧化度为10~40%,上述氧化硫酸软骨素的氧化度为10~55%。
7.根据权利要求1所述的生物降解性医疗用粘结剂或密封剂组合物,其特征在于,上述聚胺选自由聚赖氨酸、壳聚糖、白蛋白、腐胺、尸胺、亚精胺、精胺、精蛋白及聚乙烯亚胺组成的组。
8.根据权利要求1所述的生物降解性医疗用粘结剂或密封剂组合物,其特征在于,上述医疗用粘结剂或密封剂组合物具有选自由生物组织的粘结、填充、涂敷、防止粘连、伤口覆盖及止血用途构成的组中的医疗用途。
9.根据权利要求1所述的生物降解性医疗用粘结剂或密封剂组合物,其特征在于,上述生物降解性医疗用粘结剂或密封剂组合物还包含具有胺基的药物。
10.一种生物组织的粘结、填充、涂敷、防止粘连、伤口覆盖或止血的方法,其特征在于,包括将权利要求1所述的生物降解性医疗用粘结剂或密封剂组合物适用于需要粘结、填充、涂敷、防止粘连、伤口覆盖或止血的生物组织的步骤。
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CN116687959A (zh) * | 2022-05-18 | 2023-09-05 | 朱小丰 | 一种硫酸软骨素生物多胺复合物、其制备方法及用途 |
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CA2933271A1 (en) | 2015-06-18 |
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CN106061518B (zh) | 2020-10-16 |
RU2657836C1 (ru) | 2018-06-15 |
KR101664444B1 (ko) | 2016-10-12 |
EP3081236A1 (en) | 2016-10-19 |
MX366143B (es) | 2019-06-28 |
JP2017500113A (ja) | 2017-01-05 |
AU2014360958A1 (en) | 2016-07-14 |
KR20150069992A (ko) | 2015-06-24 |
US10105465B2 (en) | 2018-10-23 |
EP3081236A4 (en) | 2017-08-16 |
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JP6207745B2 (ja) | 2017-10-04 |
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