CN113041365B - 一种增强颈动脉硬化超声诊断的靶向超声造影剂及其制备方法 - Google Patents
一种增强颈动脉硬化超声诊断的靶向超声造影剂及其制备方法 Download PDFInfo
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Abstract
本发明涉及一种增强颈动脉硬化超声诊断的靶向超声造影剂及其制备方法,所述增强颈动脉硬化超声诊断的靶向超声造影剂由包含透明质酸及任选甘露糖及其衍生物的磷脂、生物惰性气体制备而成,低成本的实现了超声造影剂的颈动脉硬化靶向性,增强了颈动脉硬化的超声显像效果。
Description
技术领域
本发明属于诊断试剂领域,具体涉及一种增强颈动脉硬化超声诊断的靶向超声造影剂及其制备方法。
背景技术
动脉粥样硬化(Artherosclerosis,AS)是指动脉内膜有脂质等血液成分的沉积、平滑肌细胞增生和胶原纤维增多,形成粥糜样含脂坏死病灶和血管壁硬化。动脉粥样硬化是多因素共同作用导致的结果,其发病机制复杂,其中脂质代谢障碍为动脉粥样硬化的病变基础,其特点是受累动脉病变从内膜开始,一般先有脂质和复合糖类积聚、出血及血栓形成,进而纤维组织增生及钙质沉着,并有动脉中层的逐渐蜕变和钙化,导致动脉壁增厚变硬、血管腔狭窄。动脉粥样硬化是冠心病、脑梗死、外周血管病的主要原因。颈动脉粥样硬化是全身动脉粥样硬化在颈动脉的表现,流行病学调查发现,我国中老年人群普遍存在颈动脉粥样硬化,而易损的颈动脉粥样硬化斑块的破例、斑块内出血和微栓子脱落是导致缺血性脑卒中和心血管疾病的中药原因。因此,颈动脉粥样硬化的诊断和治疗对于预防缺血性脑卒中等动脉硬化相关疾病具有非常重要的作用。
超声诊断已经广泛应用于动脉粥样硬化的诊断,为了提高超声诊断的分辨率和清晰度,超声造影剂的使用也越来越广泛。超声造影剂是一类能够显著增强超声检测信号的诊断试剂,其一般包含微气泡结构,对超声波有强散射的特性。为了进一步增强超声造影剂的靶向性成像增强效果,靶向超声造影剂的研究也越来越多,现有的靶向超声造影往往利用抗原-抗体、生物素-抗生物素等手段实现靶向效果,具有制备方法复杂、保存运输条件要求高、使用成本高等缺点,从而限制了其应用。
本发明的目的即是致力于提供一种成本低廉、制备方法简单的颈动脉硬化超声诊断的靶向超声造影剂。
发明内容
本发明的目的是提供一种增强颈动脉硬化超声诊断的靶向超声造影剂及其制备方法。
本发明提供了一种增强颈动脉硬化超声诊断的靶向超声造影剂,所述靶向超声造影剂由包含透明质酸及任选甘露糖及其衍生物的磷脂、生物惰性气体制备而成;
优选的,所述靶向超声造影剂由包含透明质酸的磷脂、生物惰性气体制备而成;
优选的所述磷脂选自:大豆磷脂、卵磷脂;
优选的,所述包含透明质酸的磷脂中透明质酸的含量为1%-30%;更优选的,所述包含透明质酸的磷脂中透明质酸的含量为5%-20%;最优选的,所述包含透明质酸的磷脂中透明质酸的含量为7%;
优选的,所述生物惰性气体选自:全氟丙烷、全氟丁烷、全氟戊烷、全氟己烷、全氟辛烷、六氟化硫;更优选的,所述生物惰性气体选自:全氟丙烷、全氟丁烷;
优选的,所述靶向超声造影剂由包含透明质酸、甘露糖及其衍生物的磷脂、生物惰性气体制备而成;
优选的,所述甘露糖及其衍生物选自:甘露糖醇、甘露糖醛酸;更优选的,所述甘露糖及其衍生物为D-甘露糖醛酸;
优选的,所述包含透明质酸、甘露糖及其衍生物的磷脂中透明质酸与甘露糖及其衍生物的合计含量为1%-30%;更优选的,所述包含透明质酸、甘露糖及其衍生物的磷脂中透明质酸及甘露糖及其衍生物的含量为5%-20%;最优选的,所述包含透明质酸、甘露糖及其衍生物的磷脂中透明质酸及甘露糖及其衍生物的含量为7%;
优选的,所述包含透明质酸、甘露糖及其衍生物的磷脂中透明质酸与甘露糖及其衍生物的重量比为1-5:2-10;更优选的,所述包含透明质酸、甘露糖及其衍生物的磷脂中透明质酸与甘露糖及其衍生物的重量比为1-4:2-6;最优选的,所述包含透明质酸、甘露糖及其衍生物的磷脂中透明质酸与甘露糖及其衍生物的重量比为3:4;
本发明还提供了一种增强颈动脉硬化超声诊断的靶向超声造影剂的制备方法,包括以下步骤:
(1)将包含透明质酸及任选甘露糖及其衍生物的磷脂加入5-10倍重量的叔丁醇与水的混合溶液中,于20-40℃、50-200MPa压力下匀质2-10分钟后经220nm滤膜过滤除菌,得乳液;
(2)使用冻干粉分装容器将步骤(1)所得乳液分装后真空冷冻干燥得冻干粉,随后在真空状态下缓慢充入生物惰性气体至50-60KPa,随后缓慢充入生物惰性气体与氮气的混合气体至1个大气压,随后密封所述冻干粉分装容器,所述混合气体中生物惰性气体的体积占比为1-99%;
(3)将密封后的冻干粉分装容器使用60Co辐照灭菌,即得本发明所述的增强颈动脉硬化超声诊断的靶向超声造影剂。
优选的,步骤(1)所述混合溶液中叔丁醇的含量为20-60%,所述混合溶液于30℃、100MPa压力下匀质4分钟,所述步骤(2)中在真空状态下缓慢充入生物惰性气体至55KPa,所述混合气体中生物惰性气体的体积占比为10-70%;更优选的,步骤(1)所述混合溶液中叔丁醇的含量为30-50%,所述混合溶液于30℃、100MPa压力下匀质4分钟,所述步骤(2)中在真空状态下缓慢充入生物惰性气体至55KPa,所述混合气体中生物惰性气体的体积占比为20-60%;最优选的,步骤(1)所述混合溶液中叔丁醇的含量为40%,所述混合溶液于30℃、100MPa压力下匀质4分钟,所述步骤(2)中在真空状态下缓慢充入生物惰性气体至55KPa,所述混合气体中生物惰性气体的体积占比为50%。
本发明有益效果
本发明通过非抗原-抗体、生物素-抗生物素类物质透明质酸,尤其是透明质酸与甘露糖及其衍生物的特定组合制备得到了具有颈动脉粥样硬化靶向性的超声造影剂,从而一方面有效提高了超声诊断颈动脉粥样硬化的灵敏度和准确率;另一方面,本发明所制备得到靶向超声造影剂制备方法简单易行、成本低廉,非常有利于临床诊断的广泛引用;再一个方面,本发明所制备得到的靶向超声造影剂有利于降低超声造影剂的临床使用剂量,在有利于避免造影剂副作用的同时也有利于进一步降低使用成本。
具体实施方式
在下文中更详细地描述了本发明以有助于对本发明的理解。
实施例1:一种增强颈动脉硬化超声诊断的靶向超声造影剂
透明质酸7份、大豆磷脂93份、40%叔丁醇溶液、全氟丙烷适量,按照以下步骤制备:
(1)将包含透明质酸的大豆磷脂加入8倍重量的叔丁醇与水的混合溶液,于30℃、100MPa压力下匀质4分钟后经220nm滤膜过滤除菌,得乳液;
(2)使用西林瓶将步骤(1)所得乳液分装后真空冷冻干燥得冻干粉,随后在真空状态下缓慢充入全氟丙烷至55KPa,随后缓慢充入全氟丙烷与氮气的混合气体至1个标准大气压,随后使用橡胶塞密封西林瓶,所述混合气体中全氟丙烷的体积占比为50%;
(3)将密封后的冻干粉分装容器使用60Co辐照灭菌,即得本发明所述的增强颈动脉硬化超声诊断的靶向超声造影剂。
实施例2:一种增强颈动脉硬化超声诊断的靶向超声造影剂
透明质酸3份、甘露糖醛酸4份、大豆磷脂93份、40%叔丁醇溶液、全氟丙烷适量,按照以下步骤制备:
(1)将包含透明质酸、甘露糖醛酸的大豆磷脂加入8倍重量的叔丁醇与水的混合溶液,于30℃、100MPa压力下匀质4分钟后经220nm滤膜过滤除菌,得乳液;
(2)使用西林瓶将步骤(1)所得乳液分装后真空冷冻干燥得冻干粉,随后在真空状态下缓慢充入全氟丙烷至55KPa,随后缓慢充入全氟丙烷与氮气的混合气体至1个大气压,随后使用橡胶塞密封西林瓶,所述混合气体中全氟丙烷的体积占比为50%;
(3)将密封后的冻干粉分装容器使用60Co辐照灭菌,即得本发明所述的增强颈动脉硬化超声诊断的靶向超声造影剂。
对比例1:一种超声造影剂
葡萄糖醛酸7份、大豆磷脂93份、40%叔丁醇溶液、全氟丙烷适量,按照实施例1方法制备。
对比例2:一种超声造影剂
透明质酸6份、甘露糖醛酸1份、大豆磷脂93份、40%叔丁醇溶液、全氟丙烷适量,按照实施例2方法制备。
对比例3:一种超声造影剂
大豆磷脂100份、40%叔丁醇溶液、全氟丙烷适量,按照实施例1方法制备。
效果例1:靶向超声造影剂对颈动脉粥样硬化超声诊断的影响
1.实验方法:
10周龄雄性SD大鼠21只,体重360-370g,随机分为模型组、阳性对照组(声诺维)、实施例1-2组和对比例1-3组,适应性饲养2天后大鼠均尾静脉注射牛血清白蛋白40mg/Kg,隔天注射一次,共注射10次,空白组大鼠注射等量生理盐水。各组大鼠均给予高脂饲料喂养21天,饮用水中添加硫酸亚铁(30mg/100mL),每周灌胃一次维生素D3(30万单位/Kg),高脂饮食第21天于大鼠尾静脉注射各组相应的超声造影剂0.1mL,模型组注射等量生理盐水,其中阳性对照(声诺维)及各组超声造影剂均调整为2.5x108个微气泡/mL。使用超声诊断仪,探头频率10MHz,记录各组大鼠左右颈动脉的超声造影峰值强度比,其中:
峰值强度比=实验组平均峰值强度/模型组平均峰值强度。
2.实验结果
表1.靶向超声造影剂对颈动脉粥样硬化超声诊断的影响
组别 | 峰值强度比 |
模型组 | 1.00 |
实施例1 | 1.76 |
实施例2 | 2.60 |
对比例1 | 1.44 |
对比例2 | 1.41 |
对比例3 | 1.42 |
阳性对照 | 1.52 |
表1实验结果显示了未添加透明质酸及甘露糖醛酸的对比例3组仍然显示了较为明显的超声增强效果,且其效果仅稍弱于阳性对照组声诺维。另外,不包含透明质酸且仅包含甘露糖醛酸的对比例1组、透明质酸:甘露糖醛酸=6:1的对比例2组也均显示了与对比例3组相近的超声增强效果,显示了单独的甘露糖醛酸及透明质酸:甘露糖醛酸=6:1时均未显示出明显的颈动脉粥样硬化的靶向性效果。本发明包含透明质酸的实施例1组靶向超声造影剂的超声增强效果更为明显,显示了在使用剂量相同的情况下,本发明靶向超声造影剂具有一定的颈动脉粥样硬化的靶向性效果,且包含透明质酸与甘露糖醛酸的本发明实施例2靶向超声造影剂超声增强效果最为优异,在使用剂量相同的情况下其峰值强度是声诺维的1.71倍,是实施例1靶向超声造影剂的1.48倍,显示了更为优异的颈动脉粥样硬化靶向性效果。
以上描述了本发明优选实施方式,然其并非用以限定本发明。本领域技术人员对在此公开的实施方案可进行并不偏离本发明范畴和精神的改进和变化。
Claims (6)
1.一种增强颈动脉硬化超声诊断的靶向超声造影剂,其特征在于,所述靶向超声造影剂由包含透明质酸、磷脂、全氟化碳气体制备而成,所述透明质酸为透明质酸和磷脂含量之和的7%,所述增强颈动脉硬化超声诊断的靶向超声造影剂按照以下步骤制备:
(1)将包含透明质酸的磷脂加入5-10倍重量的叔丁醇与水的混合溶液,于20-40℃、50-200MPa压力下匀质2-10分钟后经220nm滤膜过滤除菌,得乳液;
(2)使用冻干粉分装容器将步骤(1)所得乳液分装后真空冷冻干燥得冻干粉,随后在真空状态下缓慢充入全氟化碳气体至50-60KPa,随后缓慢充入全氟化碳气体与氮气的混合气体至1个大气压,随后密封所述冻干粉分装容器,所述混合气体中全氟化碳气体的体积占比为1-99%;
(3)将密封后的冻干粉分装容器使用60Co辐照灭菌,即得。
2.根据权利要求1所述的增强颈动脉硬化超声诊断的靶向超声造影剂,其特征在于,所述全氟化碳气体选自:全氟丙烷、全氟丁烷、全氟戊烷、全氟己烷、全氟辛烷、六氟化硫。
3.一种增强颈动脉硬化超声诊断的靶向超声造影剂,其特征在于,所述靶向超声造影剂由透明质酸、甘露糖醛酸、磷脂、全氟化碳气体制备而成,所述透明质酸与甘露糖醛酸重量比为3:4,所述透明质酸与甘露糖醛酸占透明质酸、甘露糖醛酸、磷脂总含量的7%,所述增强颈动脉硬化超声诊断的靶向超声造影剂按照以下步骤制备:
(1)将包含透明质酸、甘露糖醛酸的磷脂加入5-10倍重量的叔丁醇与水的混合溶液,于20-40℃、50-200MPa压力下匀质2-10分钟后经220nm滤膜过滤除菌,得乳液;
(2)使用冻干粉分装容器将步骤(1)所得乳液分装后真空冷冻干燥得冻干粉,随后在真空状态下缓慢充入全氟化碳气体至50-60KPa,随后缓慢充入全氟化碳气体与氮气的混合气体至1个大气压,随后密封所述冻干粉分装容器,所述混合气体中全氟化碳气体的体积占比为1-99%;
(3)将密封后的冻干粉分装容器使用60Co辐照灭菌,即得。
4.权利要求1-3任一项所述的增强颈动脉硬化超声诊断的靶向超声造影剂的制备方法,其特征在于包括以下步骤:
(1)将包含透明质酸及任选甘露糖醛酸的磷脂加入5-10倍重量的叔丁醇与水的混合溶液,于20-40℃、50-200MPa压力下匀质2-10分钟后经220nm滤膜过滤除菌,得乳液;
(2)使用冻干粉分装容器将步骤(1)所得乳液分装后真空冷冻干燥得冻干粉,随后在真空状态下缓慢充入全氟化碳气体至50-60KPa,随后缓慢充入全氟化碳气体与氮气的混合气体至1个大气压,随后密封所述冻干粉分装容器,所述混合气体中全氟化碳气体的体积占比为1-99%;
(3)将密封后的冻干粉分装容器使用60Co辐照灭菌,即得。
5.根据权利要求4所述的制备方法,其特征在于,步骤(1)所述混合溶液中叔丁醇的含量为20-60%,所述混合溶液于30℃、100MPa压力下匀质4分钟。
6.根据权利要求4所述的制备方法,其特征在于,所述步骤(2)中在真空状态下缓慢充入全氟化碳气体至55KPa,所述混合气体中全氟化碳气体的体积占比为10-70%。
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