CN100574809C - 一种高强度聚焦超声治疗用氟碳乳剂类助剂及其应用 - Google Patents
一种高强度聚焦超声治疗用氟碳乳剂类助剂及其应用 Download PDFInfo
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Abstract
本发明公开了一种能够增加HIFU治疗时靶区组织能量沉积的HIFU治疗用氟碳乳剂类助剂，该助剂包括由成膜材料包裹芯构成的非连续相和水性介质构成的连续相，其中所述非连续相均匀地分散在所述连续相中，所述非连续相的粒径为0.1～2μm，所述成膜材料在助剂中的含量为0.1～100g/L，所述芯材料采用在38～100℃产生液/气相变的液体，在助剂中的含量为5～200ml/L。本发明提供的HIFU治疗用氟碳乳剂类助剂能够显著改善靶区的声环境，增加HIFU治疗时靶区组织能量沉积，最终可显著提高临床HIFU对肿瘤细胞的损伤效果。本发明还相应地公开了一种HIFU治疗用氟碳乳剂类助剂在HIFU治疗时的应用。
Description
技术领域
本发明涉及医药及医疗领域，具体地说，本发明涉及超声治疗领域，更具体地说，本发明涉及一种能够增加HIFU治疗时靶区组织能量沉积的HIFU治疗用氟碳乳剂类助剂及其应用。
背景技术
高强度聚焦超声(High-intensity focused ultrasound，HIFU)技术作为一种治疗肿瘤和其他疾病的新方法已经得到临床的认可。它通过聚焦超声波，在病灶上形成高强度、连续超声能量，从而产生瞬态高温效应(65～100℃)、空化效应、机械效应和声化学效应，选择性地使病灶组织凝固性坏死，使肿瘤失去增殖、浸润和转移的能力。
有研究表明，超声波在人体组织中传播的过程，其能量随传播距离的增加呈指数级衰减(刘宝琴等人，中国超声医学杂志，2002，18(8)：565-568)。另外，超声波在软组织中传播的能量衰减来自组织吸收、散射、折射、衍射等，其中最主要的能量损失来自于吸收和散射(冯若，王智彪主编，实用超声治疗学，北京：中国科学技术文献出版社，2002.14)。因此，运用HIFU技术治疗位置较深、体积较大的肿瘤时，由于能量的衰减必将导致靶区能量偏低，治疗效率下降，治疗时间延长。
当然，为了提高治疗效率，可以单纯地加大超声换能器的发射功率，但是，在高强度的超声环境中，超声波传播通道上的正常组织被烧伤的可能性就会大大增加。
另外，目前临床上在运用HIFU技术治疗声通道上有肋骨阻挡的肝脏肿瘤时，为了增加治疗靶区的能量沉积，提高治疗速度和治疗效果，常要在切除声通道上的肋骨后再治疗，这有悖于HIFU无创治疗的理念，因而很难得到患者和医生的认可。
这些因素的存在必会在一定程度上影响和限制HIFU作为一门临床适用技术的推广和普及。因此，如何增加HIFU治疗时靶区的能量沉积，使得能高效率地治疗深部肿瘤而又不损伤声通道上的正常组织或在不切除肋骨的情况下治疗被肋骨阻挡的肝脏肿瘤，就成为迫切需要解决的技术问题。
发明内容
本发明的一个目的是提供一种能够增加HIFU治疗时靶区组织能量沉积的HIFU治疗用氟碳乳剂类助剂。
本发明的另一个目的是提供本发明HIFU治疗用氟碳乳剂类助剂增加HIFU治疗时靶区能量沉积的方法。
本发明的再一个目的是提供本发明HIFU治疗用氟碳乳剂类助剂用于增强HIFU治疗疾病效果的用途。
为实现上述目的，本发明提供了一种HIFU治疗用助剂，本发明的助剂能够在施用给生物体后有助于加强待HIFU治疗靶区吸收超声能量，即能降低单位体积的靶组织(肿瘤/非肿瘤组织)被损伤所需的超声能量的物质。在本发明中，对作为HIFU治疗用助剂的物质的类型没有过多的限制，只要该物质是氟碳乳剂并在施用给靶组织后能改变该靶组织的声环境，促进靶组织对治疗性超声能量的吸收和沉积即可。
本文所用的术语“损伤”是指肿瘤或正常组织的生理状态发生实质性改变，通常是指肿瘤或正常组织的凝固性坏死。所述单位体积的靶组织被损伤所需的超声能量的多少，可用能效因子(energyefficiency factor，EEF)来量化。EEF＝ηPt/V(单位是J/mm3)，即定义为损伤单位体积的肿瘤或正常组织所需的超声能量。式中η表示HIFU换能器聚焦系数，它反映HIFU换能器对超声能量汇聚的能力，取η＝0.7；P是HIFU源总声功率，单位是瓦(W)；t是治疗总时间，单位是秒(s)；V是损伤体积，单位是立方毫米(mm3)。在一种物质施用给靶组织后，如果靶组织的能效因子下降程度的越大，该物质越适合用作本发明的HIFU助剂。
本发明的HIFU治疗用助剂，在施用给靶组织后，能使靶组织的EEF下降，从而该组织在施用HIFU助剂前测得的基础EEF(即，EEF(基 础)与该组织在施用HIFU助剂后测得的EEF(即，EEF(测量))间的比率大于1，优选大于2，更优选大于4。对于该比率的上限没有限制，应该是越大越好。
具体而言，本发明作为HIFU治疗用的助剂，包括由成膜材料包裹芯构成的非连续相和水性介质构成的连续相，其中所述非连续相均匀地分散在所述连续相中，所述非连续相的粒径为0.1～2μm，优选为0.1～1μm，更优选为0.1～0.5μm；所述成膜材料在助剂中的含量为0.1～100g/L，优选为1～50g/L，更优选为5～20g/L；所述芯材料采用在38～100℃产生液/气相变的液体(即可在HIFU治疗时在动物或人体内转变为气体的液体)，在助剂中的含量为5～200ml/L，优选为10～100ml/L，更优选为20～80ml/L。
在本发明的上述技术方案中，所述成膜材料包括脂类，如3-sn-磷脂酰胆碱(卵磷脂)、1，2-二棕榈酰基-sn-甘油基-3-磷脂酰甘油基-钠盐、1，2-二硬脂酰基-sn-甘油基-3-磷脂酰胆碱、1，2-二棕榈酰基-sn-甘油基-3-磷脂酰酸-钠盐、1，2-二棕榈酰基-sn-甘油基-3-磷脂酰胆碱、磷脂酰丝氨酸、氢化磷脂酰丝氨酸、胆固醇、糖脂；糖类，包括(例如)葡萄糖、果糖、蔗糖、淀粉及其不同链长的降解产物；蛋白类，包括(例如)白蛋白、球蛋白、纤维蛋白原、纤维蛋白、血红蛋白和植物蛋白的不同链长的降解产物等。
本发明提供的HIFU治疗用氟碳乳剂类助剂优选以生物相容性的、可降解的生物材料如脂类为成膜材料，这使得该助剂能够经静脉注射，顺利通过血液循环，并很快被人体内富含网状内皮细胞的组织所吞噬，一定时间里能够大量沉积于人体组织内，从而能显著改变人体组织的声环境，进而显著增强人体组织对声波的吸收特性，增加HIFU治疗时靶区组织的能量沉积，最终可显著提高HIFU治疗肿瘤的效率。
在本发明的上述技术方案中，所述在38～100℃产生液/气相变的液体包括C5-C6烷烃类物质如正戊烷、异戊烷和氟化C5-C12烃类物质及其他类物质(参见中国发明专利CN1068230C，专利号ZL94191564中第65～70页)。
在本发明的上述技术方案中，所述水性介质为蒸馏水、生理盐水或葡萄糖溶液。所述葡萄糖溶液浓度可达50％(W/V)，但糖尿病患者使用的HIFU治疗用氟碳乳剂类助剂中，水性介质不可采用葡萄糖溶液。
在优选的技术方案中，所述助剂还可含有乳化剂，该乳化剂一般可选用单乙二醇单C16-18脂肪酸酯、二乙二醇单C16-18脂肪酸酯、二乙二醇二C16-18脂肪酸酯、三乙二醇单C16-18脂肪酸酯、失水山梨醇脂肪酸酯(司盘系列)乳化剂、聚山梨醇酯(吐温系列)乳化剂、聚乙二醇单月桂酸酯系列乳化剂、聚氧乙烯月桂酸酯系列乳化剂、3-sn-磷脂酰胆碱(卵磷脂)、胆酸等等。该乳化剂在所述助剂中的的含量为5～150g/L。另外，所述助剂也可包含稳定剂如羧甲基纤维素钠(CMC-Na)、羧甲基纤维素钾、羧乙基纤维素钠、羧乙基纤维素钾、羧丙基纤维素钠、羧丙基纤维素钾、丙三醇(甘油)等，所述CMC-Na在助剂中的含量为0.01～10g/L，优选为0.05～0.6g/L，更优选为0.1～0.3g/L。所述丙三醇在助剂中的含量为5～100g/L。
在更为优选的技术方案中，为了增加所述助剂的稳定性，调节该助剂的pH值至7.0～9.0，优选调至7.5～8.5。无机或有机的碱都可用于调节所述助剂的pH值。
另外，为了使本发明的HIFU治疗用氟碳乳剂类助剂靶向特定的肿瘤组织或病灶部位，还可在该助剂中加入对所述的肿瘤组织或病灶部位有特异亲和性的物质，如肿瘤抗体等。
目前在超声造影领域中广泛使用的氟碳乳剂类造影剂均可以作为本发明的HIFU治疗用氟碳乳剂类助剂。因此，本发明的另一方面，提供了氟碳乳剂类超声造影剂用于制备HIFU治疗用助剂的用途。
本发明的又一个技术方案提供了本发明HIFU治疗用氟碳乳剂类助剂的制备方法，该方法包括以下步骤：
(1)分别按照0.1～100g/L、5～200ml/L的含量计算称取成膜材料和芯材料混合，加入水性介质至预定体积后搅拌分散，形成粗乳；
(2)将所述步骤(1)制得的粗乳置于高压乳匀机(参见中国发明专利CN1068230C中实施例19)中进行乳化。优选的是，对所述粗乳进行两次乳化。
在本发明HIFU治疗用氟碳乳剂类助剂的制备方法中在所述步骤(1)中优选采用在冰水浴的条件下进行搅拌分散。更为优选的是，在所述成膜材料和芯材料混合时还可加入乳化剂或/和稳定剂。
本发明还提供了一种增加HIFU治疗时靶区能量沉积的方法，其特征在于，在HIFU治疗前0～30分钟通过静脉连续快速滴注或团注方式给患者注射有效剂量的本发明HIFU治疗用氟碳乳剂类助剂。所述的有效剂量会随肿瘤类型、患者的体重、肿瘤位置、肿瘤体积等因素有所变化。但是，医师或药剂师有能力为不同的患者确定出合适的注射量。例如，可在0.005～0.1ml助剂/kg体重的范围内选择，优选在0.01～0.05ml助剂/kg体重的范围内选择。
具体实施方式
实施例1
先将3％(W/V)的乳化剂Pluronic F-68(购自Sigma公司)、0.5％(W/V)蛋黄卵磷脂(购自上海化学试剂公司)、5％(V/V)全氟戊烷(购自Sigma公司)与蒸馏水混合共1000ml，在冰水浴条件下，10000转/分钟剪切分散5分钟，制成粗乳。将该粗乳放入4℃高压乳匀机中，乳化2次得到乳剂，经1μm滤膜过滤得到颗粒小于1μm的乳剂。分装入15ml瓶中，再用20KGY的钴60辐照10小时，颗粒浓度在109/ml，冷藏备用。
实施例2
先将6％(W/V)的乳化剂Pluronic F-68(购自Sigma公司)、1％(W/V)蛋黄卵磷脂(购自上海化学试剂公司)、10％(V/V)全氟戊烷(购自Sigma公司)与生理盐水混合共1000ml，在冰水浴条件下，10000转/分钟剪切分散5分钟，制成粗乳。将该粗乳放入4℃高压乳匀机中，乳化2次得到乳剂，经1μm滤膜过滤得到颗粒小于1μm的乳剂。分装入15ml瓶中，再用20KGY的钴60辐照10小时，颗粒浓度在109/ml，冷藏备用。
实施例3～6
按照与实施例1所述的相同的方法和步骤，按照下表1所使用的材料和配比获得了本发明的HIFU治疗用氟碳乳剂类助剂，相应的参数如下表1所示：
表1
| 实施例3 | 实施例4 | 实施例5 | 实施例6 | |
| 芯材料 | 2％(V/V)全氟戊烷 | 5％(V/V)全氟己烷 | 10％(V/V)全氟己烷 | 10％(V/V)二氢十氟戊烷 |
| 卵磷脂用量 | 1％(W/V) | 2％(W/V) | 2％(W/V) | 2％(W/V) |
| 甘油用量 | 1％(W/V) | 1％(W/V) | 1％(W/V) | 1％(W/V) |
| Pluronic F-68用量 | 5％(W/V) | 3％(W/V) | 5％(W/V) | 5％(W/V) |
| 蒸馏水(加至) | 1000ml | 1000ml | 1000ml | 1000ml |
| pH值约为 | 6.98 | 7.01 | 6.99 | 7.00 |
| 非连续相粒径 | 0.5～2μm | 0.5～2μm | 0.1～2μm | 1～2μm |
下文以实施例1制得的HIFU治疗用氟碳乳剂类助剂为例，结合JC型HIFU肿瘤治疗系统的联合使用，来说明本发明助剂的效果。
试验例1新西兰大白兔肝脏损伤实验
新西兰大白兔20只(重庆医科大学动物实验中心提供)，体重2.21±0.56kg，实验前一天脱去下胸部和上腹部的毛。用JC型HIFU肿瘤治疗系统(重庆海扶(HIFU)技术有限公司生产)对实验大白兔进行辐照。JC型HIFU肿瘤治疗系统主要由可调功率发生器、B超监控系统、治疗探头、机械运动控制系统、治疗床和声耦合装置等五部分组成。该系统治疗头的直径为150mm，焦距150mm，声焦域2.3×2.4×26mm，工作频率1MHz，循环脱气水标准为含气量≤3ppm，平均声强为5500W/cm2。实验采用的换能器直径为150mm，焦距为135mm，频率为1.0MHz，声功率(P)为200W。辐照深度为20mm，辐照方式为间断定点，辐照3秒，停5秒。按0.02ml/kg的量经耳缘静脉快速注射生理盐水，60秒后HIFU定点辐照实验兔肝脏，此为对照组。按0.02ml/kg的量经耳缘静脉快速注射给予实施例1制得的助剂，60秒后HIFU辐照同一兔肝脏的另一平面的点，此为实验组。辐照靶区出现灰度改变后结束辐照，如果未见灰度改变则最多辐照20秒。3天后断颈处死实验兔，解剖测量肝脏凝固性坏死体积(V)大小。根据公式EEF＝ηPT/V计算能效因子(EEF)，T为辐照时间，η＝0.7。对照组EEF中位数为6.0160，实验组为1.2505，Wilcoxon符号秩和检验，Z＝-2.485，P＝0.013。该实验结果表明，注射氟碳乳剂后HIFU损伤兔肝脏的效率提高4.81倍。
试验例2山羊肝脏损伤实验
取南江黄羊20只，体重22.25±4.51kg，实验前当日脱去右胸部和右腹部的毛。用JC型HIFU肿瘤治疗系统(由重庆海扶(HIFU)技术有限公司生产)对实验黄羊进行辐照。实验采用换能器直径为150mm，焦距为135mm，频率为0.8MHz，声功率(P)为220W。辐照深度为30mm，辐照方式为间断定点，辐照3秒，停5秒，所有羊都未切除肋骨。HIFU辐照前先预扫描，选择辐照区域，共4个平面，每平面上辐照一点，二维超声观察通肋间隙进行。按0.02ml/kg的量经耳缘静脉快速注射给予生理盐水，60秒后HIFU定点辐照实验羊肝脏，每只羊辐照2点，此为对照组。按0.02ml/kg的量经耳缘静脉快速注射给予实施例1制得的助剂，60秒后HIFU辐照，也辐照二点，此为实验组。辐照靶区出现灰度改变再辐照4～5次后结束辐照，如果未见灰度改变则最多辐照200秒。3天后杀死羊，解剖测量肝脏凝固性坏死体积(V)大小。根据公式EEF＝ηPT/V计算能效因子(EEF)，T为辐照时间，η＝0.7。对照组的EEF中位数为无穷大，HIFU加氟碳乳剂组的中位数为5.1904。Wilcoxon符号秩和检验，P＝0.004。实验说明在不切除肋骨的情况下，HIFU对山羊肝脏的损伤在氟碳乳剂的存在下，损伤效率发生了质的改变。
试验例3山羊肾脏损伤实验
取南江黄羊20只，体重22.25±4.51kg，实验前当日脱去右胸部和右腹部的毛。用JC型HIFU肿瘤治疗系统(由重庆海扶(HIFU)技术有限公司生产)对实验黄羊进行辐照。实验采用换能器直径为150mm，焦距为135mm，频率为0.8MHz，声功率(P)为220W。辐照深度为20mm，辐照方式为间断定点，辐照3秒，停5秒，所有羊都未切除肋骨。HIFU辐照前先预扫描，选择辐照区域，肾上极和下极各选一平面共2个平面，每平面上辐照一点，二维超声观察。如右肋骨阻挡则避开。按0.02ml/kg的量经耳缘静脉快速注射给予生理盐水，30秒后HIFU定点辐照实验羊肾脏，此为对照组。按0.02ml/kg的量经耳缘静脉快速注射给予实施例1制得的助剂，60秒后HIFU辐照，此为实验组。辐照靶区出现灰度改变再辐照3～4次后结束辐照，如果未见灰度改变则最多辐照150秒。3天后杀死羊，解剖测量肝脏凝固性坏死体积(V)大小。根据公式EEF＝ηPT/V计算能效因子(EEF)，T为辐照时间，η＝0.7。实验组的EEF为10.58±3.95，对照组为486.37±215.41。Wilcoxon秩和检验精确概率P＝0.008。该实验结果提示氟碳乳剂注入后，HIFU对正常山羊肾脏的损伤效率提高了40多倍。
产业上的实用性
本发明提供的HIFU治疗用氟碳乳剂类助剂能够显著改善靶区的声环境，能降低单位体积的靶组织(肿瘤/非肿瘤组织)被损伤所需的超声能量，使得在一定功率下，可以高效率地治疗位置较深、体积较大的肿瘤，而又不损伤声通道上的正常组织。采用本发明的助剂使得在不切除患者的治疗声通道上的肋骨的情况下对肝肿瘤患者有效实施HIFU治疗成为可能。
尽管结合优选实施例对本发明进行了说明，但本发明并不局限于上述实施例，应该理解，在本发明构思的引导下，本领域技术人员可进行各种修改和改进，所附权利要求概括了本发明的范围。
Claims (16)
1.一种高强度聚焦超声治疗用助剂，该助剂包括由成膜材料包裹芯构成的非连续相和水性介质构成的连续相，其中所述非连续相均匀地分散在所述连续相中，所述非连续相的粒径为0.1～2μm，所述成膜材料在助剂中的含量为0.1～100g/L，所述芯材料采用在38～100℃产生液/气相变的液体，在助剂中的含量为5～200ml/L；其中所述助剂为氟碳乳剂。
2.根据权利要求1所述的助剂，其特征在于，所述非连续相的粒径为0.1～1μm。
3.根据权利要求2所述的助剂，其特征在于，所述非连续相的粒径为0.1～0.5μm。
4.根据权利要求1所述的助剂，其特征在于，所述成膜材料选自磷脂、胆固醇和糖脂中的一种或多种物质。
5.根据权利要求4所述的助剂，其特征在于，所述成膜材料采用磷脂，选自3-sn-磷脂酰胆碱、1，2-二棕榈酰基-sn-甘油基-3-磷脂酰甘油基-钠盐、1，2-二硬脂酰基-sn-甘油基-3-磷脂酰胆碱、1，2-二棕榈酰基-sn-甘油基-3-磷脂酰酸-钠盐、1，2-二棕榈酰基-sn-甘油基-3-磷脂酰胆碱、磷脂酰丝氨酸和氢化磷脂酰丝氨酸。
6.根据权利要求1所述的助剂，其特征在于，所述成膜材料在助剂中的含量为1～50g/L。
7.根据权利要求6所述的助剂，其特征在于，所述成膜材料在助剂中的含量为5～20g/L。
8.根据权利要求1所述的助剂，其特征在于，所述芯材料选自氟化C5-C12烃类物质中的一种或多种物质。
9.根据权利要求8所述的助剂，其特征在于，所述芯材料选自全氟戊烷和二氢十氟戊烷。
10.根据权利要求1所述的助剂，其特征在于，所述芯材料在助剂中的含量为10～100ml/L。
11.根据权利要求10所述的助剂，其特征在于，所述芯材料在助剂中的含量为20～80ml/L。
12.根据权利要求1所述的助剂，其特征在于，所述水性介质为蒸馏水、生理盐水或葡萄糖溶液。
13.根据权利要求1-12任一项所述的助剂，其特征在于，所述助剂还含有乳化剂，该乳化剂在助剂中的含量为5～150g/L，选自单乙二醇单C16-18脂肪酸酯、二乙二醇单C16-18脂肪酸酯、二乙二醇二C16-18脂肪酸酯、三乙二醇单C16-18脂肪酸酯、失水山梨醇脂肪酸酯、聚山梨醇酯、聚乙二醇单月桂酸酯、聚氧乙烯月桂酸酯、3-sn-磷脂酰胆碱、聚氧乙烯-聚氧丙烯乙二醇非离子嵌段共聚物、含氟表面活性剂和胆酸。
14.根据权利要求1-12任一项所述的助剂，其特征在于，所述助剂还含有稳定剂羧甲基纤维素钠，在助剂中的含量为0.01～10g/L。
15.根据权利要求1-12任一项所述的助剂，其特征在于，所述助剂还含有稳定剂丙三醇，在助剂中的含量为5～100g/L。
16.一种氟碳乳剂类超声造影剂的用途，其用于制备权利要求1所述的高强度聚焦超声治疗用的助剂。
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| EP05781799A EP1839677B1 (en) | 2005-01-10 | 2005-09-02 | Adjuvant of fluorocarbon emulsions for hifu therapy and the use thereof |
| KR1020077015586A KR20070094621A (ko) | 2005-01-10 | 2005-09-02 | Ｈｉｆｕ 처리용 불화탄소 에멀젼 강화제 및 그의 용도 |
| RU2007127668/15A RU2388492C2 (ru) | 2005-01-10 | 2005-09-02 | Фторуглеродный эмульсионный активатор для высокоинтенсивной фокусированной ультразвуковой терапии и его применение |
| CA2593644A CA2593644C (en) | 2005-01-10 | 2005-09-02 | Fluoro-carbon emulsion enhancement agent for high intensity focused ultrasound treatment and use thereof |
| PCT/CN2005/001391 WO2006072200A1 (fr) | 2005-01-10 | 2005-09-02 | Adjuvant d’emulsions au fluorocarbure pour un traitement hifu et utilisation de celui-ci |
| DE602005025408T DE602005025408D1 (de) | 2005-01-10 | 2005-09-02 | Adjuvans von fluorocarbon-emulsionen zur hifu-therapie und verwendung davon |
| JP2007549782A JP2008526786A (ja) | 2005-01-10 | 2005-09-02 | 高密度焦点式超音波療法のためのフッ化炭化水素乳濁液増強剤およびその使用 |
| US11/794,932 US20080138290A1 (en) | 2005-01-10 | 2005-09-02 | Fluoro-Carbon Emulsion Enhancement Agent for High Intensity Focused Ultrasound Treatment and Use thereof |
| AU2005324273A AU2005324273B2 (en) | 2005-01-10 | 2005-09-02 | Adjuvant of fluorocarbon emulsions for HIFU therapy and the use thereof |
| BRPI0518494-0A BRPI0518494A2 (pt) | 2005-01-10 | 2005-09-02 | adjuvante de emulsÕes de fléor carbono para terapia hifu e uso do mesmo |
| ES05781799T ES2355038T3 (es) | 2005-01-10 | 2005-09-02 | Adyuvante de emulsión fluorocarbonada para terapia de hifu y su uso. |
| AT05781799T ATE491476T1 (de) | 2005-01-10 | 2005-09-02 | Adjuvans von fluorocarbon-emulsionen zur hifu- therapie und verwendung davon |
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| WO2013059358A2 (en) | 2011-10-17 | 2013-04-25 | Butterfly Network, Inc. | Transmissive imaging and related apparatus and methods |
| US9667889B2 (en) | 2013-04-03 | 2017-05-30 | Butterfly Network, Inc. | Portable electronic devices with integrated imaging capabilities |
| CN103877598B (zh) * | 2014-03-18 | 2016-04-27 | 苏晓婷 | 一种超声造影剂及其制备方法 |
| CN105330786B (zh) * | 2014-07-03 | 2017-07-14 | 重庆海扶医疗科技股份有限公司 | 一种治疗用超声耦合介质材料及其制备方法 |
| CN105169420B (zh) * | 2015-09-02 | 2018-01-05 | 上海市第十人民医院 | 一种新型射频诊疗剂及其制备方法 |
| FR3082422B1 (fr) * | 2018-06-14 | 2021-01-22 | Univ D'avignon Et Des Pays De Vaucluse | Emulsion pour la chirurgie d'ablation ultrasonore |
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| JPS5832829A (ja) * | 1981-08-22 | 1983-02-25 | Green Cross Corp:The | 血管造影剤 |
| US4767610A (en) * | 1984-10-19 | 1988-08-30 | The Regents Of The University Of California | Method for detecting abnormal cell masses in animals |
| US4987154A (en) * | 1986-01-14 | 1991-01-22 | Alliance Pharmaceutical Corp. | Biocompatible, stable and concentrated fluorocarbon emulsions for contrast enhancement and oxygen transport in internal animal use |
| US6551576B1 (en) * | 1989-12-22 | 2003-04-22 | Bristol-Myers Squibb Medical Imaging, Inc. | Container with multi-phase composition for use in diagnostic and therapeutic applications |
| US6613306B1 (en) * | 1990-04-02 | 2003-09-02 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
| DE4127442C2 (de) * | 1991-08-17 | 1996-08-22 | Udo Dr Gros | Wäßrige Dispersion Fluorcarbon enthaltender Phospholipid-Vesikel und ein Verfahren zu ihrer Herstellung |
| US5196183A (en) * | 1991-12-04 | 1993-03-23 | Sterling Winthrop Inc. | Contrast agents for ultrasound imaging |
| US5716597A (en) * | 1993-06-04 | 1998-02-10 | Molecular Biosystems, Inc. | Emulsions as contrast agents and method of use |
| CA2185810A1 (en) * | 1994-03-28 | 1995-10-05 | Jo Klaveness | Liposomes |
| US5605934A (en) * | 1995-03-23 | 1997-02-25 | Baxter International Inc. | Method of manufacturing and storing solutions |
| US6165442A (en) * | 1996-02-19 | 2000-12-26 | Nycomed Imaging As | Thermally stabilized ultrasound contrast agent |
| WO1997029783A1 (en) * | 1996-02-19 | 1997-08-21 | Nycomed Imaging A/S | Improvements in or relating to contrast agents |
| US5846517A (en) * | 1996-09-11 | 1998-12-08 | Imarx Pharmaceutical Corp. | Methods for diagnostic imaging using a renal contrast agent and a vasodilator |
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| CN1194763C (zh) * | 2002-09-06 | 2005-03-30 | 中国人民解放军第三军医大学 | 新型脂质体超声造影剂及其制备方法 |
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| CA2593644C (en) | 2011-06-07 |
| KR20070094621A (ko) | 2007-09-20 |
| ES2355038T3 (es) | 2011-03-22 |
| BRPI0518494A2 (pt) | 2008-11-25 |
| EP1839677A1 (en) | 2007-10-03 |
| JP2008526786A (ja) | 2008-07-24 |
| EP1839677A4 (en) | 2008-03-19 |
| EP1839677B1 (en) | 2010-12-15 |
| AU2005324273A1 (en) | 2006-07-13 |
| WO2006072200A1 (fr) | 2006-07-13 |
| RU2007127668A (ru) | 2009-01-27 |
| DE602005025408D1 (de) | 2011-01-27 |
| AU2005324273B2 (en) | 2008-08-14 |
| US20080138290A1 (en) | 2008-06-12 |
| ATE491476T1 (de) | 2011-01-15 |
| CN1803196A (zh) | 2006-07-19 |
| CA2593644A1 (en) | 2006-07-13 |
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