CN1056634A - 超声回波记录仪用液载悬浮体之充气聚合物微气球 - Google Patents
超声回波记录仪用液载悬浮体之充气聚合物微气球 Download PDFInfo
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- CN1056634A CN1056634A CN91103411A CN91103411A CN1056634A CN 1056634 A CN1056634 A CN 1056634A CN 91103411 A CN91103411 A CN 91103411A CN 91103411 A CN91103411 A CN 91103411A CN 1056634 A CN1056634 A CN 1056634A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
Abstract
由界面间沉积聚合物膜为界面的充空气或充气
体之微气球、能够分散于水相载体液中注射到活有机
体内,或者从口部、直肠和尿道施用,以为治疗学或诊
断学上之用(回波描记)。微气球聚合物膜之性质(弹
性,渗透性,生物降解性)可以随意控制,取决于所选
择之聚合物、界面间沉积的条件以及聚合物添加剂。
Description
本发明涉及由有机聚合物气囊封入而充有空气或其它气体之微囊或微气球,它们可以分散或悬浮于水介质中并以此形式使用于口服、直肠和尿道施用的医疗操作,或者注射于人或动物体内,以作超声回波记录和其它医疗操作之用。
本发明亦提供了干态的上述微气球的制法。干态微气球是可以即时分散于水介质载体中从而得到其性质比现有类似产品优良之悬浮液。因此,随时可以施用之液载微气球悬浮体同样是本发明之一部分。
众所周知,悬浮于液体中的空气或气体之微体或微球,例如,微气泡或微气球之类的微球体,是作回波记录的特别有效之超声波反射体。在本说明书中,术语“微气泡”专指液载体中悬浮状的空气或气体微球体,这通常是由于在液载体中以分散的形式引入空气或其它气体所造成的。在液载体中最好还含有表面活性剂,以控制表面性质和气泡的稳定性。在微气泡中,气-液界面基本上由该液载体之松结合的分子所组成。术语“微囊”或“微气球”则更可取地指,空气或气体之微体是由不同于该液载体之分子构成其实质界面或气囊者。也即,具有聚合物膜壁者。微气泡和微气球两者通常都可用作超声波对照剂。例如,把于液载体中气体微气泡或微气球(大小范围为0.5至10μm)之悬浮液注射到人或动物体血液中,将大大增强超声回波记录之成像效果,从而帮助内部器官之显形。脉管及内部器字之成像能有力地帮助医疗诊断,例如查明心血管和其它疾病。
在可注射的液载体中,适用于回波记录的微气泡悬浮剂之形成,可以通过使一种在压力下溶于此液体的气体释放出来,或者通过产生气态物质的化学反应,或者通过在此液体中掺入其中吸收或吸附空气或气体的可溶或不溶性固体物质而引起。
例如,美国专利US-A-4,446,442(Schering)揭示了一系列生产减菌注射载体液中气体微气泡悬浮剂的技术,它使用(a)表面活性剂(tenside)在载体液(水的)中的溶液和(b)用作稳定剂的增粘剂溶液。为了产生气泡,其揭示的技术包括,迫使(a)、(b)和空气的混合物以高速度通过一个小孔;或者把(a)与一种生理学上可接受的气体在使用之前不久喷入(b),或者在(a)中加一种酸,并在(b)中加一种碳酸盐,两种组分恰在使用之前混在一起,于是酸同碳酸盐起反应而产生二氧化碳气泡;或者向贮器中(a)和(b)的混合物中加入超压气体,当此混合物使用于注射时,所说的气体便释放成为微气泡。
存在于微气泡的问题之一是,通常它们都是短暂的,甚至有稳定剂存在也是如此。因此,欧洲专利EP-A-131,540(Schering)中揭示了一种微气泡悬浮剂的制备方法,其中以一种稳定化的注射用载液,例如生理盐水,或者诸如麦芽糖、葡萄糖、乳糖或半乳糖之类的糖的溶液,与含有截留空气的同一种类之固态微粒(大小范围0.1至1μm)相混合。为了增进气泡在载液中之悬浮,液态和固态这两种组份在无菌条件下互相拌合数秒钟,而一旦悬浮液形成,便必须立即使用,就是说必须在5至10分钟内注射以进行回波记录测量;实际上,由于气泡是很快消失的,所以其浓度在此时间之后变得太低而不能应用。
用于回波记录之微气泡在注射之后的另一个问题是气泡大小问题。如通常所认为,气泡通过小血管转移流畅之容许大小其范围从约0.5至10μm;如若气泡比较大,则有凝块及接连而来的栓塞之危险。例如,在美国专利US-A-4,446,442(Schering)中揭示的气泡悬浮剂中,抵有大约50%之微气泡是小于40至50μm的,以致使这样的悬浮剂不适合许多回波记录之用。其制备方法是,以诸如卵磷酯、脂肪酸酯和醚,以及脂肪族醇等表面活性剂之水溶液,同聚氧乙烯以及聚氧乙烯化的多元醇(如山梨糖醇、乙二醇和丙三醇)、胆甾醇、或聚氧乙烯-聚氧丙烯聚合物一起,与提高粘度及稳定性的化合物,诸如单或多糖(葡萄糖、乳糖、蔗糖、山梨糖醇);多元醇,例如丙三醇、聚乙二醇;以及多肽,诸如蛋白质、明胶、氧化聚明胶以及血浆蛋白,一起进行剧烈的摇动。
与此对照,已经开发了微囊或微气球技术,以图消除某些或上述之缺陷。如上所述,微气泡只具有非实质或逐渐消失的气囊,即,它们仅是由液壁所包围,而其表面张力是借助表面活性剂改善的;然而微气球或微气囊则具有由不同于载体本身之实质性物质构成的气囊,例如具有一定强度之聚合物膜构成之气囊。换句话说,它们是固体物质的微球体,其中的气体或空气或多或少是被密封起来的。
例如,美国专利US-A-4,276,885(Tickner等)揭示了用于提高超声成像效果之使用表面泥的含气微囊,该表面膜包含了许多无毒且非抗原的有机分子。在揭示的一个实施例中,这些微囊具有抗凝聚的明胶膜,它们的优选大小为5-10μm。据称,这些微气泡的膜对于作回波记录仪测量来说是足够稳定的;但是,在过了一段时间之后,截留其中的空气据说将溶解于血液之中,而这气泡也将逐渐消失,这可能是由于明胶逐渐溶解所致。使用之前,微囊被保存明胶溶液中,在那里它们可以稳定地贮存。但是,在悬浮剂被用来注射的时候,明胶须进行加热融化才成为液体。
美国专利US-A-4,718,433(Feinstein)中揭示了不含明胶而改善贮藏稳定性的微球体。这种微球体是由粘蛋白例如血清的蛋白5%溶液进行声处理(5至30仟赫)而制得的,其大小在2-20μm直径范围,以2-4μm为主。微球体的稳定作用是由于成膜蛋白质经声处理之后的变性处理,例如使用加热或化学手段,如与甲醛或戊二醛进行反应。据说由该技术制得稳定微球体的浓度,约为8×106/毫升是2-4μm大小范围的,约106/毫升是4-5μm范围的,而5-6μm范围的小于5×105/毫升。这些微球体的稳定时间据称是48小时或更长,从而使它们在静脉内注射之后可以方便地进行左心成像,例如,经声处理之白蛋白微气泡注射入外表静脉是能够透过肺通道的,这就导致左心室腔以及心肌组织在超声波心动图上的不透明。
近来用于超声回波记录注射用微气球之进一步改良已于欧洲专利申请EP-A-324,938(Widder)中报道。该文献揭示高浓度(大于108)颗粒小于10μm空气充填蛋白质边界的微球体其使用期限为数月以上。这些微气球在水中的悬浮体是把可变性蛋白质溶液经超声空穴作用而制得的,例如,使用人体血清白蛋白。该操作也导致成膜蛋白质一定程度起泡沫并引入其随后的加热硬化。据称,其它蛋白质诸如血红蛋白和胶原蛋白也是很合宜的。
再新近M.A.Wheatley等人在“Biomaterials”1990年第11期,713-717页,报导了以藻朊酸盐离子移变的胶凝作用来制备聚合物涂敷之微球体的方法。该文献提到数种技术制备这种微囊;一个例子是,迫使藻朊酸盐溶液通过一个在空气射流中的小针,喷雾而产生充空气之初生囊,然后在1.2%CaCl2水溶中进行硬化。第二个例子包括气液共喷,借助一个三筒体喷头,引入气泡成为初生的囊,即,空气喷入中心毛细管,藻朊酸盐溶液被迫通过一个较大的与该毛细管同轴的管子,而无菌空气则在包围该第二根管子的套筒中流出。第三个例子是,藻朊酸盐溶液在喷雾之前既可用均质器也可用声处理使气体吸收于其中。如此制得微气球其直径在30至100μm范围,但仍然太大而不易通过肺毛细管。
欧洲专利申请EP-A-324,938揭示微气球悬浮液之高贮存稳定性使它们能够照原样投放市场,即,包括载体液相在内一起投放市场,这在商业上是一大好处,因为不再需要在使用前临时进行制备。但是,用于上述文献中的蛋白质对敏感的病人可能引起过敏反应,而且成膜物质的过份强度和稳定性还有一些缺点,例如,由于它们的刚性,膜体不能承受这些微球体可能遭到的突然压力变化,譬如说有血液中流动期间,由于心脏跳动而产生这样的压力变化。于是,在实际声波检测下,一部分微球体将破裂,从而使成像再现性变差;再者,这些微气球并不适用于口部应用,因为它们抵抗不住存在于胃肠道系统中的消化酶之作用。况且,已知的是,柔性壁之微球体较之刚性壁之相应微球体更能产生回波。
此外,在注射的情况下,微球体壁形成物质之过度稳定性将减慢被测器官有机组织对它的生物降解作用,而且可能引起代射问题。因此,十分可取的是,开发软而有弹性膜为界面之承压微气球,使其在压力变化时能够临时变形并且具有提高的回波产生率;也可以设想,具有可控生物降解性的微气球可能是很有优越性的,譬如说,以具有允许生物液体缓慢透入且可控制微孔隙的半渗透可生物降解聚合物制得之微气球就可能有较高的优越性。
本发明如权利要求1和2以及随后的权利要求所定义的微气球已经达到了这些希望的特点。而且,虽然本发明之微球体一般被制成相对地较短贮存期,即选择聚合物的类型使其易受生物降解以克服上述的代谢问题,这个特点(实际上由制备参数所控制)并不是商业上的缺点,因为本发明的微气球既可干态贮存及运送,在这状态下它们可以在长时期内稳定;也可把膜制成基本上不受载液影响,而仅在注射之后才开始发生降解。在第一种情况下,以干粉形式提供之微气球可在使用之前简易地同一定比例之水相载体混合,这种比例可按照需要进行选择。请注意这是相对于现有技术产品之另一个优点,因为浓度可以随意选择,而且远超过上述108/毫升,即在105至1010范围的初始浓度也是容易达到的。应指出的是,本发明的方法(此后即示)能够在很大程度上控制气孔率;因此,能容易地制成具有基本上不可渗透膜的微气球,它们在水性载液中悬浮体是稳定的,而且也可照原样投放市场。
权利要求1所定义在边界上沉积聚合物之膜的微球体,如以现有技术中周知的技术制成其中是以液体充满的微球体,可以通常地使第一含水相在聚合物的一种有机溶液中乳化而产生微滴(其大小可以乳化参数为函数进行控制),接着将此乳化体分散于第二水相,并且随着使此有机溶剂进行蒸发。在挥发性溶剂蒸发期间,聚合物便在微滴边界上的两表面间沉积,并且形成了微孔性的膜,使包封起来的第一含水相同周围的第二含水相有效地间隔起来。这种技术虽然可能实施,但在本发明中并非是优先的。
另外,也可以把疏水相在水相中以乳化剂进行乳化(通常在含水相中还含有增粘剂以作乳化稳定剂),如此得到疏水相微滴的一种水包油型的乳剂,虽然在其中加入溶于不与含水相混溶的挥发性有机溶剂的成膜聚合物。
如果聚合物是不溶于疏水相的,则其将在微滴与含水相边界上的两表面间沉积。换句话说,挥发性溶剂的蒸发将导致乳化之疏水相微滴周围边界上两表面间沉积膜之形成。随后包封之挥发性疏水相蒸发,便形成了以界面间沉积之聚合物膜包围的充满水的微球体。成功地使用于本发明中的这种技术,已由K.Uno等人在“Microencapsulation”期刊1984第1期3-8页上,以及由K.Makino等人在“Chem.Pharm.Bull.”1984第33期1195-1201页上发表。如上所述,微滴之大小可以改变乳化作用的参数进行控制,即,改变乳化剂的性质(表面活性剂的效能越高,就是,亲水的对亲油的差额越大,微滴便越小),以及改变搅拌条件(搅拌越快越有力,微滴便越小)。
在另一派生例中,界壁形成聚合物是溶于初始疏水相本身的;后者便在含水相中乳化成微滴,该微滴周围包封的膜便于被包封的疏水相在随后的蒸发中形成。J.R.Farnand等人在“Powde Technology”1978,22期11-16页报导了此法的一例。他们把一种聚合物(例如聚乙烯)在萘中的溶液在沸水中进行乳化,冷却之后,他们收集在冷水中呈悬浮体的聚合物为界面的微珠,然后使微珠遭到升华作用以除去萘,最终便制得了25μm大小的微气球。也有其它一些例子,其中聚合物是溶解于混合的疏水相,它包含:挥发性的疏水有机溶剂和水溶性的有机溶剂,然后使此聚合物溶液在含有乳化剂的水相中进行乳化,从而水溶性有机溶剂便分散到水相中,于是帮助疏水相微滴乳化体之形成并且使聚合物沉积在界面上;这种技术揭示于EP-A-274,961(H.Fessi)。
上述技术,趟若能够找到合适的条件以控制微球体大小在指望的范围内、室壁之渗透性或不透过性,并且以空气或挑选的气体替代包封着的液相,则它们是可以被适应来制备空气或气体充填之适于超声成像之微气球的。控制全部微球体的尺寸大小对微气球适于使用之目的显然是重要的,就是说,对注射或口部输入是重要的。注射的大小条件(约0.5-10μm平均尺寸)在前面已经讨论过了。对口服应用,尺寸范围可以宽得多,因为考虑到回波产生随着尺寸增大而增加;因此,譬如说1μm至1000μm之间的数个尺寸范围之微气球便可根据需要而使用于口服,只要膜有足够的弹性,当其移动到胃和肠中时不会破裂。控制室壁之渗透性是重要的,以保证注射用水相载体之渗透作用不存在或者足够地低,以致不会影响回波仪的测量,但在有些情况下仍相当大,以保证在测试之后有相当快的生物降解性,也就是说,由被测机体对此悬浮体进行迅速的代射作用。微气球包囊之微孔结构也是其回弹能力的一个因素(微气球包囊壁厚范围50-500mm,其气孔为几个nm至几百nm或更大),也就是说,微气球能容易地接受压力变化而不破裂。气孔之优选尺寸范围约为50-2,000nm。
获得这些结果的条件可以由采用权利要求17-18及其随后的权利要求所揭示的方法来满足。
能够控制微气球渗透性的一个因素是,权利要求17的方法第(4)步中疏水相之蒸发对于水蒸发的比率,例如在冻干的条件下,这是权利要求20中所列举之实施例的情况。举例来说,如若蒸发是在约-40至0℃之间进行,而己烷用作疏水相,聚苯乙烯是界面间沉积的聚合物,则所得微珠将有相对较大的气孔,这是因为在所选的温度范围内,碳氢化合物之蒸汽压远远地大于水的蒸汽压,这就意味着,微球内外之间的压力差将增加球膜中气孔的尺寸,因为球内的物质要通过这些膜中的气孔而蒸发。与此对照,使用环辛烷作为疏水相(它在-17℃时的蒸汽压与水的蒸汽压相同),制得的微珠将具有非常细小的气孔,因为在蒸发时,球体内外之压力被减小到了最低程度。
根据气孔率的程度,本发明微气球可以被制成在含水载体中稳定数小时至数个月,并且可以在一段较长的时间内得到可再现的回波记录信号。实际上,依赖于所选之聚合物,本发明微气球的膜可以制成,当其悬浮于有适当渗透性之载液中即含有适当浓度溶质时,基本上是不可渗透的。应该指出的是,本发明微气球包囊中微气孔之存在似乎也同回波记录的响应有关,即,当其它所有因素不变时,微气孔的小囊比相应的无气孔小囊产生更有效之回波记录信号。这个原因还不太清楚,但是可以假定,某种气体在一个封闭结构作共振时,如果该封闭结构是在气孔的还是无气孔的,其衰减作用可能是不同的。
其它在约-40℃至0℃之间其蒸汽压大小具有相同数量级的非水溶性有机溶剂也能方便地用作本发明之疏水溶剂。还包括:碳氢化合物,例如,正辛烷,环辛烷二甲基环己烷,乙基环己烷,2-,3-以及4-甲基-庚烷,3-乙基-己烷,甲苯,二甲苯,2-甲基-2-庚烷,2,2,3,3-四甲基丁烷,等等诸如此类。酯,例如,丙基和异丙基丁酸酯和异丁酸酯,甲酸丁酯,以及诸如此类也适宜在此范围使用。冻干的另一个优点是可在降低的一种气体压力之下而不是在空气的压力之下操作,因此可以制得气体充填的微气球。生理上可接受的气体例如二氧化碳,一氧化二氮,甲烷,氟利昂,氦和其它稀有气体都是可以使用的。具有放射示踪活性的气体能予以仔细考虑。
至于用本溶解沉积于界面间之聚合物的不溶于水的挥发性溶剂,可以列举卤素化合物,例如CCl4,CH3Br,CH2Cl2,氯仿,氟利昂;低沸酯,例如醋酸甲酯、乙酯和丙酯,以及弱水溶性的低级醚和酮。当使用并非完全不溶于水的溶剂,例如二乙基醚时,事先以所述溶剂饱和的水溶液作为含水相来使用是有助的。
疏水相在其中乳化咸水包油型乳化液的含水相最好含有1-20%(重量的)水溶性亲水化合物,例如糖类和聚合物作为稳定剂,例如聚乙烯醇(PVA),聚乙烯吡咯酮(PVP),聚乙二醇(PEG),明胶,聚谷氨酸,白蛋白,以及多糖例如淀粉,葡聚糖,琼脂,黄原胶(Xanthan),及诸如此类。相似的含水相可以用作在使用之前将微气球悬浮其中的载体液。
部分水溶聚合物可以保留在微气球包囊之内,或者在将它们进行蒸发其被包封的疏水芯相之前清洗这些微珠而除去这部分水溶聚合物。
用以使疏水相在含水相中生成水包油乳化体的乳化剂(0.1-5%重量)包括大部分生理上可接受的乳化剂,例如,蛋卵磷脂或大豆卵磷脂,或者合成的卵磷脂如饱和的合成卵磷脂,例如双十四烷酰磷脂酰胆碱、双十六烷酰磷脂酰胆碱或双十八烷酰磷酯酰胆碱,或不饱和的合成卵磷脂,例如二油酰磷脂酰胆碱或二亚油烯磷脂酰胆碱。乳化剂还包括表面活性剂,例如游离脂肪酸、脂肪酸与聚亚氧烷基化合物如聚亚氧丙基乙二醇和聚亚氧乙基乙二醇的酯;脂肪族醇与聚氧化亚烃基乙二醇的酯;脂肪酸与聚氧化亚烃基化的山梨糖醇(酐)的酯;皂;甘油-聚亚烃的硬脂酸盐;甘油-聚氧化乙烯的亚麻醇酸酯;聚亚烃乙二醇的均聚物和共聚物;聚乙氧基豆油和蓖麻油以及氢化的衍生物;蔗糖或其它碳水化合物与脂肪酸、脂肪族醇的醚和酯,这些是任选地进行聚氧化亚烃化的;饱和或不饱和脂肪酸的单、双和三甘油酯;甘油酯或豆油和蔗糖。
构成可注射微气球包封膜或边界膜之聚合物可选自大部分亲水的可生物降解且生理上兼容的聚合物。这些聚合物中可列举的有:弱水溶性的多糖,聚交酯和聚乙(醇酸)交酯以及它们的共聚物,交酯和内酯例如ε-己内酯、δ-戊内酯的共聚物,多肽,以及蛋白质例如明胶、骨胶原、球蛋白和白蛋白。在合成的聚合物选择中的较大通用性是本发明的另一个优点,因为,当处理过敏的病人时,可能希望避免使用如US-A-4,276,885或EP-A-324,938中使用的天然蛋白质(白蛋白,明胶)。其它合适的聚合物包括:聚-(原酸)酯(参阅诸如US-A-4,093,709;US-A-4,131,648;US-A-4,138,344;US-A-4,180,646);聚乳酸和聚乙二醇酸以及它们的共聚物,例如DEXON(参阅J.Heller《Biomaterials》1980第1期51页);聚(DL-交酯-CO-δ-己内酯),聚(DL-交酯-CO-δ-戊内酯),聚(DL-交酯-CO-δ-丁内酯)聚烷氰基丙烯酸酯(poly(alkyl)-cyano-acrylates);聚酰胺,聚羟基丁酸酯(polyhydroxybutyrate);聚二氧六环酮(polydioxanone);聚-β-氨基甲酮(Poly-β-aminoketones)(“Polymer”1982第23期1693页);聚磷嗪(polyphosphazenes)(“Science”1976第193期1214页);以及聚酐类(polyanhydrides)。关于可生物降解聚合物之参考资料可参阅R.Langer等人“Macromol.Chem.Phys.”1983第C23期,61126页上的论文。聚氨基酸例如聚谷氨酸和聚天冬氨酸以及它们的衍生物,即与低级醇或乙二醇生成之偏酯,也可以使用。这类聚合物的一个有用的例子是聚-(特丁基-谷氨酸),同其它氨基酸例如蛋氨酸、亮氨酸、缬氨酸、脯氨酸、甘氨酸、丙氨酸等的共聚物也是可能使用的。近来,已有报导具有控制的可生物降解性的聚谷氨酸和聚天冬氨酸的一些新衍生物(参阅本文引入作为参考资料的WO87/03891;US4,888,398以及EP-130,935)。这些聚合物(以及同其它氨基酸之共聚物)都具有下列类型的分子式:
-(NH-CHA-CO)x(NH-CHX-CO)y
其中X代表一种氨基酸残余的侧链,而A则是分子式为-(CH2)nCOOR1R2-OCOR(Ⅱ)之基团,其中R1和R2为H或低级烷基,R则是烷基或芳基;或者R和R1是相互由取代的或非取代的连结节联结起来以形成5-或6-节的环。
A也可以代表下列分子式的基团:
-(CH2)nCOO-CHR1COOR(Ⅰ)
以及
-(CH2)nCO(NH-CHX-CO)mNH-CH(COOH)-(CH2)pCOOH(Ⅲ)
以及相应的酐。在所有这些分子式中,n、m和P为较低的整数(不超过5),而X和Y则是为其分子量不低于5000者选用的整数。
上面提到的聚合物都适用于制备本发明的微气球,所得膜之性质例如强度、弹性及可生物降解性都可加以控制,随取代基R、R1、R2和X的性质而定。例如,X可以是甲基(丙氨酸),异丙基(缬氨酸),异丁基(亮氨酸和异亮氨酸),苯甲基(苯基丙氨酸)。
添加剂可以引入到微气球之聚合物壁中,以改善其物理性质例如分散性、弹性和水渗透性。为了引入到聚合物中,添加剂可以溶入到聚合物载送相中,例如欲被乳化入水相中之疏水相中,从而添加剂将与聚合物一道在界面间形成膜的阶段沉积出来。
在有用的添加剂中,可以列举某些化合物,它们可以使微气球膜“疏水化”,以便降低其渗水性,例如脂肪,蜡和高分子量碳氢化合物。可改善微气球在注射用液载体中分散性的添加剂有诸如磷脂等的两亲(既亲水又亲油)的化合物;它们也增加渗水性和生物降解性的速率。
用以制备在消化系统中使用的微气球的非生物降解聚合物可以选自大部分不溶于水且生理可接受的抗生化(bioresistant)聚合物,包括,聚烯烃(聚苯乙烯),丙烯酸树脂(聚丙烯酸脂,聚丙烯腈),聚酯(聚碳酸酯),聚氨酯,聚脲,以及它们的共聚物。ABS(丙烯-丁二烯-苯乙烯)是一种可取的共聚物。
增加膜弹性之添加剂是诸如异丙基肉豆蔻酸酯(十四烷酸酯)以及甘油基单硬脂酸盐之类的增塑剂。非常有用的添加剂也可以是类似于膜本身但分子量相对地低的聚合物所组成。例如,当使用聚乳酸或聚乙二醇酸类型共聚物作为成膜物质时,膜的性质可以透过引入低分子量(1,000至15,000道尔顿)聚乙二醇酸交酯或聚丙交酯作为添加剂,得到有利的改善(增加柔软性和生物降解性)。同样,中或低分子量MN的聚烷撑二醇(例如:聚乙二醇PEG2000)也是一种有用的软化添加剂。
在本发明微气球界面间沉积膜形成聚合物中引入添加剂的量是非常可变的,且可根据需要而定。在某些情况中全然不用添加剂,而在另一些情况中添加剂的量可以达到聚合物重量的约20%也是可能的。
本发明之注射用微气球,可以在有或无添加剂之存在条件下干燥地贮存在改善其守恒性并防止其聚结。作为这种添加剂,可以从0.1至20%(重量)的下列诸水溶且生理可接受的化合物中选择,例如甘露醇,半乳糖,乳糖或蔗糖或亲水聚合物如葡聚糖,黄原胶,琼脂,淀粉,PVP,聚谷氨酸,聚乙烯醇(PVA),白蛋白以及明胶。微气球在注射用液载体中的有效使用期,即,能观察到有用回波信号的时间,可以控制到延续数分钟至数个月,视需要而定。这可以控制膜的气孔率,使膜实质上对载液不渗透一直到具有几个毫微米至数百毫微米之气孔的气孔率,这样来达到上述所需使用期范围。气孔率的这种程度是能够控制的,除了适当选择成膜聚合物及聚合物添加剂之外,还可通过调节权利要求17所述方法第(4)步骤之蒸发速度和温度,以及适当选择构成疏水相之化合物的(或化合物之混合物的)性质来加以控制,即,其蒸汽分压与水相蒸汽分压之差别越大,其在微气球膜中的气孔将越大。当然,这种由选择疏水相进行之控制,还可以进一步通过选择稳定剂并调节其浓度,以控制微气球形成期间水的蒸发速率来加以精确控制。所有这些变化都能够由技术熟练人员轻而易举地无须施加创造性而做到,在此也无必要进一步讨论。
应该提到的是,虽然本发明微气球能以干燥状态投放市场,更特别地是当它们被指定一个注射后的有限寿命时,也可能希望销售随时准备的产品,即随时可以注射或口服施用的在含水载液中之微气球悬浮剂。这就要求微气球膜是基本上不渗透(至少几个月或更长)此液载体的。本发明书中已经揭示,本发明方法可以很容易地达到这种状态,只需适当选择聚合物的性质以及界间沉积的参数即可。实际上参数已经找到(例如使用聚谷氨酸聚合物[其中A是分子式Ⅱ的基团],而环辛烷作为疏水相),以致可以使膜在疏水相蒸发之后的气孔率是如此地微细,其得到的微气球是基本上对悬浮其中之水性载液不渗透的。
一种诊断用的优选之施用制剂包括每毫升含108-1010微气球于缓冲或未缓冲之盐水(0.9%的NaCl水溶液;缓冲剂10mM tris-HCl)中的悬浮液。这可以主要按照下列例子中的说明加以制备,最好是按照例3和例4;使用聚-(DL-交酯)聚合物,可从德国Ingelhcim的Bochringer公司得到此聚合物。
下列例子说明本发明是切实可行的。
例1
将1克聚苯乙烯溶解于9克100℃的液态萘。将此萘溶液在90-95℃下于含有0.1%吐温-40乳化剂之聚乙烯醇(PVA)4%(重量)水溶液中进行乳化。乳化设备是一台Polytron PT-3000,转速约为10,000rpm。然后,将乳化液在搅拌下以500毫升15℃之同一水溶液相进行稀释,于是萘滴便固化成小于50μm的微珠,这可以使其通过50μm的筛网加以确定。将此悬浮体在1,000g下进行离心处理,所得之微珠以水清洗,然后再进行离心。这一步骤重复两次。
将微珠再悬浮于溶解了0.8克乳糖的100毫升水中,然后将此悬浮体在-30℃冻成一块。此后,将此冻块在0.5-2乇的真空下于约-20℃至-10℃温度之间进行蒸发。于是便获得了平均尺寸5-10μm且有控制的气孔率的空气充填微气球。此微气球分散于水中(3%wt,分散液)之后可在2.25和7.5兆赫给出回波信号。这种微气球之稳定性在干态下是无限期地有效;一旦悬浮于水溶液载体中,其有效的回波仪使用期约为30分钟或更长。聚苯乙烯是非生物降解物质,故其并不给予注射回波记录之用,但对消化系统之探查是有用的。本例清楚地确立了本发明方法之可行性。
例2
0.3克之DL-交酯与乙交酯(杜邦Medisorb)之50∶50共聚物混合体,以及16毫克蛋卵磷脂溶解于7.5毫升之CHCl3中成为溶液(1)。
制备含有20毫克石蜡(熔点54-56℃)于10毫升环辛烷(熔点10-13℃)中的溶液(2),并将其于150毫升,含有1.2克CHCl3的,Pluronic F-108(一种环氧乙烷与氧化丙烯的嵌段共聚物)的0.13%wt.水溶液中进行乳化。以Polytron设备在室温下每分钟7000转乳化1分钟。然后,将溶液(1)在搅拌中加入(每分钟7000转),30-60秒钟之后,乳化设备换成螺旋搅拌器,继续搅拌,在室温下大约持续3个小时(22℃)。将此悬浮体滤过50μm的筛网,并冻成一块。然后将此冻块在高真空下-20至0℃之间进行蒸发(收集器温度-60至-80℃)。这样便获得了0.264克(88%)在干燥状态稳定之充空气微气球。
这种微气球在水中的悬浮液(无稳定剂)产生至少一小时强回波信号。注射于有机体之后,在几天之内便生物降解了。
例3
用200毫升四氢呋喃(THF),0.8克50:50DL-交酯:乙交酯共聚物(Boehringer AG),80毫克蛋卵磷酯,64毫克石蜡和4毫升辛烷制成溶液。此溶液在螺旋搅拌下(500r.p.m)缓慢滴入400毫升Pluronic F-108的0.1%水溶液中进行乳化。搅拌15分钟之后,将此乳状分散液置于旋蒸器(rotavapor)中在10-12乇,25℃,进行蒸发,直至它的体积减少到大约400毫升。然后将此分散液在50μm的滤筛上过滤,冷冻至-40℃,并在约1乇之下进行冷冻干燥。残留物是1.32克极细粉末,将其放入40毫升蒸馏水,经人工搅拌3分钟之后便得到非常均质的微气球分散液,以颗粒分析仪(Malvern出品之Mastersizer型)测得其平均颗粒尺寸为4.5μm,微气球的浓度约为2×109/毫升(以Coulter计数器测得)。这种悬浮液产生强回波信号持续约1小时。
如果在本例中将添加剂从成膜聚合物中略去,即,使用的只是800毫克交酯:乙交酯共聚物在THF和辛烷中的溶液,那么就会观察到壁气孔率惊人地减少,其在水载体中的分散液产生之回波信号三天之后也无显著衰减。
使用中等数量的添加剂,得到的微球具有中等程度的孔率和寿命。
例4
本例中使用的聚合物分子式如权利要求8所定义,其中侧基具有分子式(Ⅱ),其中R1和R2都是H,而R则是特丁基。该聚合物(定义为聚合物-POMEG)的制备在US-A-4,888,398中叙述。
本例的程序类似例3,使用的是0.1克聚POMEG,70毫升THF,1毫升环辛烷以及100毫升Pluronic F-108之0.1%水溶液。不加任何卵磷脂或高分子量化合物。乳白的乳化液于27℃,10乇下进行蒸发,直至剩下100毫升剩余物。然后在50μm筛网中过滤并冷冻。冻块之蒸发在0.5-1乇下进行到干燥为止。产量为0.18克,因为有表面活性剂存在。将此物分散于10毫升蒸馏水中并以Coulter计数器进行计数,测得浓度发现为1.43×109微囊/毫升。以颗粒分析仪(Malvern之Mastersizer)确定其平均颗粒尺寸为5.21μm。将此分散液稀释100×倍,即,稀释成约1.5×107微囊/毫升。测量其回波性。回波信号在7.5兆赫时的振幅为2.25兆赫时的5倍。这些信号在长时间内都能再现。
回波特性是用脉冲回波系统进行测量的,它包括一个介电有机玻璃制的样品夹持器(直径30毫米)。该夹持器带有一个20μm厚的密拉聚酯(Mylar)声学窗口;一个浸没于恒温于溶中的传感器夹;一台脉冲发生一接收器(Accutron M3010JS型),它带有一个固定增益40dB的外接前置放大器;以及带有可调增益从-40至+40dB和可更换之13毫米未聚焦传感器的内部放大器。在接收部插入一个10兆赫低通滤器以改善信噪比。IBM PC机中的A/D插件板是Sonotek STR832。测量是在2.25、3.5、5以及7.5兆赫进行的。
如果在本例中,使用的聚合物代之以乳-内酯共聚物,内酯为δ-丁内酯、δ-戊内酯或ε-已内酯(参阅Fukuzaki等人在“J.Biomedical Mater.Res.1991第25期,315-328页上的论文),可以获得相似的有利结果。在一个类似的情况中,聚烷氰基丙烯酸酯和特别是90∶10共聚物聚(DL-交酯-CO-乙交酯)也产生满意的结果。最终发现最优选的聚合物是Boehringer-Ingelheim公司销售之名称为“Resomer R-206”或Resomer R-207的聚(DL-交酯)。
例5
以例4之制剂(1.43×109/毫升)分散液0.1-2毫升注射于试验狗外表静脉冲,用一台Acuson-128仪器进行二维的回声心电仪记录。在通常期待的右半心对比增强成像之后,强而持久的左半心信号增强及心内膜清晰轮廓也被观察到了。由此证实,以(或至少含有相当大部分)聚-POMEG制备的微气球是能够横穿过肺毛细血管循环的,而且能在血液中维持足够的时间来完成有效的回波图象分析。
在另外的一系列实验中,在兔和鼠中观察到全身动脉和门静脉多普勒信号的持久增强,这是在注射了以例4揭示的方法所制备的微气球制剂之后观察到的,但其中使用的是聚(DL-乳酸)作为聚合物相,所用的制剂成分含有1.9×108微气球/毫升。
使用聚(特丁基-谷氨酸酯)按例4所述也能制得另一种制剂成分。将此制剂(0.5毫升稀释至3.4×108微气球/毫升,然后注射于鼠的门静脉,随即产生肝实质之持久对比增强作用。
例6
按例1所述制备微气球悬浮液(1.1×109微气球/毫升),其树脂为聚苯乙烯。将1毫升这种悬浮液用100毫升浓度为300mM的甘露醇溶液进行稀释,然后用7毫升所得的稀释液从胃内施用给一只试验用鼠。以一台Acuson-128仪器对此试验动物进行检测其消化系统二维回波成像,结果清晰也显示了小肠和大肠的单回路。
Claims (31)
1、以聚合物膜为界面且充满空气或合适气体之微米或亚微米级微囊或微气球,其在液相载体中形成之悬浮液,可施用于人或动物患者作治疗或诊断,如超声回波描记成像之用,其特征在于,其成膜聚合物是可变形且有回弹力的界面间沉积聚合物。
2、以弹性的界面间聚合的膜为界面且充满空气或气体之微气球,适于在相宜的生理可接受之水相载液中形成悬浮液,可从口部、直肠和尿道施用或注射入活的有机体中,以作治疗或诊断之用,其特征在于,所述微气球呈不聚结之干态,且可即时与所述之载液混合而分散于其中。
3、权利要求1或2之微气球,其尺寸大部分在0.5-10μm范围,适宜于注射入活机体的血液中,其特征在于,其膜聚合物是可生物降解的,而膜本身既可是不渗透的,也可含有可渗透生物活性液的气孔以增加生物降解速度。
4、权利要求3之微气球,其特征在于其中所述之聚合物膜具有气孔率之范围是从几个毫微米到几百或几千毫微米,最好是在50-2,000nm范围。
5、权利要求3之微气球,其特征在于其中所述之膜是弹性的,厚度为50-500nm,可承受由心跳脉博产生在血液中的压力变化。
6、权利要求3之微气球,其特征在于其中所述膜聚合物是可生物降解的聚合物,选自多糖、聚氨基酸、聚交酯和聚乙交酯以及它们的共聚物,交酯和内酯的共聚物,多肽,聚-(原)酸酯,聚二氧六环酮(polydioxanone),聚-β-氨基酮(poly-β-amino-ketones),聚磷嗪(polyphosphazenes),聚酐类(polyanhydrides)以及聚(烷基-氰基-丙烯酸酯(poly(alkyi-cyano-acrylates))。
7、权利要求3之微气球,其特征在于其中所述膜聚合物选自聚谷氨酸或聚天冬氨酸之衍生物以及它们同其它氨基酸之共聚物者。
8、权利要求7之微气球,其特征在于其中所述聚谷氨酸和聚天冬氨酸之衍生物是选自含有其羧化侧官能团的酯和酰胺,所述侧官能具有下列分子式:
-(CH2)nCOO-CHR1COOR(Ⅰ)或
-(CH2)nCOOR1R2-O-COR(Ⅱ)或
-(CH2)nCO(NH-CHX-CO)mNHCH(COOH)-(CH2)pCOOH(Ⅲ),其中R是烷基或芳基的取代基;R1和R2是H或低级烷基,或者R和R1互相由取代的或未取代的连接节接合而形成5节或6节的环,n是1或2,p是1、2或3,m是1至5的整数,而X则是氨基酸残余的一个侧链。
9、权利要求3之微气球,其特征在于其中膜聚合物含有控制弹性程度以及控制渗透性之气孔大小和密度的添加剂。
10、权利要求9之微气球,其特征在于其中所述之添加剂包括增塑剂、既亲水又亲油的(两亲的amphipatic)物质以及疏水的化合物。
11、权利要求10之微气球,其特征在于其中,增塑剂包括异丙基肉豆蔻酸盐(脂)、甘油基单硬脂酸盐(脂)以及诸如此类,以控制其柔韧性,既亲水又亲油的物质包括表面活化剂及卵磷脂之类的磷脂,以增加其气孔率来控制其渗透性,而疏水相包括石蜡之类的高分子量碳氢化合物,以降低其气孔率。
12、权利要求10之微气球,其特征在于其中添加剂包括如在1000至15000范围内的低分子量聚合物,以控制该微气球之柔软性及回弹性。
13、权利要求12之微气球,其特征在于其中所述低分子量聚合物是选自聚交酯、聚乙交酯、聚乙二醇及聚丙二醇之类的聚烷撑二醇和聚甘油之类的多元醇者。
14、权利要求1或2之微气球,尺寸大到约1000μm,适于口部、直肠或尿道施用,其特征在于,其膜聚合物在消化系统中是不能被生物降解,也不能透过生物液者。
15、权利要求14之微气球,其特征在于其中所述膜聚合物是选自聚烯烃、聚丙烯酸酯、聚丙烯腈、不可水解的聚酯、聚氨酯和聚脲者。
16、按照权利要求1或2的微气球之水成悬浮液,用于施用于病人,其特征在于,含有的浓度为约106至1010微气球/毫升,且可稳定至少一个月者。
17、一种可于载液中成悬浮液而作口部、直肠或尿道施用成作活机体注射用之充空气或充气体的微气球制备方法,其步骤包括:
(1)使一疏水有机相在含水相中乳化,以便获得所述疏水相之微滴在所述含水相中的一种水包油型乳化液,
(2)将一至少含一种聚合物于一不溶于该含水相的易挥发溶剂中之溶液加入上述乳化液,以致围绕所述微滴的整个周围将形成一层所述的聚合物。
(3)使所述易挥发溶剂蒸发,以致该聚合物将凭界面间之沉淀而沉积于所述微滴之整个周围,遂使该微滴形成具有一由所述聚合物膜包封所述疏水相核心之微珠,成为在上述水相中的微珠悬浮液,
(4)使上述微珠悬浮液在如此条件遭到减压以致所述被包封疏水相经蒸发而除去,
其特征在于所述之疏水相是如此挑选者,以致于步骤(4)中其蒸发基本与含水相同时发生并被代之以空气或气体,从而便获得了干的、自由流动而易于分散的微气球。
18、权利要求17之方法,其特征在于其中所述之聚合物是被溶解于所述疏水相的,以致步骤(2)和(3)便可省去,而聚合物膜将在步骤(4)中由界面间沉淀而形成。
19、权利要求17之方法,其特征在于步骤(4)中所述疏水相之蒸发是在其蒸汽分压、与水蒸汽分压处于同一数量级时的温度进行者。
20、权利要求17之方法,其特征在于其中所述步骤(4)之蒸发是在冷冻干燥条件下进行者。
21、权利要求20之方法,其特征在于其中所述冷冻干燥是在温度从-40℃至0℃的范围完成。
22、权利要求17或9之方法,其特征在于其中疏水相是选自在包括在约-40℃至0℃间隔内的一温度具有约1乇蒸汽压之有机化合物者。
23、权利要求17或18之方法,其特征在于其中含水相包括溶于其中的约从1%至20%(重量)之稳定剂,其包括之亲水化合物选自糖、PVA、PVP、明胶、淀粉、葡聚糖、聚右旋糖(polydextrose)、白蛋白以及类似物者。
24、权利要求18之方法,其特征在于其中,控制微气球膜渗透程度之添加剂是加入于疏水相者,而微气球注射于活机体之后其聚合物生物降解速度是所述渗透程度之函数。
25、权利要求24之方法,其特征在于其中所述之添加剂包括诸如脂肪、蜡以及高分子量碳氢化合物之类的疏水固态相,其于微气球膜聚合物中之存在将降低对含水液相之渗透性者。
26、权利要求24之方法,其特征在于其中所述之添加剂包括磷脂之类的两亲化合物或低分子量聚合物,其于膜聚合物中之存在将增加微气球对含水液相之渗透性者。
27、权利要求18之方法,其特征在于其中所述在含水相中进行乳化之疏水相还包含-可水溶之溶剂,经其于乳化期间掺入所述含水相中,将协助减少微滴之尺寸,并于步骤(4)进行之前诱导所述聚合物于界面间之沉淀者。
28、一种可于载液中成悬浮液而作口部、直肠或尿道施用或作活机体注射施用之充空气或充气体的微气球之制备方法,其步骤包括:
(1)使一疏水有机相在含水相中乳化,以便获得所述疏水有机相之微滴在所述含水相中的水包油型乳化液,所述有机相含有溶于其中之一种或多种非水溶性聚合物,
(2)使所述乳化液在蒸发除去所述疏水相的条件下进行减压,从而溶于微滴中的聚合物将在界面间沉积并形成聚合物边界膜,微滴便同时转变成微气球,
其特征在于,所述疏水相是挑选而于步骤(2)中其蒸发基本上与含水相同时进行并被代之以空气或气体,从而便获得了干的、自由流动而易于分散的微气球者。
29、权利要求28之方法,其特征在于其中所述在含水相中进行乳化之疏水聚合物溶液相还含有一可水溶之溶剂,经其于乳化期间掺入所述含水相中,将协助减小微滴之尺寸,并于步骤(2)进行之前诱导该聚合物于界面间之沉淀者。
30、权利要求28之方法,其特征在于其中所述于步骤(1)中被乳化之有机疏水相不含任何聚合物溶于其中,而且在完成步骤(2)之前还进行了下列之附加步骤:
(1a)将溶于不溶于水相之易挥发溶剂中至少一种聚合物之溶液加入所述乳化液,以致在所述微滴之整个周围将形成一层所述聚合物,
(1b)使所述易挥发溶剂蒸发,以致该聚合物将由界面沉淀而沉积于微滴整个周围,形成具有由所述聚合物膜包封疏水相核心之微气球或微珠,该微气球或珠是在所述含水相中之悬浮液,从而于步骤(2)中所述疏水相通过所述膜进行蒸发,使该膜形成了显著气孔率。
31、一种注射用微气球水成悬浮液,其特征在于其中微气球含量为108-1010微气球/毫升,微气球是由面间沉淀之DL-交酯聚合物作为界面膜。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1064851C (zh) * | 1992-06-13 | 2001-04-25 | 舍林股份公司 | 微粒,其制造方法以及在诊断中的应用 |
CN115400230A (zh) * | 2022-09-03 | 2022-11-29 | 福建医科大学附属协和医院 | 一种新型的多功能胃肠超声造影剂 |
Families Citing this family (272)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6088613A (en) | 1989-12-22 | 2000-07-11 | Imarx Pharmaceutical Corp. | Method of magnetic resonance focused surgical and therapeutic ultrasound |
US5585112A (en) | 1989-12-22 | 1996-12-17 | Imarx Pharmaceutical Corp. | Method of preparing gas and gaseous precursor-filled microspheres |
US5469854A (en) * | 1989-12-22 | 1995-11-28 | Imarx Pharmaceutical Corp. | Methods of preparing gas-filled liposomes |
US5580575A (en) * | 1989-12-22 | 1996-12-03 | Imarx Pharmaceutical Corp. | Therapeutic drug delivery systems |
US20020150539A1 (en) * | 1989-12-22 | 2002-10-17 | Unger Evan C. | Ultrasound imaging and treatment |
US5776429A (en) | 1989-12-22 | 1998-07-07 | Imarx Pharmaceutical Corp. | Method of preparing gas-filled microspheres using a lyophilized lipids |
US5922304A (en) | 1989-12-22 | 1999-07-13 | Imarx Pharmaceutical Corp. | Gaseous precursor filled microspheres as magnetic resonance imaging contrast agents |
US6146657A (en) | 1989-12-22 | 2000-11-14 | Imarx Pharmaceutical Corp. | Gas-filled lipid spheres for use in diagnostic and therapeutic applications |
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 |
US5542935A (en) * | 1989-12-22 | 1996-08-06 | Imarx Pharmaceutical Corp. | Therapeutic delivery systems related applications |
US6001335A (en) | 1989-12-22 | 1999-12-14 | Imarx Pharmaceutical Corp. | Contrasting agents for ultrasonic imaging and methods for preparing the same |
US5352435A (en) * | 1989-12-22 | 1994-10-04 | Unger Evan C | Ionophore containing liposomes for ultrasound imaging |
IN172208B (zh) * | 1990-04-02 | 1993-05-01 | Sint Sa | |
US20040208826A1 (en) * | 1990-04-02 | 2004-10-21 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
US20010024638A1 (en) * | 1992-11-02 | 2001-09-27 | Michel Schneider | Stable microbubble suspensions as enhancement agents for ultrasound echography and dry formulations thereof |
US6613306B1 (en) | 1990-04-02 | 2003-09-02 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
US6989141B2 (en) * | 1990-05-18 | 2006-01-24 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
USRE39146E1 (en) | 1990-04-02 | 2006-06-27 | Bracco International B.V. | Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof |
US5578292A (en) | 1991-11-20 | 1996-11-26 | Bracco International B.V. | Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof |
US5445813A (en) * | 1992-11-02 | 1995-08-29 | Bracco International B.V. | Stable microbubble suspensions as enhancement agents for ultrasound echography |
US7083778B2 (en) * | 1991-05-03 | 2006-08-01 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
AU636481B2 (en) * | 1990-05-18 | 1993-04-29 | Bracco International B.V. | Polymeric gas or air filled microballoons usable as suspensions in liquid carriers for ultrasonic echography |
US20030194376A1 (en) * | 1990-05-18 | 2003-10-16 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
US5562099A (en) * | 1990-10-05 | 1996-10-08 | Massachusetts Institute Of Technology | Polymeric microparticles containing agents for imaging |
US5487390A (en) * | 1990-10-05 | 1996-01-30 | Massachusetts Institute Of Technology | Gas-filled polymeric microbubbles for ultrasound imaging |
US5370901A (en) | 1991-02-15 | 1994-12-06 | Bracco International B.V. | Compositions for increasing the image contrast in diagnostic investigations of the digestive tract of patients |
GB9106673D0 (en) * | 1991-03-28 | 1991-05-15 | Hafslund Nycomed As | Improvements in or relating to contrast agents |
GB9106686D0 (en) † | 1991-03-28 | 1991-05-15 | Hafslund Nycomed As | Improvements in or relating to contrast agents |
US5205290A (en) | 1991-04-05 | 1993-04-27 | Unger Evan C | Low density microspheres and their use as contrast agents for computed tomography |
US5874062A (en) | 1991-04-05 | 1999-02-23 | Imarx Pharmaceutical Corp. | Methods of computed tomography using perfluorocarbon gaseous filled microspheres as contrast agents |
US5993805A (en) | 1991-04-10 | 1999-11-30 | Quadrant Healthcare (Uk) Limited | Spray-dried microparticles and their use as therapeutic vehicles |
GB9107628D0 (en) * | 1991-04-10 | 1991-05-29 | Moonbrook Limited | Preparation of diagnostic agents |
DK0586524T3 (zh) * | 1991-06-03 | 1997-05-20 | Nycomed Imaging As | |
GB9116610D0 (en) * | 1991-08-01 | 1991-09-18 | Danbiosyst Uk | Preparation of microparticles |
NZ244147A (en) † | 1991-09-03 | 1994-09-27 | Hoechst Ag | Echogenic particles which comprise a gas and at least one shaping substance, and their use as diagnostic agents |
US6875420B1 (en) | 1991-09-17 | 2005-04-05 | Amersham Health As | Method of ultrasound imaging |
US5409688A (en) * | 1991-09-17 | 1995-04-25 | Sonus Pharmaceuticals, Inc. | Gaseous ultrasound contrast media |
MX9205298A (es) * | 1991-09-17 | 1993-05-01 | Steven Carl Quay | Medios gaseosos de contraste de ultrasonido y metodo para seleccionar gases para usarse como medios de contraste de ultrasonido |
JP3231768B2 (ja) * | 1991-09-17 | 2001-11-26 | ソーナス ファーマシューティカルス,インコーポレイテッド | 気体状超音波造影剤及び超音波造影剤として使用する気体の選定方法 |
US6723303B1 (en) | 1991-09-17 | 2004-04-20 | Amersham Health, As | Ultrasound contrast agents including protein stabilized microspheres of perfluoropropane, perfluorobutane or perfluoropentane |
GB9200391D0 (en) * | 1992-01-09 | 1992-02-26 | Nycomed As | Improvements in or relating to contrast agents |
GB9200388D0 (en) * | 1992-01-09 | 1992-02-26 | Nycomed As | Improvements in or relating to contrast agents |
IL104084A (en) * | 1992-01-24 | 1996-09-12 | Bracco Int Bv | Sustainable aqueous suspensions of pressure-resistant and gas-filled blisters, their preparation, and contrast agents containing them |
US5674468A (en) * | 1992-03-06 | 1997-10-07 | Nycomed Imaging As | Contrast agents comprising gas-containing or gas-generating polymer microparticles or microballoons |
GB9204918D0 (en) | 1992-03-06 | 1992-04-22 | Nycomed As | Chemical compounds |
ES2135466T3 (es) * | 1992-03-06 | 1999-11-01 | Nycomed Imaging As | Mejoras introducidas en agentes de contraste. |
US6383470B1 (en) | 1992-09-26 | 2002-05-07 | Thomas Fritzsch | Microparticle preparations made of biodegradable copolymers |
DE4232755A1 (de) * | 1992-09-26 | 1994-03-31 | Schering Ag | Mikropartikelpräparationen aus biologisch abbaubaren Mischpolymeren |
GB9221329D0 (en) | 1992-10-10 | 1992-11-25 | Delta Biotechnology Ltd | Preparation of further diagnostic agents |
IL108416A (en) | 1993-01-25 | 1998-10-30 | Sonus Pharma Inc | Colloids with phase difference as contrast ultrasound agents |
CA2154590C (en) * | 1993-01-25 | 2001-06-12 | Steven C. Quay | Phase shift colloids as ultrasound contrast agents |
US5558855A (en) * | 1993-01-25 | 1996-09-24 | Sonus Pharmaceuticals | Phase shift colloids as ultrasound contrast agents |
JP2905598B2 (ja) * | 1993-07-02 | 1999-06-14 | モレキュラー バイオシステムズ,インコーポレイテッド | 熱変性されたタンパク質からカプセル化されたマイクロスフェアを製造する方法 |
US5855865A (en) * | 1993-07-02 | 1999-01-05 | Molecular Biosystems, Inc. | Method for making encapsulated gas microspheres from heat denatured protein in the absence of oxygen gas |
US5798091A (en) | 1993-07-30 | 1998-08-25 | Alliance Pharmaceutical Corp. | Stabilized gas emulsion containing phospholipid for ultrasound contrast enhancement |
DE69434119T3 (de) * | 1993-07-30 | 2011-05-05 | Imcor Pharmaceutical Co., San Diego | Stabilisierte mikrogasbläschen-zusammensetzungen für echographie |
GB9318288D0 (en) * | 1993-09-03 | 1993-10-20 | Nycomed Imaging As | Improvements in or relating to contrast agents |
EP0717617B1 (de) * | 1993-09-09 | 2000-10-25 | Schering Aktiengesellschaft | Wirkstoffe und gas enthaltende mikropartikel |
US7083572B2 (en) * | 1993-11-30 | 2006-08-01 | Bristol-Myers Squibb Medical Imaging, Inc. | Therapeutic delivery systems |
PT682530E (pt) | 1993-12-15 | 2003-06-30 | Bracco Research Sa | Misturas de gases uteis como meios de contraste para ultrassons |
WO1995029705A1 (en) * | 1994-05-03 | 1995-11-09 | Molecular Biosystems, Inc. | Composition for ultrasonically quantitating myocardial perfusion |
US5965109A (en) * | 1994-08-02 | 1999-10-12 | Molecular Biosystems, Inc. | Process for making insoluble gas-filled microspheres containing a liquid hydrophobic barrier |
US5730955A (en) * | 1994-08-02 | 1998-03-24 | Molecular Biosystems, Inc. | Process for making gas-filled microspheres containing a liquid hydrophobic barrier |
US5562893A (en) * | 1994-08-02 | 1996-10-08 | Molecular Biosystems, Inc. | Gas-filled microspheres with fluorine-containing shells |
DE4428589C2 (de) * | 1994-08-12 | 1996-11-07 | Byk Gulden Lomberg Chem Fab | Orales Echokontrastmittel |
GB9417941D0 (en) * | 1994-09-06 | 1994-10-26 | Nycomed Imaging As | Improvements in or relating to contrast agents |
US5540909A (en) * | 1994-09-28 | 1996-07-30 | Alliance Pharmaceutical Corp. | Harmonic ultrasound imaging with microbubbles |
GB9423419D0 (en) * | 1994-11-19 | 1995-01-11 | Andaris Ltd | Preparation of hollow microcapsules |
US6333021B1 (en) * | 1994-11-22 | 2001-12-25 | Bracco Research S.A. | Microcapsules, method of making and their use |
US6743779B1 (en) | 1994-11-29 | 2004-06-01 | Imarx Pharmaceutical Corp. | Methods for delivering compounds into a cell |
US5830430A (en) | 1995-02-21 | 1998-11-03 | Imarx Pharmaceutical Corp. | Cationic lipids and the use thereof |
DE19510690A1 (de) | 1995-03-14 | 1996-09-19 | Schering Ag | Polymere Nano- und/oder Mikropartikel, Verfahren zu deren Herstellung, sowie Verwendung in medizinischen Diagnostik und Therapie |
US5759539A (en) * | 1995-06-06 | 1998-06-02 | Georgia Research Foundation, Inc. | Method for rapid enzymatic alcohol removal |
US5997898A (en) | 1995-06-06 | 1999-12-07 | Imarx Pharmaceutical Corp. | Stabilized compositions of fluorinated amphiphiles for methods of therapeutic delivery |
AU6378096A (en) * | 1995-06-07 | 1996-12-30 | Brown University Research Foundation | Spray dried polymeric microparticles containing imaging agen ts |
US6033645A (en) | 1996-06-19 | 2000-03-07 | Unger; Evan C. | Methods for diagnostic imaging by regulating the administration rate of a contrast agent |
US6521211B1 (en) | 1995-06-07 | 2003-02-18 | Bristol-Myers Squibb Medical Imaging, Inc. | Methods of imaging and treatment with targeted compositions |
US5804162A (en) | 1995-06-07 | 1998-09-08 | Alliance Pharmaceutical Corp. | Gas emulsions stabilized with fluorinated ethers having low Ostwald coefficients |
US5820850A (en) * | 1995-06-07 | 1998-10-13 | Molecular Biosystems, Inc. | Gas-filled amino acid block co-polymer microspheres useful as ultrasound contrast agents |
US6231834B1 (en) | 1995-06-07 | 2001-05-15 | Imarx Pharmaceutical Corp. | Methods for ultrasound imaging involving the use of a contrast agent and multiple images and processing of same |
US6139819A (en) | 1995-06-07 | 2000-10-31 | Imarx Pharmaceutical Corp. | Targeted contrast agents for diagnostic and therapeutic use |
WO1997022409A1 (en) * | 1995-12-21 | 1997-06-26 | Drexel University | Hollow polymer microcapsules and method of producing |
US5611344A (en) * | 1996-03-05 | 1997-03-18 | Acusphere, Inc. | Microencapsulated fluorinated gases for use as imaging agents |
HU226714B1 (en) * | 1996-03-05 | 2009-07-28 | Acusphere | Microencapsulated fluorinated gases for use as imaging agents |
DE19611769A1 (de) * | 1996-03-14 | 1997-09-18 | Schering Ag | Mikropartikel, Verfahren zu deren Herstellung, sowie deren Verwendung in der Ultraschall Diagnostik |
EP0935415B1 (en) | 1996-05-01 | 2006-11-22 | Imarx Pharmaceutical Corp. | In vitro methods for delivering nucleic acids into a cell |
US5985309A (en) * | 1996-05-24 | 1999-11-16 | Massachusetts Institute Of Technology | Preparation of particles for inhalation |
US5874064A (en) | 1996-05-24 | 1999-02-23 | Massachusetts Institute Of Technology | Aerodynamically light particles for pulmonary drug delivery |
US6652837B1 (en) | 1996-05-24 | 2003-11-25 | Massachusetts Institute Of Technology | Preparation of novel particles for inhalation |
US5976501A (en) * | 1996-06-07 | 1999-11-02 | Molecular Biosystems, Inc. | Use of pressure resistant protein microspheres encapsulating gases as ultrasonic imaging agents for vascular perfusion |
US5837221A (en) * | 1996-07-29 | 1998-11-17 | Acusphere, Inc. | Polymer-lipid microencapsulated gases for use as imaging agents |
US6414139B1 (en) | 1996-09-03 | 2002-07-02 | Imarx Therapeutics, Inc. | Silicon amphiphilic compounds and the use thereof |
US6017310A (en) * | 1996-09-07 | 2000-01-25 | Andaris Limited | Use of hollow microcapsules |
US5846517A (en) † | 1996-09-11 | 1998-12-08 | Imarx Pharmaceutical Corp. | Methods for diagnostic imaging using a renal contrast agent and a vasodilator |
ATE366588T1 (de) | 1996-09-11 | 2007-08-15 | Imarx Pharmaceutical Corp | Verfahren zur diagnostischen bilderzeugung der nierenregion unter verwendung eines kontrastmittels und eines vasodilators |
US6068600A (en) * | 1996-12-06 | 2000-05-30 | Quadrant Healthcare (Uk) Limited | Use of hollow microcapsules |
US6120751A (en) | 1997-03-21 | 2000-09-19 | Imarx Pharmaceutical Corp. | Charged lipids and uses for the same |
US6090800A (en) | 1997-05-06 | 2000-07-18 | Imarx Pharmaceutical Corp. | Lipid soluble steroid prodrugs |
US6537246B1 (en) * | 1997-06-18 | 2003-03-25 | Imarx Therapeutics, Inc. | Oxygen delivery agents and uses for the same |
US6143276A (en) | 1997-03-21 | 2000-11-07 | Imarx Pharmaceutical Corp. | Methods for delivering bioactive agents to regions of elevated temperatures |
CA2289088C (en) * | 1997-04-30 | 2007-08-07 | Point Biomedical Corporation | Microparticles useful as ultrasonic contrast agents and for delivery of drugs into the bloodstream |
US20050019266A1 (en) * | 1997-05-06 | 2005-01-27 | Unger Evan C. | Novel targeted compositions for diagnostic and therapeutic use |
US6610764B1 (en) | 1997-05-12 | 2003-08-26 | Metabolix, Inc. | Polyhydroxyalkanoate compositions having controlled degradation rates |
US6867248B1 (en) | 1997-05-12 | 2005-03-15 | Metabolix, Inc. | Polyhydroxyalkanoate compositions having controlled degradation rates |
US6416740B1 (en) | 1997-05-13 | 2002-07-09 | Bristol-Myers Squibb Medical Imaging, Inc. | Acoustically active drug delivery systems |
US6045777A (en) * | 1997-06-30 | 2000-04-04 | Acusphere, Inc. | Method for enhancing the echogenicity and decreasing the attenuation of microencapsulated gases |
CN1265045A (zh) * | 1997-07-04 | 2000-08-30 | 奈科姆成像有限公司 | 从微粒状药物产品中筛选具有预选粒径粒子的方法 |
US6828357B1 (en) | 1997-07-31 | 2004-12-07 | Metabolix, Inc. | Polyhydroxyalkanoate compositions having controlled degradation rates |
ATE252916T1 (de) * | 1997-08-12 | 2003-11-15 | Bracco Research Sa | Verabreichbare formulierugen und ihre anwendung in mri |
US6548047B1 (en) | 1997-09-15 | 2003-04-15 | Bristol-Myers Squibb Medical Imaging, Inc. | Thermal preactivation of gaseous precursor filled compositions |
US7637948B2 (en) | 1997-10-10 | 2009-12-29 | Senorx, Inc. | Tissue marking implant |
US8668737B2 (en) | 1997-10-10 | 2014-03-11 | Senorx, Inc. | Tissue marking implant |
US6123923A (en) | 1997-12-18 | 2000-09-26 | Imarx Pharmaceutical Corp. | Optoacoustic contrast agents and methods for their use |
JP4376455B2 (ja) | 1997-12-22 | 2009-12-02 | メタボリックス,インコーポレイテッド | 制御された分解速度を有するポリヒドロキシアルカノエート組成物 |
GB9727102D0 (en) * | 1997-12-22 | 1998-02-25 | Andaris Ltd | Microparticles and their therapeutic use |
US20010003580A1 (en) | 1998-01-14 | 2001-06-14 | Poh K. Hui | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
IT1298269B1 (it) * | 1998-02-18 | 1999-12-20 | Promefarm S R L | Uso di un polietilenglicole come mezzo di contrasto in ecografia |
US6347241B2 (en) | 1999-02-02 | 2002-02-12 | Senorx, Inc. | Ultrasonic and x-ray detectable biopsy site marker and apparatus for applying it |
US6238677B1 (en) * | 1998-08-18 | 2001-05-29 | The United States Of America As Represented By The Secretary Of Agriculture | Starch microcapsules for delivery of active agents |
US8498693B2 (en) | 1999-02-02 | 2013-07-30 | Senorx, Inc. | Intracorporeal marker and marker delivery device |
US7983734B2 (en) | 2003-05-23 | 2011-07-19 | Senorx, Inc. | Fibrous marker and intracorporeal delivery thereof |
US6862470B2 (en) | 1999-02-02 | 2005-03-01 | Senorx, Inc. | Cavity-filling biopsy site markers |
US8361082B2 (en) | 1999-02-02 | 2013-01-29 | Senorx, Inc. | Marker delivery device with releasable plug |
US6725083B1 (en) | 1999-02-02 | 2004-04-20 | Senorx, Inc. | Tissue site markers for in VIVO imaging |
US20090030309A1 (en) | 2007-07-26 | 2009-01-29 | Senorx, Inc. | Deployment of polysaccharide markers |
US9820824B2 (en) | 1999-02-02 | 2017-11-21 | Senorx, Inc. | Deployment of polysaccharide markers for treating a site within a patent |
US7651505B2 (en) | 2002-06-17 | 2010-01-26 | Senorx, Inc. | Plugged tip delivery for marker placement |
WO2000051662A1 (en) | 1999-03-04 | 2000-09-08 | Tepha, Inc. | Bioabsorbable, biocompatible polymers for tissue engineering |
DE60036863T2 (de) * | 1999-03-25 | 2008-07-31 | Metabolix, Inc., Cambridge | Medizinische vorrichtungen und verwendungen von polyhydroxyalkanoatpolymeren |
US6575991B1 (en) | 1999-06-17 | 2003-06-10 | Inrad, Inc. | Apparatus for the percutaneous marking of a lesion |
AU6635900A (en) | 1999-08-13 | 2001-03-13 | Point Biomedical Corporation | Microparticles useful as ultrasonic contrast agents and for lymphatic system |
WO2001012069A1 (en) * | 1999-08-13 | 2001-02-22 | Point Biomedical Corporation | Hollow microspheres with controlled fragility for medical use |
US7678364B2 (en) | 1999-08-25 | 2010-03-16 | Alkermes, Inc. | Particles for inhalation having sustained release properties |
US6749835B1 (en) | 1999-08-25 | 2004-06-15 | Advanced Inhalation Research, Inc. | Formulation for spray-drying large porous particles |
US6368275B1 (en) | 1999-10-07 | 2002-04-09 | Acuson Corporation | Method and apparatus for diagnostic medical information gathering, hyperthermia treatment, or directed gene therapy |
US20030144570A1 (en) * | 1999-11-12 | 2003-07-31 | Angiotech Pharmaceuticals, Inc. | Compositions and methods for treating disease utilizing a combination of radioactive therapy and cell-cycle inhibitors |
DE10013850A1 (de) * | 2000-03-15 | 2001-09-20 | Schering Ag | Gasgefüllte Mikrokapseln enthaltend funktionalisiertes Polyalkylcyanacrylat, sowie Verfahren zu deren Herstellung |
EP1780283A1 (en) | 2000-04-21 | 2007-05-02 | Martek Biosciences Corporation | Trophic conversion of obligate photographic algae through metabolic engineering |
EP2286843A3 (en) | 2000-06-02 | 2011-08-03 | Bracco Suisse SA | Compounds for targeting endothelial cells |
DE10027393B4 (de) * | 2000-06-02 | 2007-05-16 | Wella Ag | Poly- und Oligoester kationischer Hydroxysäuren, Verfahren zu ihrer Herstellung und ihre Verwendung |
ES2409758T3 (es) | 2000-11-20 | 2013-06-27 | Senorx, Inc. | Marcadores de sitios tisulares para formación de imagen in vivo |
EP1345629A2 (en) | 2000-12-29 | 2003-09-24 | Advanced Inhalation Research, Inc. | Particles for inhalation having sustained release properties |
US7897141B2 (en) * | 2002-04-01 | 2011-03-01 | Drexel University | Echogenic polymer microcapsules and nanocapsules and methods for production and use thereof |
AU2002307056B2 (en) * | 2001-03-30 | 2005-08-04 | Drexel University | Echogenic polymer microcapsules and nanocapsules and methods for production and use thereof |
DE60223239T2 (de) * | 2001-04-06 | 2008-08-14 | Bracco Research S.A. | Vorrichtung zur Messung lokaler physikalischer Parameter in einem flüssigkeitsgefüllten Hohlraum |
DE10119522A1 (de) * | 2001-04-20 | 2002-12-05 | Innovacell Biotechnologie Gmbh | Herstellung und Anwendung einer Suspensionszusammensetzung mit einem Ultraschall-Kontrastmittel |
US7794693B2 (en) | 2002-03-01 | 2010-09-14 | Bracco International B.V. | Targeting vector-phospholipid conjugates |
US7211240B2 (en) | 2002-03-01 | 2007-05-01 | Bracco International B.V. | Multivalent constructs for therapeutic and diagnostic applications |
EP2301587B1 (en) | 2002-03-01 | 2014-06-25 | Dyax Corp. | KDR and VEGF/KDR binding peptides and their use in diagnosis |
US7261876B2 (en) | 2002-03-01 | 2007-08-28 | Bracco International Bv | Multivalent constructs for therapeutic and diagnostic applications |
US8623822B2 (en) | 2002-03-01 | 2014-01-07 | Bracco Suisse Sa | KDR and VEGF/KDR binding peptides and their use in diagnosis and therapy |
AU2003278807A1 (en) | 2002-03-01 | 2004-08-13 | Bracco International B.V. | Kdr and vegf/kdr binding peptides and their use in diagnosis and therapy |
US6890592B2 (en) | 2002-03-13 | 2005-05-10 | Appleton Papers Inc. | Uniform microcapsules |
US7462366B2 (en) | 2002-03-29 | 2008-12-09 | Boston Scientific Scimed, Inc. | Drug delivery particle |
US20030215394A1 (en) * | 2002-05-17 | 2003-11-20 | Short Robert E. | Microparticles having a matrix interior useful for ultrasound triggered delivery of drugs into the bloodstream |
US6919068B2 (en) * | 2002-05-17 | 2005-07-19 | Point Biomedical Corporation | Method of preparing gas-filled polymer matrix microparticles useful for echographic imaging |
US7842377B2 (en) | 2003-08-08 | 2010-11-30 | Boston Scientific Scimed, Inc. | Porous polymeric particle comprising polyvinyl alcohol and having interior to surface porosity-gradient |
US8012454B2 (en) | 2002-08-30 | 2011-09-06 | Boston Scientific Scimed, Inc. | Embolization |
US7883490B2 (en) | 2002-10-23 | 2011-02-08 | Boston Scientific Scimed, Inc. | Mixing and delivery of therapeutic compositions |
US20060036158A1 (en) | 2003-11-17 | 2006-02-16 | Inrad, Inc. | Self-contained, self-piercing, side-expelling marking apparatus |
US20070128117A1 (en) * | 2003-02-04 | 2007-06-07 | Bracco International B.V. | Ultrasound contrast agents and process for the preparation thereof |
EP1590006B1 (en) * | 2003-02-04 | 2010-09-08 | Bracco Suisse SA | Ultrasound contrast agents and process for the preparation thereof |
JP2006517558A (ja) | 2003-02-13 | 2006-07-27 | ブラッコ イメージング エッセ ピ ア | コントラスト増強x線位相画像診断 |
SI2949658T1 (sl) | 2003-03-03 | 2018-10-30 | Dyax Corp. | Peptidi, ki specifično vežejo HGF receptor (cMet) in njihove uporabe |
US20040185108A1 (en) * | 2003-03-18 | 2004-09-23 | Short Robert E. | Method of preparing gas-filled polymer matrix microparticles useful for delivering drug |
ITFI20030077A1 (it) * | 2003-03-26 | 2004-09-27 | Actis Active Sensors S R L | Metodo per l'indagine ecografica tramite mezzi di contrasto |
CA2525132C (en) | 2003-05-08 | 2011-06-28 | Tepha, Inc. | Polyhydroxyalkanoate medical textiles and fibers |
US7877133B2 (en) | 2003-05-23 | 2011-01-25 | Senorx, Inc. | Marker or filler forming fluid |
KR101025490B1 (ko) | 2003-06-12 | 2011-04-04 | 브라코 인터내셔날 비.브이. | 초음파 콘트라스트 조영에서 보충 커브 피팅을 통한 혈류 개산 |
US8021303B2 (en) | 2003-06-12 | 2011-09-20 | Bracco Research Sa | System for extracting morphological information through a perfusion assessment process |
US20060222694A1 (en) * | 2003-06-27 | 2006-10-05 | Oh Choon K | Stabilized topotecan liposomal composition and methods |
EP1651273B1 (en) * | 2003-07-08 | 2012-08-29 | Tepha, Inc. | Poly-4-hydroxybutyrate matrices for sustained drug delivery |
US20060287659A1 (en) * | 2003-08-22 | 2006-12-21 | Tepha, Inc. | Polyhydroxyalkanoate nerve regeneration devices |
US7976823B2 (en) | 2003-08-29 | 2011-07-12 | Boston Scientific Scimed, Inc. | Ferromagnetic particles and methods |
SE0302794D0 (sv) * | 2003-10-24 | 2003-10-24 | Per Hansson | Novel microparticles for ultrasound contrast imaging and drug delivery |
AU2004285595A1 (en) | 2003-10-31 | 2005-05-12 | Point Biomedical Corporation | Reconstitutable microsphere compositions useful as ultrasonic contrast agents |
US7901770B2 (en) | 2003-11-04 | 2011-03-08 | Boston Scientific Scimed, Inc. | Embolic compositions |
US20050273002A1 (en) | 2004-06-04 | 2005-12-08 | Goosen Ryan L | Multi-mode imaging marker |
CA2547024C (en) * | 2003-12-22 | 2013-12-17 | Bracco Research Sa | Gas-filled microvesicle assembly for contrast imaging |
US20070081946A1 (en) * | 2003-12-22 | 2007-04-12 | Bracco Research S.A. | Assembly of gas-filled microvesicle with active component for contrast imaging |
ATE466596T1 (de) | 2004-01-20 | 2010-05-15 | Sunnybrook & Womens College | Hochfrequenz-ultraschall-darstellung mit kontrastmitteln |
US7025726B2 (en) | 2004-01-22 | 2006-04-11 | The Regents Of The University Of Nebraska | Detection of endothelial dysfunction by ultrasonic imaging |
US7736671B2 (en) | 2004-03-02 | 2010-06-15 | Boston Scientific Scimed, Inc. | Embolization |
US8173176B2 (en) | 2004-03-30 | 2012-05-08 | Boston Scientific Scimed, Inc. | Embolization |
US7311861B2 (en) | 2004-06-01 | 2007-12-25 | Boston Scientific Scimed, Inc. | Embolization |
US8012457B2 (en) | 2004-06-04 | 2011-09-06 | Acusphere, Inc. | Ultrasound contrast agent dosage formulation |
WO2006015276A2 (en) * | 2004-08-03 | 2006-02-09 | Tepha, Inc. | Non-curling polyhydroxyalkanoate sutures |
GB2445322B (en) | 2004-08-13 | 2008-08-06 | Stichting Tech Wetenschapp | Intravasular ultrasound techniques |
JP4837663B2 (ja) | 2004-08-18 | 2011-12-14 | ブラッコ・シュイス・ソシエテ・アノニム | 造影画像化のためのガス充填微小胞組成物 |
US8425550B2 (en) | 2004-12-01 | 2013-04-23 | Boston Scientific Scimed, Inc. | Embolic coils |
EP1833373B1 (en) | 2004-12-23 | 2015-12-16 | Bracco Suisse SA | A perfusion assessment method and system based on bolus administration |
EP1853333A1 (en) * | 2004-12-23 | 2007-11-14 | Bracco Research S.A. | Liquid transfer device for medical dispensing containers |
ATE481088T1 (de) * | 2005-01-28 | 2010-10-15 | Tepha Inc | Embolisierung unter verwendung von poly-4- hydroxybutyrat-partikeln |
US7858183B2 (en) | 2005-03-02 | 2010-12-28 | Boston Scientific Scimed, Inc. | Particles |
US7727555B2 (en) | 2005-03-02 | 2010-06-01 | Boston Scientific Scimed, Inc. | Particles |
WO2006094951A1 (en) | 2005-03-03 | 2006-09-14 | Bracco Research Sa | Medical imaging system based on a targeted contrast agent |
EP1714642A1 (en) * | 2005-04-18 | 2006-10-25 | Bracco Research S.A. | Pharmaceutical composition comprising gas-filled microcapsules for ultrasound mediated delivery |
US10357328B2 (en) | 2005-04-20 | 2019-07-23 | Bard Peripheral Vascular, Inc. and Bard Shannon Limited | Marking device with retractable cannula |
US7963287B2 (en) | 2005-04-28 | 2011-06-21 | Boston Scientific Scimed, Inc. | Tissue-treatment methods |
US9463426B2 (en) | 2005-06-24 | 2016-10-11 | Boston Scientific Scimed, Inc. | Methods and systems for coating particles |
CA2562580C (en) | 2005-10-07 | 2014-04-29 | Inrad, Inc. | Drug-eluting tissue marker |
US8007509B2 (en) | 2005-10-12 | 2011-08-30 | Boston Scientific Scimed, Inc. | Coil assemblies, components and methods |
US9198639B2 (en) | 2005-11-10 | 2015-12-01 | Bracco Suisse S.A. | Detection of immobilized contrast agent in medical imaging applications based on flow dynamics analysis |
CN101500746A (zh) * | 2005-11-10 | 2009-08-05 | 沃尔弗林管件公司 | 具有含焊剂的弹性体的连续长度层的铜焊材料 |
EP1952349B1 (en) | 2005-11-10 | 2018-10-17 | Bracco Suisse SA | Instantaneous visualization of contrast agent concentration in imaging applications |
EP1797919A1 (en) * | 2005-12-16 | 2007-06-20 | Bracco Research S.A. | Liquid transfer device for medical dispensing containers |
US8101197B2 (en) | 2005-12-19 | 2012-01-24 | Stryker Corporation | Forming coils |
US8152839B2 (en) | 2005-12-19 | 2012-04-10 | Boston Scientific Scimed, Inc. | Embolic coils |
US7947368B2 (en) | 2005-12-21 | 2011-05-24 | Boston Scientific Scimed, Inc. | Block copolymer particles |
JP2007196223A (ja) * | 2005-12-28 | 2007-08-09 | National Institute Of Advanced Industrial & Technology | 中空マイクロカプセルの製造方法 |
JP5154554B2 (ja) | 2006-08-01 | 2013-02-27 | ボストン サイエンティフィック サイムド,インコーポレイテッド | 非線形イメージングのためのパルスインバージョンシーケンス |
ES2443526T3 (es) | 2006-10-23 | 2014-02-19 | C.R. Bard, Inc. | Marcador mamario |
US8414927B2 (en) | 2006-11-03 | 2013-04-09 | Boston Scientific Scimed, Inc. | Cross-linked polymer particles |
US7943683B2 (en) * | 2006-12-01 | 2011-05-17 | Tepha, Inc. | Medical devices containing oriented films of poly-4-hydroxybutyrate and copolymers |
EP3542748B1 (en) | 2006-12-12 | 2023-08-16 | C. R. Bard, Inc. | Multiple imaging mode tissue marker |
US8401622B2 (en) | 2006-12-18 | 2013-03-19 | C. R. Bard, Inc. | Biopsy marker with in situ-generated imaging properties |
WO2008075192A2 (en) * | 2006-12-19 | 2008-06-26 | Bracco International Bv | Targeting and therapeutic compounds and gas-filled microvesicles comprising said com ounds |
WO2008074889A1 (en) | 2006-12-21 | 2008-06-26 | Bracco International Bv | Detection of the detachment of immobilized contrast agent in medical imaging applications |
JP4967101B2 (ja) * | 2006-12-28 | 2012-07-04 | 独立行政法人産業技術総合研究所 | 中空マイクロカプセルの製造方法 |
EP2476703A1 (en) | 2011-01-14 | 2012-07-18 | Bracco Imaging S.p.A | Human antibodies cross-reacting with a bacterial and a self antigen from atherosclerotic plaques |
US20090191244A1 (en) * | 2007-09-27 | 2009-07-30 | Children's Medical Center Corporation | Microbubbles and methods for oxygen delivery |
WO2009083557A1 (en) | 2007-12-28 | 2009-07-09 | Bracco Research S.A. | Quantification analisys of immobilized contrast agent in medical imaging applications |
US10130342B2 (en) | 2007-12-28 | 2018-11-20 | Bracco Suisse Sa | Initialization of fitting parameters for perfusion assessment based on bolus administration |
US8311610B2 (en) | 2008-01-31 | 2012-11-13 | C. R. Bard, Inc. | Biopsy tissue marker |
EP2090322A1 (en) | 2008-02-18 | 2009-08-19 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of fsh receptor ligands for diagnosis and therapy of cancer |
EP2103313A1 (en) * | 2008-03-19 | 2009-09-23 | Koninklijke Philips Electronics N.V. | Method for the synthesis of hollow spheres |
GB0811856D0 (en) | 2008-06-27 | 2008-07-30 | Ucl Business Plc | Magnetic microbubbles, methods of preparing them and their uses |
EP2147684A1 (en) | 2008-07-22 | 2010-01-27 | Bracco Imaging S.p.A | Diagnostic Agents Selective Against Metalloproteases |
US9327061B2 (en) | 2008-09-23 | 2016-05-03 | Senorx, Inc. | Porous bioabsorbable implant |
WO2010040772A2 (en) * | 2008-10-07 | 2010-04-15 | Bracco Research Sa | Targeting construct comprising anti-polymer antibody and liposomes or microvesicles binding to the same |
EP2189112A1 (en) | 2008-11-24 | 2010-05-26 | Bracco Research S.A. | Real-time perfusion imaging and quantification |
CA2744296C (en) | 2008-12-16 | 2016-05-17 | Laurent Jakob | Device for bolus administration of contrast agent |
CA2742765C (en) | 2008-12-30 | 2016-04-12 | C.R. Bard Inc. | Marker delivery device for tissue marker placement |
US9307957B2 (en) | 2009-06-08 | 2016-04-12 | Bracco Suisse Sa | Auto-scaling of parametric images |
EP2473972B1 (en) | 2009-09-01 | 2019-11-06 | Bracco Suisse SA | Method for producing medical parametric images |
US8420259B2 (en) * | 2009-10-14 | 2013-04-16 | GM Global Technology Operations LLC | Electrodes including an embedded compressible or shape changing component |
EP2516053B1 (en) * | 2009-12-22 | 2019-11-20 | Evonik Corporation | Emulsion-based process for preparing microparticles and workhead assembly for use with same |
EP2345732A1 (en) | 2010-01-19 | 2011-07-20 | Universite Paris Descartes | Methods for intracellular delivery of nucleic acids |
EP2544593B1 (en) | 2010-03-09 | 2014-12-31 | Bracco Suisse SA | Initialization of fitting parameters for perfusion assessment based on bolus administration |
US20110269657A1 (en) * | 2010-04-28 | 2011-11-03 | Jiten Odhavji Dihora | Delivery particles |
BR112013002945A2 (pt) | 2010-08-09 | 2016-06-07 | Inst Nat Sante Rech Med | composição farmacâutica formulada com agente de eco-contraste de microbolhas e um ácido nucleico terapêutico de interesse para uso em um método para tratamento de uma doença ocular em um sujeito |
DK2603242T3 (en) | 2010-08-09 | 2018-06-18 | Bracco Suisse Sa | TARGETED GAS FILLED MICROVESICLES |
WO2012085072A1 (en) | 2010-12-24 | 2012-06-28 | Bracco Suisse Sa | Gas-filled microvesicles for use as vaccine |
EP2474327A1 (en) | 2011-01-07 | 2012-07-11 | RWTH Aachen | Microdosing of ultrasound contrast agents |
WO2012095516A1 (en) | 2011-01-14 | 2012-07-19 | Bracco Imaging Spa | Human antibodies cross-reacting with a bacterial and a self antigen from atherosclerotic plaques |
DE102011005444A1 (de) * | 2011-03-11 | 2012-09-13 | Innora Gmbh | Festes, negatives Röntgenkontrastmittel zur Darstellung des Gastrointestinaltraktes |
WO2012136813A2 (en) | 2011-04-07 | 2012-10-11 | Universitetet I Oslo | Agents for medical radar diagnosis |
EP2545908A1 (en) | 2011-07-11 | 2013-01-16 | RWTH Aachen | Medium for microbubbles or microparticles and preparation thereof |
US20150037375A1 (en) * | 2011-07-19 | 2015-02-05 | Trustees Of Boston University Et Al | Doping agents and polymeric compositions thereof for controlled drug delivery |
WO2013151682A1 (en) | 2012-04-06 | 2013-10-10 | Children's Medical Center Corporation | Process for forming microbubbles with high oxygen content and uses thereof |
RU2508094C1 (ru) * | 2012-08-03 | 2014-02-27 | Андрей Юрьевич Хоменко | Способы получения трансдермальных терапевтических систем на основе сополимеров молочной и гликолевой кислот (варианты) |
JP6333287B2 (ja) | 2012-12-21 | 2018-05-30 | ブラッコ・シュイス・ソシエテ・アノニムBracco Suisse SA | 時間に対する統計的分析に基づく画像診断応用におけるセグメンテーション |
US10577554B2 (en) | 2013-03-15 | 2020-03-03 | Children's Medical Center Corporation | Gas-filled stabilized particles and methods of use |
AU2014230447A1 (en) | 2013-03-15 | 2015-09-17 | Westfaelische Wilhelms-Universitaet Muenster | Detection of acute renal allograft rejection |
WO2015000953A1 (en) | 2013-07-03 | 2015-01-08 | Bracco Suisse S.A. | Devices and methods for the ultrasound treatment of ischemic stroke |
USD716451S1 (en) | 2013-09-24 | 2014-10-28 | C. R. Bard, Inc. | Tissue marker for intracorporeal site identification |
USD715942S1 (en) | 2013-09-24 | 2014-10-21 | C. R. Bard, Inc. | Tissue marker for intracorporeal site identification |
USD716450S1 (en) | 2013-09-24 | 2014-10-28 | C. R. Bard, Inc. | Tissue marker for intracorporeal site identification |
USD715442S1 (en) | 2013-09-24 | 2014-10-14 | C. R. Bard, Inc. | Tissue marker for intracorporeal site identification |
US10368842B2 (en) | 2014-04-07 | 2019-08-06 | Bracco Suisse S.A. | Estimation of acoustic level in-situ with non-fundamental analysis |
US10449156B2 (en) | 2014-07-23 | 2019-10-22 | Universidad Andrés Bello | Controlled release system including a gas or volatile encapsulated in a polymeric support and a matrix system, a method of preparing the system, and their use |
US10500303B2 (en) | 2014-08-15 | 2019-12-10 | Tepha, Inc. | Self-retaining sutures of poly-4-hydroxybutyrate and copolymers thereof |
US10626521B2 (en) | 2014-12-11 | 2020-04-21 | Tepha, Inc. | Methods of manufacturing mesh sutures from poly-4-hydroxybutyrate and copolymers thereof |
WO2016094669A1 (en) | 2014-12-11 | 2016-06-16 | Tepha, Inc. | Methods of orienting multifilament yarn and monofilaments of poly-4-hydroxybutyrate and copolymers thereof |
CA2972423A1 (en) | 2014-12-31 | 2016-07-07 | Lantheus Medical Imaging, Inc. | Lipid-encapsulated gas microsphere compositions and related methods |
EP3386589B1 (en) | 2015-12-09 | 2022-02-09 | Koninklijke Philips N.V. | Interleaved beam pattern for sonothrombolysis and other vascular acoustic resonator mediated therapies |
CN108289654B (zh) | 2015-12-10 | 2021-03-30 | 博莱科瑞士股份有限公司 | 通过动态阈值化来检测固定化造影剂 |
CN108699130A (zh) | 2016-02-09 | 2018-10-23 | 博莱科瑞士股份有限公司 | 用于选择素靶向的重组嵌合蛋白 |
TWI740937B (zh) | 2016-05-04 | 2021-10-01 | 美商藍瑟斯醫學影像公司 | 用於製備超音波顯影劑之裝置及方法 |
US9789210B1 (en) | 2016-07-06 | 2017-10-17 | Lantheus Medical Imaging, Inc. | Methods for making ultrasound contrast agents |
WO2018160752A1 (en) | 2017-02-28 | 2018-09-07 | Children's Medical Center Corporation | Stimuli-responsive particles encapsulating a gas and methods of use |
US11866594B2 (en) | 2017-06-27 | 2024-01-09 | Lawrence Livermore National Security, Llc | Elastomeric shape memory polymer composites |
Family Cites Families (80)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3968203A (en) * | 1965-10-01 | 1976-07-06 | Jerome G. Spitzer | Aerosol astringent composition |
US3615972A (en) * | 1967-04-28 | 1971-10-26 | Dow Chemical Co | Expansible thermoplastic polymer particles containing volatile fluid foaming agent and method of foaming the same |
US3650831A (en) * | 1969-03-10 | 1972-03-21 | Armour Dial Inc | Method of cleaning surfaces |
US3900420A (en) * | 1970-05-18 | 1975-08-19 | Felix Sebba | Microgas emulsions and method of forming same |
US4027007A (en) * | 1970-12-09 | 1977-05-31 | Colgate-Palmolive Company | Antiperspirants formulated with borax |
US4089800A (en) * | 1975-04-04 | 1978-05-16 | Ppg Industries, Inc. | Method of preparing microcapsules |
GB1575343A (en) * | 1977-05-10 | 1980-09-17 | Ici Ltd | Method for preparing liposome compositions containing biologically active compounds |
CH624011A5 (zh) * | 1977-08-05 | 1981-07-15 | Battelle Memorial Institute | |
CH621479A5 (zh) * | 1977-08-05 | 1981-02-13 | Battelle Memorial Institute | |
US4235871A (en) * | 1978-02-24 | 1980-11-25 | Papahadjopoulos Demetrios P | Method of encapsulating biologically active materials in lipid vesicles |
US4192859A (en) * | 1978-09-29 | 1980-03-11 | E. R. Squibb & Sons, Inc. | Contrast media containing liposomes as carriers |
IL58965A (en) * | 1978-12-19 | 1982-08-31 | Mars Inc | Production of microcapsules |
US4276885A (en) * | 1979-05-04 | 1981-07-07 | Rasor Associates, Inc | Ultrasonic image enhancement |
US4265251A (en) * | 1979-06-28 | 1981-05-05 | Rasor Associates, Inc. | Method of determining pressure within liquid containing vessel |
US4316391A (en) * | 1979-11-13 | 1982-02-23 | Ultra Med, Inc. | Flow rate measurement |
US4442843A (en) * | 1980-11-17 | 1984-04-17 | Schering, Ag | Microbubble precursors and methods for their production and use |
US4681119A (en) * | 1980-11-17 | 1987-07-21 | Schering Aktiengesellschaft | Method of production and use of microbubble precursors |
US4657756A (en) * | 1980-11-17 | 1987-04-14 | Schering Aktiengesellschaft | Microbubble precursors and apparatus for their production and use |
US4675189A (en) * | 1980-11-18 | 1987-06-23 | Syntex (U.S.A.) Inc. | Microencapsulation of water soluble active polypeptides |
FR2504408B1 (fr) * | 1981-04-24 | 1986-02-14 | Couvreur Patrick | Procede de preparation de particules submicroscopiques, particules ainsi obtenues et compositions pharmaceutiques les contenant |
DE3141641A1 (de) * | 1981-10-16 | 1983-04-28 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Ultraschall-kontrastmittel und dessen herstellung |
US4511515A (en) * | 1983-06-28 | 1985-04-16 | Corning Glass Works | Method for making a volatile cerium diketonate compound |
US4718433A (en) * | 1983-01-27 | 1988-01-12 | Feinstein Steven B | Contrast agents for ultrasonic imaging |
US4572203A (en) * | 1983-01-27 | 1986-02-25 | Feinstein Steven B | Contact agents for ultrasonic imaging |
DE3313947A1 (de) * | 1983-04-15 | 1984-10-18 | Schering AG, 1000 Berlin und 4709 Bergkamen | Mikropartikel und gasblaeschen enthaltende ultraschall-kontrastmittel |
US5141738A (en) * | 1983-04-15 | 1992-08-25 | Schering Aktiengesellschaft | Ultrasonic contrast medium comprising gas bubbles and solid lipophilic surfactant-containing microparticles and use thereof |
DE3313946A1 (de) * | 1983-04-15 | 1984-10-18 | Schering AG, 1000 Berlin und 4709 Bergkamen | Mikropartikel und gasblaeschen enthaltende ultraschall-kontrastmittel |
US4900540A (en) * | 1983-06-20 | 1990-02-13 | Trustees Of The University Of Massachusetts | Lipisomes containing gas for ultrasound detection |
DE3324235A1 (de) * | 1983-07-01 | 1985-01-10 | Schering AG, 1000 Berlin und 4709 Bergkamen | Neue komplexbildner, komplexe und komplexsalze |
US5618514A (en) * | 1983-12-21 | 1997-04-08 | Nycomed Imaging As | Diagnostic and contrast agent |
CA1215922A (en) * | 1984-05-25 | 1986-12-30 | Connaught Laboratories Limited | Microencapsulation of living tissue and cells |
GB8504916D0 (en) * | 1985-02-26 | 1985-03-27 | Isc Chemicals Ltd | Emulsions of perfluorocarbons in aqueous media |
DE3529195A1 (de) * | 1985-08-14 | 1987-02-26 | Max Planck Gesellschaft | Kontrastmittel fuer ultraschalluntersuchungen und verfahren zu seiner herstellung |
CH667874A5 (fr) * | 1985-12-19 | 1988-11-15 | Battelle Memorial Institute | Polypeptide synthetique biodegradable et son utilisation pour la preparation de medicaments. |
US4927623A (en) * | 1986-01-14 | 1990-05-22 | Alliance Pharmaceutical Corp. | Dissolution of gas in a fluorocarbon liquid |
DE3637926C1 (de) * | 1986-11-05 | 1987-11-26 | Schering Ag | Ultraschall-Manometrieverfahren in einer Fluessigkeit mittels Mikroblaeschen |
FR2608942B1 (fr) * | 1986-12-31 | 1991-01-11 | Centre Nat Rech Scient | Procede de preparation de systemes colloidaux dispersibles d'une substance, sous forme de nanocapsules |
US5283067A (en) * | 1987-01-30 | 1994-02-01 | Ciba-Geigy Corporation | Parenteral suspensions |
US5089181A (en) * | 1987-02-24 | 1992-02-18 | Vestar, Inc. | Method of dehydrating vesicle preparations for long term storage |
CH672733A5 (zh) * | 1987-05-22 | 1989-12-29 | Bracco Ind Chimica Spa | |
DE3721721C1 (de) * | 1987-07-01 | 1988-06-09 | Hoechst Ag | Verfahren zur Umhuellung von Granulaten |
DE3741201A1 (de) * | 1987-12-02 | 1989-06-15 | Schering Ag | Ultraschallarbeitsverfahren und mittel zu dessen durchfuehrung |
IE61591B1 (en) * | 1987-12-29 | 1994-11-16 | Molecular Biosystems Inc | Concentrated stabilized microbubble-type ultrasonic imaging agent and method of production |
US4844882A (en) * | 1987-12-29 | 1989-07-04 | Molecular Biosystems, Inc. | Concentrated stabilized microbubble-type ultrasonic imaging agent |
US5425366A (en) * | 1988-02-05 | 1995-06-20 | Schering Aktiengesellschaft | Ultrasonic contrast agents for color Doppler imaging |
US5730954A (en) * | 1988-08-23 | 1998-03-24 | Schering Aktiengesellschaft | Preparation comprising cavitate- or clathrate-forming host/guest complexes as contrast agent |
US4957656A (en) * | 1988-09-14 | 1990-09-18 | Molecular Biosystems, Inc. | Continuous sonication method for preparing protein encapsulated microbubbles |
DE3934656A1 (de) * | 1989-10-13 | 1991-04-18 | Schering Ag | Verfahren zur herstellung von waessrigen dispersionen |
US5776429A (en) * | 1989-12-22 | 1998-07-07 | Imarx Pharmaceutical Corp. | Method of preparing gas-filled microspheres using a lyophilized lipids |
US5123414A (en) * | 1989-12-22 | 1992-06-23 | Unger Evan C | Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same |
US5228446A (en) * | 1989-12-22 | 1993-07-20 | Unger Evan C | Gas filled liposomes and their use as ultrasonic contrast agents |
US5088499A (en) * | 1989-12-22 | 1992-02-18 | Unger Evan C | Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same |
US5209720A (en) * | 1989-12-22 | 1993-05-11 | Unger Evan C | Methods for providing localized therapeutic heat to biological tissues and fluids using gas filled liposomes |
DE4004430A1 (de) * | 1990-02-09 | 1991-08-14 | Schering Ag | Aus polyaldehyden aufgebaute kontrastmittel |
US5556610A (en) * | 1992-01-24 | 1996-09-17 | Bracco Research S.A. | Gas mixtures useful as ultrasound contrast media, contrast agents containing the media and method |
IN172208B (zh) * | 1990-04-02 | 1993-05-01 | Sint Sa | |
US5445813A (en) * | 1992-11-02 | 1995-08-29 | Bracco International B.V. | Stable microbubble suspensions as enhancement agents for ultrasound echography |
US5578292A (en) * | 1991-11-20 | 1996-11-26 | Bracco International B.V. | Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof |
US5137928A (en) * | 1990-04-26 | 1992-08-11 | Hoechst Aktiengesellschaft | Ultrasonic contrast agents, processes for their preparation and the use thereof as diagnostic and therapeutic agents |
US5190982A (en) * | 1990-04-26 | 1993-03-02 | Hoechst Aktiengesellschaft | Ultrasonic contrast agents, processes for their preparation and the use thereof as diagnostic and therapeutic agents |
US5205287A (en) * | 1990-04-26 | 1993-04-27 | Hoechst Aktiengesellschaft | Ultrasonic contrast agents, processes for their preparation and the use thereof as diagnostic and therapeutic agents |
AU636481B2 (en) * | 1990-05-18 | 1993-04-29 | Bracco International B.V. | Polymeric gas or air filled microballoons usable as suspensions in liquid carriers for ultrasonic echography |
US5487390A (en) * | 1990-10-05 | 1996-01-30 | Massachusetts Institute Of Technology | Gas-filled polymeric microbubbles for ultrasound imaging |
US5149329A (en) * | 1990-12-12 | 1992-09-22 | Wayne State University | Surgical suture carrier and method for urinary bladder neck suspension |
DE4100470A1 (de) * | 1991-01-09 | 1992-07-16 | Byk Gulden Lomberg Chem Fab | Echokontrastmittel |
GB9106686D0 (en) * | 1991-03-28 | 1991-05-15 | Hafslund Nycomed As | Improvements in or relating to contrast agents |
GB9106673D0 (en) * | 1991-03-28 | 1991-05-15 | Hafslund Nycomed As | Improvements in or relating to contrast agents |
US5205290A (en) * | 1991-04-05 | 1993-04-27 | Unger Evan C | Low density microspheres and their use as contrast agents for computed tomography |
US5874062A (en) * | 1991-04-05 | 1999-02-23 | Imarx Pharmaceutical Corp. | Methods of computed tomography using perfluorocarbon gaseous filled microspheres as contrast agents |
US5147631A (en) * | 1991-04-30 | 1992-09-15 | Du Pont Merck Pharmaceutical Company | Porous inorganic ultrasound contrast agents |
US5364612A (en) * | 1991-05-06 | 1994-11-15 | Immunomedics, Inc. | Detection of cardiovascular lesions |
EP0593627A1 (en) * | 1991-07-05 | 1994-04-27 | The University Of Rochester | Ultrasmall non-aggregated porous particles entrapping gas-bubbles |
US5409688A (en) * | 1991-09-17 | 1995-04-25 | Sonus Pharmaceuticals, Inc. | Gaseous ultrasound contrast media |
GB9200388D0 (en) * | 1992-01-09 | 1992-02-26 | Nycomed As | Improvements in or relating to contrast agents |
IL104084A (en) * | 1992-01-24 | 1996-09-12 | Bracco Int Bv | Sustainable aqueous suspensions of pressure-resistant and gas-filled blisters, their preparation, and contrast agents containing them |
CA2148372A1 (en) * | 1992-11-02 | 1994-05-11 | Margaret A. Wheatley | Surfactant-stabilized microbubble mixtures, process for preparing and methods of using the same |
US5716597A (en) * | 1993-06-04 | 1998-02-10 | Molecular Biosystems, Inc. | Emulsions as contrast agents and method of use |
JP2905598B2 (ja) * | 1993-07-02 | 1999-06-14 | モレキュラー バイオシステムズ,インコーポレイテッド | 熱変性されたタンパク質からカプセル化されたマイクロスフェアを製造する方法 |
DE69434119T3 (de) * | 1993-07-30 | 2011-05-05 | Imcor Pharmaceutical Co., San Diego | Stabilisierte mikrogasbläschen-zusammensetzungen für echographie |
US5601085A (en) * | 1995-10-02 | 1997-02-11 | Nycomed Imaging As | Ultrasound imaging |
-
1991
- 1991-04-29 AU AU76144/91A patent/AU636481B2/en not_active Expired
- 1991-05-14 EP EP91810366A patent/EP0458745B2/en not_active Expired - Lifetime
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- 1991-05-16 PL PL91290271A patent/PL166827B1/pl not_active IP Right Cessation
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- 1991-05-17 RU SU4895423A patent/RU2110991C1/ru active
- 1991-05-17 CN CN91103411A patent/CN1055414C/zh not_active Expired - Lifetime
- 1991-05-17 JP JP3113100A patent/JP2897190B2/ja not_active Expired - Fee Related
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1994
- 1994-08-10 US US08/288,550 patent/US5711933A/en not_active Expired - Lifetime
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1997
- 1997-03-04 US US08/810,447 patent/US5863520A/en not_active Expired - Lifetime
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1064851C (zh) * | 1992-06-13 | 2001-04-25 | 舍林股份公司 | 微粒,其制造方法以及在诊断中的应用 |
CN115400230A (zh) * | 2022-09-03 | 2022-11-29 | 福建医科大学附属协和医院 | 一种新型的多功能胃肠超声造影剂 |
CN115400230B (zh) * | 2022-09-03 | 2023-12-22 | 福建医科大学附属协和医院 | 一种新型的多功能胃肠超声造影剂 |
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