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1. 发明授权

US6045777A Method for enhancing the echogenicity and decreasing the attenuation of microencapsulated gases 失效
标题翻译：增强微囊化气体的回声和减少衰减的方法
公开(公告)号：US6045777A
公开(公告)日：2000-04-04
申请号：US885933
申请日：1997-06-30
申请人： Charles C. Church , Howard Bernstein , Julie Ann Straub , Henry T. Brush
发明人： Charles C. Church , Howard Bernstein , Julie Ann Straub , Henry T. Brush
IPC分类号： A61K49/00 , A61B8/00 , A61K49/22 , A61K49/04 , A61B8/14
CPC分类号： A61B8/481 , A61K49/223
摘要： It has been discovered microparticles formed from natural or synthetic polymer with thicker walls have significantly enhanced echogenicity as compared with microparticles having thinner walls. The effect of wall thickness has been determined experimentally as well as inserted into a formula for use in predicting the optimum conditions. In the preferred embodiment, the polymers are synthetic biodegradable polymers and the wall thickness is between about 100 and 660 nm, although wall thicknesses from about 20 nm to in excess of 500 nm can be used. The microparticles are manufactured with a diameter suitable for the targeted tissue to be imaged, for example, with a diameter of between 0.5 and 8 microns for intravascular administration, and a diameter of between 0.5 and 5 mm for oral administration for imaging of the gastrointestinal tract or other lumens. Preferred polymers are polyhydroxy acids such as polylactic acid-co-glycolic acid, polylactide or polyglycolide, most preferably conjugated to polyethylene glycol or other materials inhibiting uptake by the reticuloendothelial system (RES). The microspheres may be used in a variety of ultrasound imaging applications including cardiology applications, blood perfusion applications as well as for organ and peripheral vein imaging.
摘要翻译：与具有较薄壁的微粒相比，发现由具有较厚壁的天然或合成聚合物形成的微粒具有显着增强的回声性。实验确定了壁厚的影响，并将其插入到用于预测最佳条件的公式中。在优选的实施方案中，聚合物是合成的可生物降解聚合物，并且壁厚度在约100至660nm之间，尽管可以使用约20nm至超过500nm的壁厚。制造具有适于待成像的目标组织的直径的微粒，例如，用于血管内施用的直径为0.5至8微米，并且用于口服给药以用于胃肠道成像的直径为0.5至5毫米或其他流明。优选的聚合物是聚羟酸，例如聚乳酸 - 共 - 乙醇酸，聚丙交酯或聚乙交酯，最优选与聚乙二醇缀合或抑制网状内皮系统（RES）吸收的其它物质。微球可以用于各种超声成像应用，包括心脏应用，血液灌注应用以及器官和外周静脉成像。

2. 发明授权

US5837221A Polymer-lipid microencapsulated gases for use as imaging agents 失效
标题翻译：用作成像剂的聚合物 - 脂质微胶囊化气体
公开(公告)号：US5837221A
公开(公告)日：1998-11-17
申请号：US681710
申请日：1996-07-29
申请人： Howard Bernstein , Julie Ann Straub , Henry T. Brush , Charles C. Church
发明人： Howard Bernstein , Julie Ann Straub , Henry T. Brush , Charles C. Church
IPC分类号： A61K49/00 , A61K49/22 , C08J3/20 , A61K49/04 , A61K9/14
CPC分类号： A61K49/0002 , A61K49/0004 , A61K49/223
摘要： It has been discovered that the incorporation of gases, especially fluorinated gases such as perfluorocarbons, into microparticles formed from the combination of a natural or synthetic polymer and lipid have significantly enhanced echogenicity as compared with microparticles not including the lipid. Compounds other than lipids which are hydrophobic and limit the penetration and/or uptake of water into the microparticles can also be incorporated into the microparticles to enhance echogenicity. In the preferred embodiment, the polymers are synthetic biodegradable polymers. The microparticles are manufactured with a diameter suitable for the targeted tissue to be imaged, for example, with a diameter of between 0.5 and 8 microns for intravascular administration, and a diameter of between 0.5 and 5 mm for oral administration for imaging of the gastrointestinal tract or other lumens. Preferred polymers are polyhydroxy acids such as polylactic acid-co-glycolic acid, most preferably conjugated to polyethylene glycol or other materials inhibiting uptake by the reticuloendothelial system (RES). The most preferred lipids are phospholipids, preferably dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), diarachidoylphosphatidylcholine (DAPC), dibehenoylphosphatidylcholine (DBPC), ditricosanoylphosphatidylcholine, dilignoceroylphatidylcholine (DLPC), incorporated at a ratio of between 0.01-30 (w lipid/w polymer), most preferably between 0.1-10 (w lipid/w polymer). Microparticles for imaging using other detectable agents can be similarly manufactured.
摘要翻译：已经发现，与不包括脂质的微粒相比，将天然或合成聚合物和脂质的组合形成的气体，特别是氟化气体（例如全氟化碳）并入微型颗粒中显着增强了回声反应性。疏水性的脂质以外的化合物也限制在微粒中的渗透和/或吸收也可以并入微粒中以增强回声性。在优选的实施方案中，聚合物是合成的可生物降解的聚合物。制造具有适于待成像的目标组织的直径的微粒，例如直径为0.5至8微米，用于血管内施用，并且用于口服给药的直径在0.5至5mm之间以用于胃肠道成像或其他流明。优选的聚合物是聚羟基酸，例如聚乳酸 - 共 - 乙醇酸，最优选与聚乙二醇缀合或抑制网状内皮系统（RES）摄取的其它物质。最优选的脂质是磷脂，优选二棕榈酰磷脂酰胆碱（DPPC），二硬脂酰磷脂酰胆碱（DSPC），二酰氨基磷脂酰胆碱（DAPC），二苯甲酰磷脂酰胆碱（DBPC），二硫代酰基磷脂酰胆碱，二烯酰基脂肪酰胆碱（DLPC），其比例为0.01-30（w脂质/ ），最优选0.1-10（w脂/ w聚合物）。可以类似地制造用于使用其它可检测试剂成像的微粒。

3. 发明授权

US6132699A Microencapsulated fluorinated gases for use as imaging agents 有权
标题翻译：微胶囊化氟化气体用作成像剂
公开(公告)号：US6132699A
公开(公告)日：2000-10-17
申请号：US158295
申请日：1998-09-22
申请人： Howard Bernstein , Julie Ann Straub , Henry T. Brush , Richard E. Wing
发明人： Howard Bernstein , Julie Ann Straub , Henry T. Brush , Richard E. Wing
IPC分类号： A61K47/06 , A61B8/00 , A61K49/00 , A61K49/22 , A61B8/13
CPC分类号： A61B8/481 , A61K49/223
摘要： It has been discovered that the incorporation of fluorinated gases, especially a perfluorocarbon such as octafluoropropane, into synthetic polymeric microparticles, significantly enhances echogenicity as compared with microparticles having air incorporated therein. The microencapsulated perfluorocarbon is manufactured with a diameter suitable for the targeted tissue to be imaged, for example, for intravenous or oral administration. In one embodiment, bioadhesive microparticles are formed for enhanced imaging of mucosal surfaces.
摘要翻译：已经发现，与合并有空气的微粒相比，将氟化气体，特别是全氟化碳如八氟丙烷掺入到合成的聚合物微粒中显着增强回波反应性。制造微胶囊化全氟化碳，其直径适用于待成像的目标组织，例如用于静脉内或口服给药。在一个实施方案中，形成生物粘附微粒用于增强粘膜表面的成像。

4. 发明授权

US5853698A Method for making porous microparticles by spray drying 失效
标题翻译：通过喷雾干燥制备多孔微粒的方法
公开(公告)号：US5853698A
公开(公告)日：1998-12-29
申请号：US745676
申请日：1996-11-08
申请人： Julie Ann Straub , Edith Mathiowitz , Howard Bernstein , Henry T. Brush , Richard E. Wing
发明人： Julie Ann Straub , Edith Mathiowitz , Howard Bernstein , Henry T. Brush , Richard E. Wing
IPC分类号： A61B8/00 , A61K49/22 , A61B8/13
CPC分类号： A61B8/481 , A61K49/223
摘要： It has been discovered that the incorporation of fluorinated gases, especially a perfluorocarbon such as octafluoropropane, into synthetic polymeric microparticles, significantly enhances echogenicity as compared with microparticles having air incorporated therein. The microencapsulated perfluorocarbon is manufactured with a diameter suitable for the targeted tissue to be imaged, for example, for intravenous or oral administration. In one embodiment, bioadhesive microparticles are formed for enhanced imaging of mucosal surfaces.
摘要翻译：已经发现，与合并有空气的微粒相比，将氟化气体，特别是全氟化碳如八氟丙烷掺入到合成的聚合物微粒中显着增强回波反应性。制造微胶囊化全氟化碳，其直径适用于待成像的目标组织，例如用于静脉内或口服给药。在一个实施方案中，形成生物粘附微粒用于增强粘膜表面的成像。

5. 发明授权

US5611344A Microencapsulated fluorinated gases for use as imaging agents 失效
标题翻译：微胶囊化氟化气体用作成像剂
公开(公告)号：US5611344A
公开(公告)日：1997-03-18
申请号：US611248
申请日：1996-03-05
申请人： Howard Bernstein , Julie A. Straub , Henry T. Brush , Richard E. Wing
发明人： Howard Bernstein , Julie A. Straub , Henry T. Brush , Richard E. Wing
IPC分类号： A61B8/00 , A61K49/22
CPC分类号： A61B8/481 , A61K49/223
摘要： It has been discovered that the incorporation of fluorinated gases, especially a perfluorocarbon such as octafluoropropane, into synthetic polymeric microparticles, significantly enhances echogenicity as compared with microparticles having air incorporated therein. The microencapsulated perfluorocarbon is manufactured with a diameter suitable for the targeted tissue to be imaged, for example, for intravenous or oral administration. In one embodiment, bioadhesive microparticles are formed for enhanced imaging of mucosal surfaces.
摘要翻译：已经发现，与合并有空气的微粒相比，将氟化气体，特别是全氟化碳如八氟丙烷掺入到合成的聚合物微粒中显着增强回波反应性。制造微胶囊化全氟化碳，其直径适用于待成像的目标组织，例如用于静脉内或口服给药。在一个实施方案中，形成生物粘附微粒用于增强粘膜表面的成像。

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