Acusphere, Inc.

Henry T Brush

Howard Bernstein

Julie A Straub

Richard E Wing

Charles C Church

Edith Mathiowitz

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.

Microencapsulated fluorinated gases for use as imaging agents

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.

Method for enhancing the echogenicity and decreasing the attenuation of

Method for making porous microparticles by spray drying

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.

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Somerville, MA, United States of America

Henry T Brush