Microparticles useful as ultrasonic contrast agents and for delivery of drugs into the bloodstream

Abstract

Microparticles are provided comprising a shell of an outer layer of a biologically compatible material and an inner layer of biodegradable polymer. The core of the microparticles contain a gas, liquid or solid for use in drug delivery or as a contrast agent for ultrasonic contrast imaging. The microparticles are capable of passing through the capillary systems of a subject.

1 . A composition comprising:
 a plurality of microparticles, a majority of which have diameters in the range of about 1 to 10 micrometers, each of which comprises a shell enclosing a gas-filled hollow core, said shell comprising an outer layer composed of a cross-linked amphiphilic protein and an inner layer composed of a biodegradable synthetic polymer; and   a sugar.   
   
   
       2 . The composition of  claim 1  in which the sugar is sucrose. 
   
   
       3 . The composition of  claim 1  which further comprises a surfactant. 
   
   
       4 . The composition of  claim 3  in which the surfactant is a poloxomer. 
   
   
       5 . The composition of  claim 1  which further comprises a water-soluble polymer. 
   
   
       6 . The composition of  claim 5  in which the water-soluble polymer is a medium molecular weight polyethylene glycol. 
   
   
       7 . The composition of  claim 1  in which the gas is nitrogen. 
   
   
       8 . The composition of  claim 1  in which the biodegradable polymer is selected from the group consisting of polycaprolactone, polylactide, polyglycolide, polylactide-polyglycolide copolymers, copolymers of lactides and lactones, delta-valerolactone, polyalkylcyanoacrylates, polyamides, polyhydroxybutyrates, polydioxanones, poly-beta-aminoketones, polyanhydrides, poly-(ortho)esters, polyglutamic acid, polyaspartic acid and esters of polyglutamic and polyaspartic acids. 
   
   
       9 . The composition of  claim 1  in which the cross-linked amphiphilic protein is a cross-linked human serum albumin. 
   
   
       10 . The composition of  claim 1  in which the cross-linked amphiphilic protein is cross-linked with glutaraldehyde. 
   
   
       11 . A composition comprising:
 a plurality of microparticles, a majority of which have diameters in the range of about 1 to 10 micrometers, each of which comprises a shell enclosing a gas-filled hollow core, said shell comprising an inner layer composed of polylactide and an outer layer composed of glutaraldehyde cross-linked human serum albumin;   glycine; and   polyethylene glycol 3350.   
   
   
       12 . The composition of  claim 11  which is in the form of a dry cake and/or powder. 
   
   
       13 . The composition of  claim 11  which is in the form of an aqueous suspension. 
   
   
       14 . The composition of  claim 1  in which the microparticles do not contain a drug. 
   
   
       15 . The composition of  claim 11  in which the microparticles do not contain a drug.