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.

What is claimed is:  
     
         1 . A microparticle composition containing microparticles having diameters within the range of about 1 to 10 microns, an outer layer of a biologically compatible material and an inner layer comprising a biodegradable polymer.  
     
     
         2 . A composition according to    claim 1   , wherein at least a majority of said microparticles have diameters within said range.  
     
     
         3 . A composition according to    claim 1   , wherein said microparticles have hollow cores.  
     
     
         4 . A composition according to    claim 1   , wherein said microparticles comprise solid cores.  
     
     
         5 . A composition according to    claim 1   , wherein said biologically compatible material is blood compatible.  
     
     
         6 . A composition according to    claim 1   , wherein said outer layer comprises a chemically cross-linked amphiphilic biopolymer.  
     
     
         7 . A composition according to    claim 3   , wherein said cores contain a gas.  
     
     
         8 . A composition according to    claim 3   , wherein said cores contain a liquid.  
     
     
         9 . A composition according to    claim 1    or    7   , wherein said microparticles contain a drug.  
     
     
         10 . A composition comprising gas-filled microparticles of a size capable of passing the capillary circulation system of the body, wherein said microparticles are mechanically adjusted to resonate at a predetermined resonant frequency.  
     
     
         11 . A composition according to    claim 10   , wherein said microparticles are selected to resonate at said frequency by particle size selection.  
     
     
         12 . A composition according to    claim 11   , wherein the particle diameter is within the range of about 1 to 10 microns.  
     
     
         13 . A composition according to    claim 10   , wherein said resonant frequency is ≧2 MHz.  
     
     
         14 . A composition according to    claim 13   , wherein said frequency is ≧5 MHz.  
     
     
         15 . A composition according to    claim 10   , wherein the mechanical adjustment is made by selection of wall thickness.  
     
     
         16 . A composition according to    claim 10   , wherein the mechanical adjustment is made by selection of wall material for said microparticles.  
     
     
         17 . A composition according to    claim 10   , wherein the mechanical adjustment is made by selection of the extent of cross-linking of the wall material of said microparticles.  
     
     
         18 . A composition according to    claim 10   , wherein the mechanical adjustment is made by the adjustment of the internal pressure within said microparticles.  
     
     
         19 . A composition according to    claim 10   , wherein said resonant frequency is in the range of the transmitted frequencies of a diagnostic body imaging system.  
     
     
         20 . A composition according to    claim 10   , wherein said resonant frequency is a harmonic of a diagnostic body imaging system.  
     
     
         21 . A composition according to    claim 10   , wherein the microparticles are mechanically adjusted to remain stable when exposed to a threshold diagnostic imaging level of power of ultrasound irradiation, and are rupturable when exposed to an increase in said power.  
     
     
         22 . A composition according to    claim 10   , wherein the microparticles are mechanically adjusted to remain stable when exposed to a threshold diagnostic imaging level of power of ultrasound irradiation, and are rupturable when exposed to frequencies near the resonant frequency of the microparticles.  
     
     
         23 . A composition according to    claim 21    or    22   , wherein said microparticles contain a drug.  
     
     
         24 . A composition according to    claim 21    or    22   , wherein said microparticles contain blood soluble or insoluble gases.  
     
     
         25 . A composition comprising gas-filled microparticles of a size capable of passing the capillary circulation system of the body and comprising surface targeting moieties for binding to selected tissues.  
     
     
         26 . A composition comprising gas-filled microparticles of a size capable of passing the capillary circulation system of the body and comprising surface conjugated hydrophilic polymers.  
     
     
         27 . A composition according to    claim 26    wherein said hydrophilic polymers comprise polyethylene glycol.  
     
     
         28 . A composition according to    claim 26    comprising polyethylene glycol, polypropylene glycol, their derivatives, and combinations thereof.  
     
     
         29 . A composition according to    claim 25    comprising a chemically-charged outer surface.  
     
     
         30 . A composition according to    claim 28    wherein said outer surface is PEGylated.  
     
     
         31 . A composition according to    claim 29    wherein said outer surface is succinylated.  
     
     
         32 . A composition according to    claim 25   , wherein said targeting moieties are selected from the group consisting of antibodies, cell receptors, lectins, selecting, integrins, receptor targets, receptor analogues, and active fragments thereof.  
     
     
         33 . A composition according to    claim 1   , wherein said biologically compatible material comprise a protein.  
     
     
         34 . A composition according to    claim 1   , wherein said biologically compatible material comprises collagen, gelatin, albumin, globulin, or glycosaminoglycan.  
     
     
         35 . A composition according to    claim 1   , wherein said biologically compatible material comprises albumin.  
     
     
         36 . A composition according to    claim 1   , wherein said biologically compatible material comprises a biopolymer.  
     
     
         37 . A composition according to    claim 1   , wherein said biologically compatible material comprises gelatin.  
     
     
         38 . A composition according to    claim 1   , wherein said biodegradable polymer comprises a synthetic polymer.  
     
     
         39 . A composition according to    claim 38   , wherein said polymer comprises polycaprolactone.  
     
     
         40 . A composition according to    claim 38   , wherein said polymer comprises polylactide, polyglycolide, or copolymers thereof.  
     
     
         41 . A composition according to    claim 38   , wherein said polymer comprises copolymers of caprolactone with lactic or glycolic acid.  
     
     
         42 . A composition according to    claim 1   , wherein said inner layer is porous.  
     
     
         43 . A process for forming multilayer microparticles which are suspendable in a medium suitable for injection, comprising the steps: 
 a. forming a mixture of a first aqueous dispersion of a biologically compatible material and mixing with a second solution of a biodegradable polymer wherein said second solution comprises a relatively volatile water-immiscible solvent and a relatively non-volatile water-immiscible non-solvent for said polymer;    b. emulsifying said mixture from step (a) to form microdroplets having an interior containing said polymer solution and an outer layer comprising said biologically compatible material;    c. removing said relatively volatile solvent from said microparticles to form an inner layer of said polymer on said biopolymer;    d. drying said microparticles to remove said non-solvent and residual water.    
     
     
         44 . A process according to    claim 43   , wherein said step (c) said volatile solvent is removed by evaporation.  
     
     
         45 . A process according to    claim 43   , wherein said step (c) said volatile is removed by dilution.  
     
     
         46 . A process according to    claim 43    further comprising the step of cross-linking said outer layer.  
     
     
         47 . A process according to    claim 43   , wherein said step (d) is by freeze drying.  
     
     
         48 . A process according to    claim 43    further comprising the step of loading said microparticles after drying with a gas other than air.  
     
     
         49 . A process according to    claim 43    further comprising the step of microparticle size selection.  
     
     
         50 . A method of generating an image for echogenic inspection comprising the steps of: 
 a. introducing into a subject a composition of gas-filled microparticles capable of passing the capillary circulation system of said subject wherein said microparticles have an outer layer comprising a biologically compatible material and an inner layer comprising a biodegradable polymer;    b. subjecting said subject to suitable ultrasonic radiation;    c. detecting ultrasonic radiation reflected, transmitted, resonated and/or frequency and/or amplitude modulated by said microparticles in said subject.    
     
     
         51 . A method according to    claim 50   , wherein at least a majority of said microparticles have diameters within the range of about 1 to 10 microns.  
     
     
         52 . A method of delivering a pharmaceutically active agent to a subject comprising the steps of introducing into the subject a composition comprising microparticles capable of passing the capillary circulation of said subject, having an outer layer comprising a biologically compatible material, an inner layer comprising a biodegradable polymer and containing said pharmaceutically active agent.  
     
     
         53 . A method according to    claim 52   , wherein at least a majority of said microparticles has a diameter within the range of about 1 to 10 microns.  
     
     
         54 . A method according to    claim 52    further comprising the step of applying localized ultrasound energy to the target tissue or organ to release the pharmaceutically active agent at the specifically desired site.  
     
     
         55 . A method according to    claim 54    where the target organ is the heart.  
     
     
         56 . A method according to    claim 55    where the target tissue is a tumor.