Composition comprising gas-filled microcapsules for ultrasound mediated delivery

Abstract

Composition comprising gas filled microcapsules and a bioactive agent, useful for an ultrasound-mediated delivery of said bioactive agent. The microcapsules comprise a relatively stiff shell of polymeric or lipid material and have in particular a resistance to a mechanical index of at least 0.15, while the bioactive agent is substantially unbound to the shell of the microcapsules. The composition of the invention is particularly suitable for effectively delivering a genetic material into a cell, upon exposure of the composition to a level of acoustic pressure capable of destroying a portion of the microcapsules and releasing the gas contained therein.

1 . A composition comprising a bioactive agent and a plurality of gas-filled microcapsules having a polymeric and/or lipid shell, wherein said microcapsules have a resistance to a mechanical index (MI) of an applied ultrasound wave of at least 0.15 and said bioactive agent is substantially unbound to said shell. 
   
   
       2 . The composition according to  claim 1  wherein said microcapsules have a resistance to a mechanical index of at least 0.18. 
   
   
       3 . The composition according to any one of  claims 1  or  2  wherein the shell of said microcapsules comprises a biodegradable physiologically compatible polymer. 
   
   
       4 . The composition according to any one of  claims 1  or  2  wherein the shell of said microcapsules comprises a biodegradable water-insoluble lipid. 
   
   
       5 . The composition according to any one of  claims 1  or  2  wherein the shell of said microcapsules comprises a biodegradable water-insoluble lipid selected from mono-, di- or tri-glycerides, fatty acids, fatty acid esters, sterols and mixtures thereof. 
   
   
       6 . The composition according to any one of  claims 1  or  2  wherein the microcapsules have a stiffness Sp of at least 5 N/m. 
   
   
       7 . The composition according to any one of  claims 1  or  2  wherein the gas contained in the microcapsules comprises a perfluorinated gas. 
   
   
       8 . The composition according to any one of  claims 1  or  2  wherein said bioactive agent is a drug or a genetic material. 
   
   
       9 . The composition according to any one of  claims 1  or  2  wherein said bioactive agent is associated with a carrier. 
   
   
       10 . The composition according to  claim 9  wherein said bioactive agent and said carrier are associated in the form of a micelle or of a liposome. 
   
   
       11 . The composition according to  claim 9  wherein said carrier further comprises a targeting ligand. 
   
   
       12 . The composition according to any one of  claims 1  or  2  which further comprises a diagnostic agent. 
   
   
       13 . The composition according to any one of  claims 1  or  2  which further comprises adjuvants for enhancing the delivery of the bioactive agent into cells. 
   
   
       14 . (canceled) 
   
   
       15 . A method for delivering a bioactive agent into a cell which comprises:
 administering a composition comprising a bioactive agent and a plurality of gas filled microcapsules having a polymeric and/or lipid shell to a body part comprising said cell in a patient in need thereof, said microcapsules having a resistance to a mechanical index of at least 0.15 and said bioactive agent being substantially unbound to said shell; and   applying an ultrasound wave to said body part, said wave having an acoustic pressure capable of destroying a portion of said microcapsules, to effectively deliver said bioactive agent to said cell.   
   
   
       16 . The method of  claim 15  wherein the shell of said microcapsules comprises a biodegradable physiologically compatible polymer and/or a biodegradable water-insoluble lipid. 
   
   
       17 . The method of  claim 15  wherein the gas contained in the microcapsules comprises a perfluorinated gas. 
   
   
       18 . The method of  claim 15  wherein said bioactive agent is a drug or a genetic material. 
   
   
       19 . The method of  claim 15  wherein said bioactive agent is associated with a carrier. 
   
   
       20 . The method of  claim 19  wherein said carrier further comprises a targeting ligand. 
   
   
       21 . The method of  claim 15  wherein the applied ultrasound wave is in the frequency range of from about 20 kHz to less than about 50 MHz, with an energy level of from about 0.5 mW/cm 2  to about 10 W/cm 2 . 
   
   
       22 . The method of  claim 15  wherein the acoustic pressure of the applied ultrasound wave is of at least 200 kPa at a frequency of 1.15 MHz, or at least 300 kPa at a frequency of 2.25 MHz. 
   
   
       23 . A pharmaceutical kit for delivering a bioactive agent into a cell, comprising a suspension of a bioactive agent and suspension of a plurality of gas-filled microcapsules having a polymeric and/or lipid shell, said microcapsules having a resistance to a mechanical index (MI) of an applied ultrasound wave of at least 0.15 and said bioactive agent being substantially unbound to said shell. 
   
   
       24 . A pharmaceutical kit for delivering a bioactive agent into a cell, comprising a bioactive agent and a plurality of microcapsules having a polymeric and/or lipid shell in form a dry powder form wherein, upon reconstitution with a physiologically acceptable carrier in the presence of a gas, said kit provides a suspension of said bioactive agent and of a plurality of gas-filled microcapsules, said microcapsules having a resistance to a mechanical index (MI) of an applied ultrasound wave of at least 0.15 and said bioactive agent being substantially unbound to said shell. 
   
   
       25 . The pharmaceutical kit of  claim 24  wherein the bioactive agent and the microcapsules are stored as separate freeze-dried components. 
   
   
       26 . The pharmaceutical kit of any one of  claims 24  or  25  further comprising a physiologically acceptable aqueous carrier. 
   
   
       27 . The pharmaceutical kit of any one of  claims 23  or  24  wherein the shell of said microcapsules comprises a biodegradable physiologically compatible polymer and/or a biodegradable water-insoluble lipid. 
   
   
       28 . The pharmaceutical kit of any one of  claims 23  or  24  wherein the gas contained in the microcapsules comprises a perfluorinated gas. 
   
   
       29 . The pharmaceutical kit of any one of  claims 23  or  24  wherein said bioactive agent is a drug or a genetic material. 
   
   
       30 . The pharmaceutical kit of any one of  claims 23  or 24 wherein said bioactive agent is associated with a carrier. 
   
   
       31 . The pharmaceutical kit of any one of  claims 23  or  24  wherein said carrier further comprises a targeting ligand.