Micellar drug delivery systems for hydrophobic drugs

Abstract

This invention provides compositions comprising a hydrophobic drug, a biocompatible micelle forming polymer, and a biocompatible low molecular weight, water-soluble polymer. Also provided are devices for injection of such compositions and for the use of such compositions to form hydrophobic drug containing micelles within the body of a patient.

1 . A micelle forming composition comprising: 
 (a) one or more hydrophobic drugs;    (b) one or more biocompatible, micelle forming polymers; and,    (c) one or more biocompatible, low molecular weight, water soluble polymers,    wherein the one or more water soluble polymers are present in an amount sufficient that the composition is injectable.    
     
     
         2 . The composition of  claim 1 , wherein the composition is substantially free of non-polymeric organic solvent.  
     
     
         3 . The composition of  claim 1  or  2 , wherein the one or more micelle forming polymers comprises a block copolymer.  
     
     
         4 . The composition of  claim 3 , wherein the block copolymer comprises a hydrophobic portion comprising a polymer block selected from the group consisting of: a polyester and a polyanhydride.  
     
     
         5 . The composition of  claim 4 , wherein the polymer block is selected from the group consisting of: polyglycolic acid, polybutrylactone, polyhydroxybutyrate, polylactic acid and polylacaprolactone.  
     
     
         6 . The composition of  claim 4  or  5 , wherein the hydrophobic portion is a polymer having a molecular weight of about 200 to about 500.  
     
     
         7 . The composition of any one of claims  3 - 6 , wherein the block copolymer comprises a hydrophilic portion that is a polyethylene oxide.  
     
     
         8 . The composition of  claim 7 , wherein the polyethylene oxide is selected from the group consisting of polyethylene glycol (PEG) and methoxypolyethylene glycol (MePEG).  
     
     
         9 . The composition of  claim 7  or  8 , wherein the hydrophilic portion is a polymer having a molecular weight of at least 750.  
     
     
         10 . The composition of  claim 9 , wherein the molecular weight is less than about 8000.  
     
     
         11 . The composition of  claim 9 , wherein the molecular weight is from about 1000 to about 5000.  
     
     
         12 . The composition of  claim 9 , wherein the molecular weight is from about 1000 to about 3000.  
     
     
         13 . The composition of  claim 9 , wherein the molecular weight is from about 1000 to about 2000.  
     
     
         14 . The composition of  claim 9 , wherein the molecular weight is about 2000.  
     
     
         15 . The composition of any one of claims  1 - 14 , wherein the water soluble polymer is selected from the group consisting of: a polyethylene oxide, low molecular weight polylactic acid, low molecular weight polyglycolic acid and a pluronic, wherein the water soluble polymer is a liquid or semi-solid at room temperature.  
     
     
         16 . The composition of any  claim 15 , wherein the water soluble polymer is a polyethylene oxide.  
     
     
         17 . The composition of  claim 16 , wherein the polyethylene oxide is selected from the group consisting of PEG and MePEG.  
     
     
         18 . The composition of  claim 16  or  17 , wherein the polyethylene oxide has a molecular weight of about 1000 or less.  
     
     
         19 . A device for injection of a substance into the body of a patient wherein the device comprises a composition of any one of claims  1 - 18  for injection.  
     
     
         20 . The device of  claim 19 , wherein the device is a syringe.  
     
     
         21 . The device of  claim 20 , wherein the syringe further comprises a needle cannula.  
     
     
         22 . A method of forming micelles comprising a hydrophobic drug wherein a composition according to any one of claims  1 - 17  is placed into an aqueous media.  
     
     
         23 . The method of  claim 22 , wherein said placing is by injection into a site in a patient's body and micelles are formed at the site.  
     
     
         24 . The use of a composition according to any one of claims  1 - 17  for administration to a patient to form hydrophobic drug containing micelles within the body of the patient.  
     
     
         25 . The use of  claim 24 , wherein the administration is by injection to a site within the patient's body and the micelles form at the site.  
     
     
         26 . A micelle forming composition comprising: 
 (a) one or more hydrophobic drugs;    (b) one or more biocompatible, micelle forming polymers; and,    (c) one or more biocompatible, low molecular weight, water soluble polymers,    wherein the micelle forming polymer is a block copolymer comprising a hydrophobic and a hydrophilic portion, the hydrophobic portion comprising a polymer block selected from the group consisting of: a polyester and a polyanhydride; and, the hydrophilic portion is a polyethylene oxide having a molecular weight of about 750 or more.    
     
     
         27 . The composition of  claim 26 , wherein the hydrophobic portion comprises a polymer block selected from the group consisting of: polyglycolic acid, polybutrylactone, polyhydroxybutyrate, polylactic acid and polylacaprolactone.  
     
     
         28 . The composition of  claim 26  or  27 , wherein the hydrophobic portion is a polymer having a molecular weight of about 200 to about 500.  
     
     
         29 . The composition of any one of claims  26 - 28 , wherein the water soluble polymer is a water soluble, low molecular weight, polylactic or polyglycolic acid; a water soluble pluronic polymer; or, a polyethylene oxide, wherein the water soluble polymer is a liquid or semi-solid at room temperature.  
     
     
         30 . The composition of  claim 29 , wherein the water soluble polymer is a polyethylene oxide having a molecular weight of about 1000 or less selected from the group consisting of PEG and MePEG.  
     
     
         31 . The composition of any one of claims  26 - 30 , wherein the amount of water soluble polymer in the composition is sufficient for the composition to be injectable.  
     
     
         32 . The composition of any one of claims  26 - 31 , wherein the composition is substantially free of organic solvent.  
     
     
         33 . A composition according to any one of claims  26 - 32 , wherein the composition is capable of forming micelles in aqueous medium at a critical micelle concentration (CMC) of about 500 μM or less.  
     
     
         34 . The composition according to  claim 33 , wherein the CMC is about 100 μM or less.  
     
     
         35 . The composition according to  claim 33 , wherein the CMC is about 50 μM or less.  
     
     
         36 . A method of forming micelles comprising a hydrophobic drug, wherein a composition according to any one of claims  26 - 35  is placed in an aqueous media whereby micelles comprising the hydrophobic drug are formed therein.  
     
     
         37 . The method of  claim 36 , wherein said placing is in vitro.  
     
     
         38 . The method of  claim 36 , wherein said placing is in vivo.  
     
     
         39 . The use of a composition according to any one of claims  26 - 35 , for forming hydrophobic drug containing micelles in vivo.  
     
     
         40 . The use of a composition according to any one of claims  26 - 35  for preparation of a medicament for administration to a patient.