Polymer lung surfactants

Abstract

Disclosed herein are fully synthetic polymer-based lung surfactant materials, for the first time, as next generation SRT. In vitro studies on these polymer lung surfactants show that the candidate materials effectively mimic the surface tension controlling properties of currently marketed natural lung surfactants. Further, the polymer lung surfactants have strong protein resistance, which makes this class of materials promising also for potential use in Acute Respiratory Distress Syndrome (ARDS) treatment.

1 . A method of treating a pulmonary disorder of a mammal caused by deficiency and/or deactivation of functional lung surfactant in said mammal, the method comprising: administering to said mammal a therapeutically effective amount of a polymer lung surfactant composition, wherein the polymer lung surfactant composition comprises a synthetic biocompatible amphiphilic block copolymer, wherein the hydrophilic (water soluble) block comprises a monomer selected from the group consisting of ethylene glycol (EG), ethylene oxide (EO), vinyl alcohol (VA), and oxazoline (OZ), wherein the hydrophobic (water-insoluble) block copolymer comprises a monomer selected from the group consisting of lactic acid or lactide (LA), glycolic acid or glycolide (GA), caprolactone (CL), methacrylate (MA), acrylate (Ac), butadiene (BD), and isoprene (IP), and wherein said polymer lung surfactant composition forms stable micelles in aqueous solution, wherein the micelles are used in uncomplexed form not loaded with any other therapeutic agents. 
     
     
         2 . The method of  claim 1 , wherein said pulmonary disorder is a neonatal respiratory distress syndrome (NRDS) or acute respiratory distress syndrome (ARDS) caused by deficiency and/or deactivation of functional lung surfactant. 
     
     
         3 . The method of  claim 1 , wherein the block copolymer lung surfactant composition comprises at least one polymerized hydrophobic block comprising tert-butyl methacrylate (PtBMA) and at least one polymerized hydrophilic block comprising ethylene glycol (PEG). 
     
     
         4 . The method of  claim 1 , wherein the block copolymer lung surfactant composition comprises at least one polymerized hydrophobic block comprising lactic acid or lactide (PLA) and at least one polymerized hydrophilic block comprising ethylene glycol (PEG). 
     
     
         5 . The method of  claim 1 , wherein the block copolymer lung surfactant composition comprises at least one polymerized hydrophobic block comprising butadiene (PBD) and at least one polymerized hydrophilic block comprising ethylene glycol (PEG). 
     
     
         6 . The method according to  claim 1 , wherein the therapeutically effective amount of the polymer lung surfactant composition is administered to the lungs of said mammal in the form of an aqueous solution via endotracheal instillation. 
     
     
         7 . The method according to  claim 1 , wherein the therapeutically effective amount of the polymer lung surfactant composition is administered to the lungs of said mammal in the form of liquid drop or lyophilized powder-type aerosols through application of continuous positive airway pressure or mechanical ventilation. 
     
     
         8 . The method according to  claim 7  wherein the therapeutically effective amount of the polymer lung surfactant composition is administered to the lung in combination with other therapeutics, wherein said other therapeutics are not loaded within or do not form complex with micelles formed by said polymer lung surfactant. 
     
     
         9 . A therapeutic lung surfactant formulation comprising a synthetic biocompatible or biodegradable amphiphilic block copolymer, wherein the hydrophilic (water-soluble) block comprises a monomer selected from the group consisting of ethylene glycol (EG), ethylene oxide (EO), vinyl alcohol (VA), and oxazoline (OZ), wherein the hydrophobic (water-insoluble) block comprises a monomer selected from the group consisting of styrene (PS), lactic acid or lactide (LA), glycolic acid or glycolide (GA), caprolactone (CL), methacrylate (MA), acrylate (Ac), butadiene (BD), and isoprene (IP), and wherein said polymer lung surfactant composition forms stable micelles in aqueous solution, wherein the micelles are in uncomplexed form not loaded with any other therapeutic agents. 
     
     
         10 . The polymer of  claim 9 , wherein said block copolymer comprises at least one polymerized hydrophobic block comprising styrene (PS) and at least one polymerized hydrophilic block comprising ethylene glycol (PEG). 
     
     
         11 . The polymer of  claim 9 , wherein said block copolymer comprises at least one polymerized hydrophobic block comprising tert-butyl methacrylate (PtBMA) and at least one polymerized hydrophilic block comprising ethylene glycol (PEG). 
     
     
         12 . The polymer of  claim 9 , wherein said block copolymer comprises at least one polymerized hydrophobic block comprising lactic acid or lactide (PLA) and at least one polymerized hydrophilic block comprising ethylene glycol (PEG). 
     
     
         13 . The polymer of  claim 9 , wherein said block copolymer comprises at least one polymerized hydrophobic block comprising butadiene (PBD) and at least one polymerized hydrophilic block comprising ethylene glycol (PEG). 
     
     
         14 . A bulk or aerosolized liquid composition used as a lung surfactant comprising about 0.02-40 wt. % of amphiphilic block copolymers dispersed in micelle form in an aqueous or aqueous saline solution at the time of administration to a patient, wherein the micelle is used in uncomplexed form not loaded with any other therapeutic agents. 
     
     
         15 . The composition of  claim 14 , wherein said amphiphilic polymer comprises a plurality of hydrophilic blocks having an average molecular weight in the range of about 50 Da-1000 kDa and a plurality of hydrophobic blocks having an average molecular weight in the range of about 50 Da-1000 kDa. 
     
     
         16 . The composition of  claim 14 , wherein said block copolymer comprises at least one polymerized hydrophobic block comprising styrene (PS) and at least one polymerized hydrophilic block comprising ethylene glycol (PEG). 
     
     
         17 . The composition of  claim 14 , wherein said block copolymer comprises at least one polymerized hydrophobic block comprising tert-butyl methacrylate (PtBMA) and at least one polymerized hydrophilic block comprising ethylene glycol (PEG). 
     
     
         18 . The composition of  claim 14 , wherein said block copolymer comprises at least one polymerized hydrophobic block comprising lactic acid or lactide (PLA) and at least one polymerized hydrophilic block comprising ethylene glycol (PEG). 
     
     
         19 . The composition of  claim 14 , wherein said block copolymer comprises at least one polymerized hydrophobic block comprising butadiene (PBD) and at least one polymerized hydrophilic block comprising ethylene glycol (PEG). 
     
     
         20 . The composition of  claim 14 , wherein said amphiphilic block copolymer comprises a polymerized hydrophilic block comprising a monomer selected from the group consisting of ethylene glycol (EG), ethylene oxide (EO), vinyl alcohol (VA), and oxazoline (OZ), and a polymerized hydrophobic block comprising a monomer selected from the group consisting of styrene (PS), lactic acid or lactide (LA), glycolic acid or glycolide (GA), caprolactone (CL), methacrylate (MA), acrylate (Ac), butadiene (BD), and isoprene (IP). 
     
     
         21 . A bulk or aerosolized liquid composition used as a polymer lung surfactant comprising, at the time of administration to a patient, about 0.02-40 wt. % amphiphilic block copolymers dispersed in micelle form in aqueous or aqueous saline solution, wherein the amphiphilic block copolymer compound comprises a hydrophilic block (e.g., PEG) having an average molecular weight in the range between about 50 Da and about 1000 kDa and a hydrophobic block (e.g., PS) having an average molecular weight in the range between about 50 Da and about 1000 kDa, wherein the micelle is used in uncomplexed form not loaded with any other therapeutic agents.