Methods of administering liquid droplet aerosols of nanoparticulate drugs

Abstract

There is disclosed an aerosol comprising droplets of an aqueous dispersion of nanoparticles, said nanoparticles comprising insoluble therapeutic or diagnostic agent particles having a surface modifier on the surface thereof. There is also disclosed a method for making the aerosol and methods for treatment and diagnosis using the aerosol.

1 .- 9 . (canceled) 
     
     
         10 . A method of treating a respiratory illness in a mammal comprising the steps of:
 (a) providing an aerosol composition, wherein the composition comprises aqueous droplets having a particle size of less than about ten microns in diameter, wherein the aqueous droplets comprise:
 (i) water; 
 (ii) crystalline particles of a therapeutic agent which is poorly soluble in water, wherein the crystalline particles have a submicron particle size; and 
 (iii) at least one surface modifier adsorbed on the surface of the crystalline therapeutic agent particles; and 
   (b) administering the aerosol composition to the lungs of the mammal.   
     
     
         11 . The method of  claim 10 , wherein the crystalline particles of a poorly soluble therapeutic agent have an average particle size selected from the group of less than about 400 nm, less than about 300 nm, and less than about 100 nm. 
     
     
         12 . The method of  claim 10 , wherein the surface modifier is selected from the group consisting of gelatin, casein, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, tyloxapol, a polymer, a polyoxamine, dextran, lecithin, a dialkylester of sodium sulfosuccinic acid, sodium lauryl sulfate, an alkyl aryl polyether sulfonate, a polyoxyethylene sorbitan fatty acid ester, a mixture of sucrose stearate and sucrose distearate, C 18 H 37 CH 2 (CON 9 CH 3 )CH 2 (CHOH) 4 (CH2)H) 2 , a sulfated block copolymer of ethylene oxide and propylene oxide, and a triblock copolymer of the structure—(PEO) (PBO) (PEO)—having a molecular weight of about 3800 to about 5000. 
     
     
         13 . The method of  claim 10  comprising at least two surface modifiers. 
     
     
         14 . The method of  claim 10 , wherein:
 (a) the surface modifier is present at an amount selected from the group consisting of from about 0.1% to about 90% (w/w), from about 1% to about 75% (w/w), and from about 20% to about 60% (w/w), based upon the total weight of the combined therapeutic agent and surface modifier;   (b) the therapeutic agent is present at an amount of from about 0.1% to about 60% (w/w), or from about 5% to about 30% (w/w), based on the total weight of the therapeutic agent and surface modifier; or   (c) any combination thereof.   
     
     
         15 . The method of  claim 10 , wherein step (a) further comprises:
 (i) providing a suspension of the particles of the therapeutic agent; and   (ii) nebulizing the suspension by a jet nebulizer to form the aerosol.   
     
     
         16 . The method of  claim 10 , wherein step (a) further comprises:
 (i) providing a suspension of the particles of the therapeutic agent; and   (ii) nebulizing the suspension by an ultrasonic nebulizer to form the aerosol.   
     
     
         17 . The method of  claim 10 , wherein at least about 90%, at least about 95%, or at least about 99% of the therapeutic agent particles have a particle size of less than about 400 nm. 
     
     
         18 . The method of  claim 10 , wherein at least about 90%, at least about 95%, or at least about 99% of the therapeutic agent particles have a particle size of less than about 300 nm. 
     
     
         19 . The method of  claim 10 , wherein at least about 90%, at least about 95%, or at least about 99% of the therapeutic agent particles have a particle size of less than about 100 nm. 
     
     
         20 . The method of  claim 10 , wherein the respiratory illness is selected from the group consisting of asthma, emphysema, respiratory distress syndrome, chronic bronchitis, and cystic fibrosis. 
     
     
         21 . A method for diagnosing a mammal comprising:
 (a) providing an aerosol composition, wherein the composition comprises aqueous droplets having a particle size of less than about ten microns in diameter, wherein the aqueous droplets comprise:
 (i) water; 
 (ii) crystalline particles of a diagnostic imaging agent which is poorly soluble in water, wherein the crystalline particles have a submicron particle size; and 
 (iii) at least one surface modifier adsorbed on the surface of the crystalline diagnostic imaging agent particles; 
   (b) administering the aerosol composition to the lungs of the mammal; and   (c) imaging the diagnostic imaging agent in the lungs of the mammal.   
     
     
         22 . The method of  claim 21 , wherein the crystalline particles of a poorly soluble diagnostic imaging agent have an average particle size selected from the group of less than about 400 nm, less than about 300 nm, and less than about 100 nm. 
     
     
         23 . The method of  claim 21 , wherein the surface modifier is selected from the group consisting of gelatin, casein, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, tyloxapol, a polymer, a polyoxamine, dextran, lecithin, a dialkylester of sodium sulfosuccinic acid, sodium lauryl sulfate, an alkyl aryl polyether sulfonate, a polyoxyethylene sorbitan fatty acid ester, a mixture of sucrose stearate and sucrose distearate, C 18 H 37 CH 2 (CON 9 CH 3 )CH 2 (CHOH) 4 (CH2)H) 2 , a sulfated block copolymer of ethylene oxide and propylene oxide, and a triblock copolymer of the structure—(PEO) (PBO) (PEO)—having a molecular weight of about 3800 to about 5000. 
     
     
         24 . The method of  claim 21  comprising at least two surface modifiers. 
     
     
         25 . The method of  claim 21 , wherein:
 (a) the surface modifier is present at an amount selected from the group consisting of from about 0.1% to about 90% (w/w), from about 1% to about 75% (w/w), and from about 20% to about 60% (w/w), based upon the total weight of the combined diagnostic imaging agent and surface modifier;   (b) the diagnostic imaging agent is present at an amount of from about 0.1% to about 60% (w/w), or from about 5% to about 30% (w/w), based on the total weight of the diagnostic imaging agent and surface modifier; or   (c) any combination thereof.   
     
     
         26 . The method of  claim 21 , wherein step (a) further comprises:
 (i) providing a suspension of the particles of the diagnostic imaging agent; and   (ii) nebulizing the suspension by a jet nebulizer to form the aerosol.   
     
     
         27 . The method of  claim 21 , wherein step (a) further comprises:
 (i) providing a suspension of the particles of the diagnostic imaging agent; and   (ii) nebulizing the suspension by an ultrasonic nebulizer to form the aerosol.   
     
     
         28 . The method of  claim 21 , wherein at least about 90%, at least about 95%, or at least about 99% of the diagnostic imaging agent particles have a particle size of less than about 400 nm. 
     
     
         29 . The method of  claim 21 , wherein at least about 90%, at least about 95%, or at least about 99% of the diagnostic imaging agent particles have a particle size of less than about 300 nm. 
     
     
         30 . The method of  claim 21 , wherein at least about 90%, at least about 95%, or at least about 99% of the diagnostic imaging agent particles have a particle size of less than about 100 nm.