Dry powder aerosols of nanoparticulate drugs

Abstract

There invention discloses aqueous dispersions of nanoparticulate aerosol formulations, dry powder nanoparticulate aerosol formulation, propellant-based aerosol formulations, methods of using the formulations in aerosol delivery devices, and methods of making such formulations. The nanoparticles of the aqueous dispersions or dry powder formulations comprise insoluble drug particles having a surface modifier on the surface thereof.

1 .- 50 . (canceled) 
     
     
         51 . A propellant-based dry powder composition prepared by a process comprising the steps of:
 (a) obtaining a dry powder of a nanoparticulate drug composition, wherein the nanoparticulate drug composition comprises particles of a drug having an effective average particle size of less than or equal to about 2000 nm and a surface modifier adsorbed on the surface of the drug particles, wherein the dry powder of the nanoparticulate drug composition is obtained by:
 (i) forming an aqueous nanoparticulate dispersion of the drug and surface modifier; and 
 (ii) spray-drying or freeze-drying the nanoparticulate drug dispersion to form a dry powder of spherically shaped aggregates of the nanoparticulate drug and surface modifier; and 
   (b) dispersing the dry powder in at least one propellant.   
     
     
         52 . The composition prepared by the process of  claim 51 , wherein the aggregates have a mass median aerodynamic diameter of less than or equal to about 100 microns. 
     
     
         53 . The composition prepared by the process of  claim 51 , wherein the process further comprises adding a diluent to the nanoparticulate drug dispersion prior to spray-drying. 
     
     
         54 . The composition prepared by the process of  claim 53 , wherein the diluent is lactose or mannitol. 
     
     
         55 . The composition prepared by the process of  claim 51 , wherein the process further comprises adding a diluent to the nanoparticulate drug dispersion prior to freeze-drying. 
     
     
         56 . The composition prepared by the process of  claim 51 , wherein the diluent is lactose or mannitol. 
     
     
         57 . The composition prepared by the process of  claim 51 , wherein the propellant is selected from the group consisting of a chlorinated propellant, a non-chlorinated propellant, a hydrofluorinated alkane, and a halogenated hydrocarbon propellant having a low boiling point. 
     
     
         58 . The composition prepared by the process of  claim 51 , wherein the drug is selected from the group consisting of proteins, peptides, elastase inhibitors, analgesics, a drug for treating cystic-fibrosis, a drug for treating asthma, a drug for treating emphysema, a drug for treating respiratory distress syndrome, a drug for treating chronic bronchitis, a drug for treating chronic obstructive pulmonary disease, a drug for treating organ-transplant rejection a drug for treating tuberculosis and other infections of the lung, antifungal drugs, a drug for treating fungal infection, a drug for treating respiratory illness caused by acquired immune deficiency syndrome, an oncology drug, an anti-emetic, a cardiovascular agent, beclomethasone dipropionate, naproxen, triamcinolone acetonide, budesonide, and an anti-emetic. 
     
     
         59 . The composition prepared by the process of  claim 51 , wherein the surface modifier is selected from the group consisting of a nonionic surfactant and an ionic surfactant. 
     
     
         60 . The composition prepared by the process of  claim 51 , wherein the surface modifier is selected from the group consisting of tyloxapol, cetyl pyridinium chloride, gelatin, casein, lecithin, dextran, glycerol, 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, polyoxyethylene sorbitan fatty acid esters; polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, poloxamers, poloxamines, a charged phospholipid, dioctylsulfosuccinate (DOSS), dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether, sulfonate, a mixture of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), C 18 H 37 CH 2 (CON(CH 3 )—CH 2 (CHOH) 4 (CH 2 OH) 2 , decanoyl-N-methylglucamide, n-decyl β-D-glucopyranoside, n-decyl β-D-maltopyranoside, n-dodecyl β-D-glucopyranoside, n-dodecyl β-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside, n-heptyl β-D-thioglucoside, n-hexyl β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, octyl β-D-thioglucopyranoside. 
     
     
         61 . The composition prepared by the process of  claim 51 , wherein the drug has a concentration selected from the group consisting of about 10 mg/g or more, about 100 mg/g or more, about 200 mg/g or more, about 400 mg/g or more, about 600 mg/g or more, and about 900 mg/g. 
     
     
         62 . The composition prepared by the process of  claim 51 , wherein the aggregates have a mass median aerodynamic diameter selected from the group consisting of from about 5 μm to about 100 μm, from about 30 μm to about 60 μm, from about 2 μm to about 10 μm, from about 2 μm to about 6 μm, and about 2 μm.