Nanoparticulate beclomethasone dipropionate compositions

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 . A nanoparticulate composition comprising:
 (a) beclomethasone dipropionate particles having an average particle size of less than about 1000 nm; and   (b) at least one surface modifier.   
     
     
         2 . The composition of  claim 1 , wherein the effective average particle size of the beclomethasone dipropionate particles is less than about 1000 nm, meaning that at least 90% of the particles have a particle size of less than about 1000 nm. 
     
     
         3 . The composition of  claim 1 , wherein the effective average particle size of the beclomethasone dipropionate particles is less than about 400 nm, meaning that at least 90% of the particles have a particle size of less than about 400 nm. 
     
     
         4 . The composition of  claim 1 , wherein the effective average particle size of the beclomethasone dipropionate particles is less than about 300 nm, meaning that at least 90% of the particles have a particle size of less than about 300 nm. 
     
     
         5 . The composition of  claim 1 , wherein the effective average particle size of the beclomethasone dipropionate particles is less than about 100 nm, meaning that at least 90% of the particles have a particle size of less than about 100 nm. 
     
     
         6 . The composition of any of  claims 2 - 5 , wherein at least 95% of the beclomethasone dipropionate particles have a particle size less than the effective average. 
     
     
         7 . The composition of any of  claims 2 - 5 , wherein at least 99% of the beclomethasone dipropionate particles have a particle size less than the effective average. 
     
     
         8 . The composition of  claim 1 , wherein the surface modifier is present in an amount of from about 0.1% to about 90%, by weight, based on the total combined weight of the beclomethasone dipropionate and surface modifier. 
     
     
         9 . The composition of  claim 1 , wherein the surface modifier is present in an amount of from about 0.1% to about 75%, by weight, based on the total combined weight of the beclomethasone dipropionate and surface modifier. 
     
     
         10 . The composition of  claim 1 , wherein the surface modifier is present in an amount of from about 20% to about 60%, by weight, based on the total combined weight of the beclomethasone dipropionate and surface modifier. 
     
     
         11 . The composition of  claim 1 , formulated as an aqueous dispersion. 
     
     
         12 . The composition of  claim 1 , formulated as a dispersion in a liquid media selected from the group consisting of aqueous salt solutions, safflower oil, and a solvent. 
     
     
         13 . The composition of  claim 12 , wherein the solvent is selected from the group consisting of ethanol, t-butanol, hexane, and glycol. 
     
     
         14 . The composition of  claim 1 , formulated as a dry composition. 
     
     
         15 . The composition of  claim 1 , comprising two or more surface modifiers. 
     
     
         16 . The composition of  claim 1 , wherein the surface modifier is selected from the group consisting of nonionic and ionic surfactants. 
     
     
         17 . The composition of  claim 1 , wherein the surface modifier is selected from the group consisting of gelatin, casein, lecithin, 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 derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxy propylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, tyloxapol, poloxamers, poloxamines, dextran, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonate, mixtures of sucrose stearate and sucrose distearate, C 18 H 37 CH 2 C(O)N(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, p-isononylphenoxypoly(glycidol), dioctylsulfosuccinate (DOSS), glycerol, dodecyl trimethyl ammonium bromide, a charged phospholipid, the triblock copolymer B20-3800, and the triblock copolymer B20-5000. 
     
     
         18 . The composition of  claim 17 , wherein the surface modifier is selected from the group consisting of block copolymers of ethylene oxide and propylene oxide, tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine, a dioctyl ester of sodium sulfosuccinic acid, and dimyristoyl phophatidyl glycerol. 
     
     
         19 . The composition of  claim 1 , wherein the surface modifier is polyvinyl alcohol. 
     
     
         20 . A method of making a nanoparticulate beclomethasone dipropionate composition comprising contacting particles of beclomethasone dipropionate with at least one surface stabilizer for a time and under conditions to reduce the average particle size of the beclomethasone dipropionate particles to less than about 1000 nm. 
     
     
         21 . The method of  claim 20 , comprising:
 (a) dispersing particles of beclomethasone dipropionate in a liquid dispersion media in which the particles are poorly soluble; and   (b) applying mechanical means in the presence of grinding media to reduce the average particle size of beclomethasone dipropionate to less than about 1000 nm,   wherein the beclomethasone dipropionate particles are reduced in size in the presence of at least one surface modifier, or wherein at least one surface modifier is added to the liquid dispersion media following particle size reduction of beclomethasone dipropionate.   
     
     
         22 . The method of  claim 21 , wherein the mechanical means is a dispersion mill. 
     
     
         23 . The method of  claim 22 , wherein the dispersion mill is selected from the group consisting of a ball mill, an attritor mill, a vibratory mill, and a media mill. 
     
     
         24 . The method of  claim 20  or  21 , wherein the time required to reduce the particle size of beclomethasone dipropionate is from about 1 minute up to about 5 days. 
     
     
         25 . The method of  claim 20  or  21 , wherein the beclomethasone dipropionate particles are reduced in size at an ambient temperature. 
     
     
         26 . The method of  claim 20  or  21 , wherein the beclomethasone dipropionate particles are reduced in size at a less than about of less than about 40° C. 
     
     
         27 . The method of  claim 21 , wherein the grinding media is spherical in shape and has an average particle size of from about 0.1 mm to about 3 mm. 
     
     
         28 . The method of  claim 27 , wherein the grinding media has an average particle size of from 0.2 mm to about 2 mm. 
     
     
         29 . The method of  claim 28 , wherein the grinding media has an average particle size of from 0.25 mm to about 1 mm. 
     
     
         30 . The method of  claim 28 , wherein the grinding media has an average particle size of from 0.25 mm to about 1 mm. 
     
     
         31 . The method of  claim 21 , wherein the grinding media is spherical in shape and has an average particle size of less than about 75 microns. 
     
     
         32 . The method of  claim 21 , wherein the grinding media has a density greater than about 3 g/cm 3 . 
     
     
         33 . The method of  claim 21 , wherein the grinding media comprises a compound selected from the group consisting of zirconium oxide, zirconium silicate, glass, stainless steel, titania, alumina, 95% ZrO 2  stabilized with yttrium, and polymeric resin grinding media. 
     
     
         34 . The method of  claim 33 , wherein the grinding media comprises spherical particles consisting essentially of a polymeric resin. 
     
     
         35 . The method of  claim 33 , wherein the grinding media comprises spherical particles comprising a core which is coated with a polymeric resin. 
     
     
         36 . The method of  claim 33 , wherein the polymeric resin is selected from the group consisting of crosslinked polystyrenes, styrene copolymers, polycarbonates, polyacetals, vinyl chloride polymers, vinyl chloride copolymers, polyurethanes, polyamides, fluoropolymers, high density polyethylenes, polypropylenes, cellulose ethers, cellulose esters, polyhydroxymethacrylate, polyhydroxyethyl acrylate, and silicone containing polymers. 
     
     
         37 . The method of  claim 36 , wherein the polymeric resin is selected from the group consisting of polystyrene crosslinked with divinylbenzene, poly(tetrafluoroethylenes), cellulose acetate, and polysiloxanes. 
     
     
         38 . The method of  claim 33 , wherein the polymeric resin is biodegradable. 
     
     
         39 . The method of  claim 37 , wherein the biodegradable polymer is selected from the group consisting of poly(lactides), poly(glycolide) copolymers of lactides, copolymers of glycolide, polyanhydrides, poly(hydroxyethyl methacylate), poly(imino carbonates), poly(N-acylhydroxyproline)esters, poly(N-palmitoyl hydroxyproline) esters, ethylene-vinyl acetate copolymers, poly(orthoesters), poly(caprolactones), and poly(phosphazenes). 
     
     
         40 . The method of  claim 33 , wherein the polymeric resin has a density of from about 0.8 to about 3.0 g/cm 3 . 
     
     
         41 . The method of  claim 35 , wherein the core material of the grinding media is selected from the group consisting of zirconium oxides, zirconium silicate, glass, stainless steel, titania, alumina, and ferrite. 
     
     
         42 . The method of  claim 35 , wherein the core material of the grinding media has a density greater than about 2.5 g/cm 3 . 
     
     
         43 . The method of  claim 35 , wherein the thickness of the polymeric resin coating on the core is from about 1 to about 500 microns. 
     
     
         44 . The method of  claim 35 , wherein the thickness of the polymeric resin coating on the core is less than the diameter of the core. 
     
     
         45 . The method of  claim 21 , comprising:
 (a) continuously introducing particles of beclomethasone dipropionate and rigid grinding media into a milling chamber,   (b) contacting the beclomethasone dipropionate particles with the grinding media while in the chamber to reduce the particle size of the beclomethasone dipropionate particles;   (c) continuously removing beclomethasone dipropionate particles and the grinding media from the milling chamber, and   (d) separating the beclomethasone dipropionate particles from the grinding media.   
     
     
         46 . The method of  claim 21 , comprising recirculating the beclomethasone dipropionate particles and the grinding media through the milling chamber. 
     
     
         47 . The method of  claim 21 , comprising using grinding media having more than one particle size. 
     
     
         48 . The method of  claim 47 , comprising at least two sizes of grinding media:
 (a) having a mean particle size between about 1 and 300 mm; and   (b) having a mean particle size between about 300 and 1000 mm.   
     
     
         49 . The method of  claim 20 , wherein the effective average particle size of the beclomethasone dipropionate particles is selected from the group consisting of less than about 1000 nm, less than about 400 nm, less than about 300 nm, and less than about 100 nm, meaning that at least 90% of the particles have a particle size less than the effective average. 
     
     
         50 . The method of  claim 49 , wherein at least 95% of the beclomethasone dipropionate particles have a particle size less than the effective average. 
     
     
         51 . The method of  claim 49 , wherein at least 99% of the beclomethasone dipropionate particles have a particle size less than the effective average. 
     
     
         52 . The method of  claim 20 , wherein the surface modifier is present in an amount selected from the group consisting of from about 0.1% to about 90%, about 0.1% to about 75%, and about 20% to about 60%, by weight, based on the total combined weight of the beclomethasone dipropionate and surface modifier. 
     
     
         53 . The method of  claim 20 , utilizing two or more surface modifiers. 
     
     
         54 . The method of  claim 20 , wherein the surface modifier is selected from the group consisting of nonionic and ionic surfactants. 
     
     
         55 . The method of  claim 20 , wherein the surface modifier is selected from the group consisting of gelatin, casein, lecithin, 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 derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxy propylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, tyloxapol, poloxamers, poloxamines, dextran, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonate, mixtures of sucrose stearate and sucrose distearate, C 18 H 37 CH 2 C(O)N(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, p-isononylphenoxypoly(glycidol), dioctylsulfosuccinate (DOSS), glycerol, dodecyl trimethyl ammonium bromide, a charged phospholipid, the triblock copolymer B20-3800, and the triblock copolymer B20-5000. 
     
     
         56 . The method of  claim 55 , wherein the surface modifier is selected from the group consisting of block copolymers of ethylene oxide and propylene oxide, tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine, a dioctyl ester of sodium sulfosuccinic acid, and dimyristoyl phophatidyl glycerol. 
     
     
         57 . The method of  claim 20 , wherein the surface modifier is polyvinyl alcohol. 
     
     
         58 . A method of making a nanoparticulate beclomethasone dipropionate composition comprising
 (a) dissolving beclomethasone dipropionate in an aqueous base with stirring;   (b) adding the solution of beclomethasone dipropionate with stirring to a solution of one or more surface modifiers to form a clear solution;   (c) neutralizing the formulation from step (b) with stirring with an appropriate acid solution, and   (d) recovering particles of beclomethasone dipropionate having an average particle size of less than about 1000 nm.   
     
     
         59 . The method of  claim 58 , further comprising removing any formed salt by dialysis or diafiltration. 
     
     
         60 . The method of  claim 58 , further comprising concentrating the resulting beclomethasone dipropionate dispersion to a desired concentration of beclomethasone dipropionate. 
     
     
         61 . The method of  claim 58 , wherein step (c) is carried out in semicontinuous, continuous batch, or continuous methods at constant flow rates of the reacting components. 
     
     
         62 . The method of  claim 58 , further comprising dissolving a crystal growth modifier in step (a) with the beclomethasone dipropionate. 
     
     
         63 . The method of  claim 58 , wherein the effective average particle size of the beclomethasone dipropionate particles is selected from the group consisting of less than about 1000 nm, less than about 400 nm, less than about 300 nm, and less than about 100 nm, meaning that at least 90% of the particles have a particle size less than the effective average. 
     
     
         64 . The method of  claim 63 , wherein at least 95% of the beclomethasone dipropionate particles have a particle size less than the effective average. 
     
     
         65 . The method of  claim 63 , wherein at least 99% of the beclomethasone dipropionate particles have a particle size less than the effective average.