Nanoparticulate megestrol formulations

Abstract

The present invention is directed to nanoparticulate compositions comprising megestrol. The megestrol particles of the composition have an effective average particle size of less than about 2000 nm.

1 - 112 . (canceled) 
     
     
         113 . A megestrol formulation comprising:
 (a) a first composition comprising:
 particles of megestrol, megestrol acetate, or a salt thereof; and 
 (ii) at least one surface stabilizer adsorbed to the surface of said particles, wherein said particles have an effective average particle size of less than about 2000 nm, and 
   (b) at least one additional composition comprising megestrol, megestrol acetate, or a salt thereof, wherein said additional composition provides a different pharmacokinetic profile than said first composition.   
     
     
         114 . The formulation of  claim 113 , wherein the megestrol of the first composition is selected from the group consisting of a crystalline phase, an amorphous phase, and a semi-crystalline phase. 
     
     
         115 . The formulation of  claim 113 , wherein the effective average particle size of the nanoparticulate megestrol particles of the first composition is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm. 
     
     
         116 . The formulation of  claim 113 , wherein the formulation is formulated for administration selected from the group consisting of oral, pulmonary, rectal, opthalmic, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administration. 
     
     
         117 . The formulation of  claim 113 , wherein the formulation is formulated into a dosage form selected from the group consisting of liquid dispersions, gels, aerosols, ointments, creams, controlled release formulations, fast melt formulations, lyophilized formulations, tablets, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations. 
     
     
         118 . The formulation of  claim 113 , wherein the formulation further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof. 
     
     
         119 . The formulation of  claim 113 , wherein the megestrol of the first composition is present in an amount selected from the group consisting of from about 99.5% to about 0.001%, from about 95% to about 0.1%, and from about 90% to about 0.5%, by weight, based on the total combined weight of the megestrol and at least one surface stabilizer, not including other excipients. 
     
     
         120 . The formulation of  claim 113 , wherein the at least one surface stabilizer of the first composition is present in an amount selected from the group consisting of from about 0.5% to about 99.999%, from about 5.0% to about 95%, and from about 10% to about 99.5%, by weight, based on the total combined dry weight of the megestrol and at least one surface stabilizer, not including other excipients. 
     
     
         121 . The formulation of  claim 113 , wherein the first composition comprises at least two surface stabilizers, including a primary and a secondary surface stabilizer. 
     
     
         122 . The formulation of  claim 121 , wherein at least one surface stabilizer of the first composition is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, and random copolymers of vinyl acetate and vinyl pyrrolidone. 
     
     
         123 . The formulation of  claim 121 , wherein at least one surface stabilizer of the first composition is selected from the group consisting of sodium lauryl sulfate and dioctyl sodium sulfosuccinate. 
     
     
         124 . The formulation of  claim 121 , wherein at least one secondary surface stabilizer of the first composition is present in an amount selected from the group consisting of from about 0.01% to about 99%, from about 0.1% to about 95%, and from about 1% to about 90%, by weight, based on the total combined dry weight of the megestrol, at least one primary surface stabilizer, and at least one secondary surface stabilizer, not including other excipients. 
     
     
         125 . The formulation of  claim 113 , wherein the surface stabilizer of the first composition is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, an ionic surface stabilizer, and a zwitterionic surface stabilizer. 
     
     
         126 . The formulation of  claim 125 , wherein the at least one surface stabilizer of the first composition is selected from the group consisting of cetyl pyridinium chloride, gelatin, casein, phosphatides, 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 derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, 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, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonates, mixtures of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), 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; lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-vitamin A, PEG-vitamin E, and random copolymers of vinyl acetate and vinyl pyrrolidone. 
     
     
         127 . The formulation of  claim 125 , wherein the at least one cationic surface stabilizer of the first composition is selected from the group consisting of a polymer, a biopolymer, a polysaccharide, a cellulosic, an alginate, a nonpolymeric compound, and a phospholipid. 
     
     
         128 . The formulation of  claim 125 , wherein the surface stabilizer of the first composition is selected from the group consisting of polymethylmethacrylate trimethyl ammonium bromide, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethyl ammonium bromide, cationic lipids, sulfonium compounds, phosphonium compounds, quarternary ammonium compounds, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride, coconut trimethyl ammonium bromide, coconut methyl dihydroxyethyl ammonium chloride, coconut methyl dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride bromide, C 12-15 dimethyl hydroxyethyl ammonium chloride, C 12-15 dimethyl hydroxyethyl ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy) 4  ammonium chloride, lauryl dimethyl (ethenoxy) 4  ammonium bromide, N-alkyl (C 12-18 )dimethylbenzyl ammonium chloride, N-alkyl (C 14-18 )dimethyl-benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C 12-14 ) dimethyl 1-napthylmethyl ammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salts, dialkyl-dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(C 12-14 ) dimethyl 1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C 12  trimethyl ammonium bromides, C 15  trimethyl ammonium bromides, C 17  trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, polyquaternium 10, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, quaternized ammonium salt polymers, alkyl pyridinium salts; amines, amine salts, amine oxides, imide azolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, lysozyme, and cationic guar. 
     
     
         129 . The formulation of  claim 125 , wherein the first composition is bioadhesive. 
     
     
         130 . The formulation of  claim 113 , wherein the amount of megestrol in the first composition is selected from the group consisting of 3 percent by weight, 5 percent by weight, and 9 percent by weight. 
     
     
         131 . The formulation of  claim 130 , wherein the first composition additionally comprises hydroxypropyl methyl cellulose and dioctyl sodium sulfosuccinate as surface stabilizers. 
     
     
         132 . The formulation of  claim 113 , wherein the particles of megestrol, megestrol acetate, or a salt thereof in the at least one additional composition have an effective average particle size of greater than about 2 microns. 
     
     
         133 . The formulation of  claim 113 , wherein the at least one additional composition comprises solubilized megestrol, megestrol acetate, or a salt thereof. 
     
     
         134 . The formulation of  claim 113 , wherein:
 (a) the at least one additional composition comprises particles of megestrol, megestrol acetate, or a salt thereof, wherein the particles have an effective average particle size of less than about 2 microns; and   (b) the first composition and the at least one additional composition have different effective average particle sizes.   
     
     
         135 . The formulation of  claim 133 , wherein the at least one additional composition comprises at least one surface stabilizer. 
     
     
         136 . The formulation of  claim 134 , wherein the surface stabilizer of the at least one additional composition is the same as the surface stabilizer of the first composition. 
     
     
         137 . The formulation of  claim 134 , wherein the surface stabilizer of the at least one additional composition is different from the surface stabilizer of the first composition. 
     
     
         138 . The formulation of  claim 113 , wherein:
 (a) the first composition has a shorter T max  and a higher C max  than those of the at least one additional composition; and   (b) each composition has a different T max  and C max .   
     
     
         139 . The formulation of  claim 113 , wherein the first composition and the at least one additional composition are co-administered. 
     
     
         140 . The formulation of  claim 113 , wherein the first composition and the at least one additional composition are administered sequentially. 
     
     
         141 . The formulation of  claim 113 , wherein the first composition and the at least one additional composition are combined. 
     
     
         142 . The formulation of  claim 141 , wherein the formulation is a dual-release formulation. 
     
     
         143 . The formulation of  claim 113 , wherein the first composition and the at least one additional composition have different dosages.