Claims for Patent: 11,253,478

Summary for Patent: 11,253,478

Title:	Reduction of flake-like aggregation in nanoparticulate active agent compositions
Abstract:	This invention is directed to reduction of flake-like aggregation in nanoparticulate compositions. Also encompassed by the invention are compositions comprising a nanoparticulate active agent, at least one surface stabilizer and a flake-like aggregation reducing agent, such as a buffer and a sugar. The nanoparticulate active agent compositions comprise particles of the active agent having an effective average particle size of less than about 2000 nm.
Inventor(s):	Ryde; Niels P. (Malvern, PA), Snyder; Peter (King of Prussia, PA), Liu; Wei (Exton, PA), Slifer; David M. (Downingtown, PA)
Assignee:	Alkermes Pharma Ireland Limited (Dublin, IE)
Application Number:	15/971,616
Patent Claims:	1. An injectable, nanoparticulate meloxicam composition consisting of: (a) about 2.5% to about 5% (w/w) of meloxicam particles having an effective average particle size of less than about 400 nm; (b) about 0.5% to about 1.625% (w/w) of at least one non-crosslinked surface stabilizer adsorbed on the surface of the meloxicam particles; (c) about 1.25% to about 20% (w/w) of a flake-like aggregation reducing agent; wherein the flake-like aggregation reducing agent consists of sucrose; and (d) water; wherein the injectable, nanoparticulate meloxicam composition comprises no more than 3,000 meloxicam particles that are greater than 10 .mu.m in size and no more than 300 active meloxicam particles that are greater than 25 .mu.m in size when measured in a nominal volume of 25 mL, and wherein meloxicam is the only active agent in the composition, and wherein the composition is stable and suitable for injection after storage for at least 3 months at 25.degree. C. 2. The nanoparticulate meloxicam composition of claim 1, wherein the meloxicam particles have an effective average particle size of less than about 300 nm. 3. The nanoparticulate meloxicam composition of claim 1, wherein the meloxicam particles have an effective average particle size of less than about 200 nm. 4. The nanoparticulate meloxicam composition of claim 1, wherein the surface stabilizer is selected from the group consisting of a non-ionic surface stabilizer, an ionic surface stabilizer, an anionic surface stabilizer, a cationic surface stabilizer, and a zwitterionic surface stabilizer. 5. The nanoparticulate meloxicam composition of claim 1, wherein the surface stabilizer 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 dodecyl sulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hypromellose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hypromellose 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 .beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside; n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside; n-heptyl .beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl .beta.-D-thioglucopyranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, random copolymers of vinyl acetate and vinyl pyrrolidone, a cationic polymer, a cationic biopolymer, a cationic polysaccharide, a cationic cellulosic, a cationic alginate, a cationic nonpolymeric compound, a cationic phospholipids, cationic lipids, polymethylmethacrylate trimethylammonium bromide, sulfonium compounds, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethyl ammonium bromide, 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, C12-15_dimethyl hydroxyethyl ammonium chloride, C12-15_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 (C12-18)_dimethylbenzyl ammonium chloride, N-alkyl (C14-18)_dimethyl-benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C12-14) 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_(C12-14) 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, C12 trimethyl ammonium bromides, C15 trimethyl ammonium bromides, C17 trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, polydiallyldimethylammonium chloride, dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, alkyl pyridinium salts; amines, amine salts, amine oxides, imide azolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guar. 6. The nanoparticulate meloxicam composition of claim 1, wherein the at least one surface stabilizer is polyvinylpyrrolidone. 7. The nanoparticulate meloxicam composition of claim 6, wherein the composition consists of about 0.5% (w/w) polyvinylpyrrolidone. 8. The nanoparticulate meloxicam composition of claim 1, wherein the at least one surface stabilizer is sodium deoxycholate. 9. The nanoparticulate meloxicam composition of claim 8, wherein the composition consists of about 0.25% (w/w) sodium deoxycholate as a surface stabilizer. 10. The nanoparticulate meloxicam composition of claim 1, wherein the composition consists of fewer than about 1,000 active agent particles that are greater than about 10 .mu.m in size. 11. The nanoparticulate meloxicam composition of claim 1, wherein the composition consists of: (a) about 0.5% (w/w) polyvinylpyrrolidone and about 0.25% (w/w) sodium deoxycholate as the surface stabilizer; and (b) about 5% (w/w) flake-like aggregation reducing agent; wherein the flake-like reducing agent comprises sucrose. 12. A method of administering the injectable, nanoparticulate meloxicam composition of claim 1 to a human comprising intravenously, intramuscularly, or subcutaneously injecting the composition into the human. 13. A method of administering the injectable, nanoparticulate meloxicam composition of claim 1 to a human comprising intravenously injecting the composition into the human. 14. The nanoparticulate meloxicam composition of claim 1, wherein the composition consists of: (a) about 0.75% (w/w) polyvinylpyrrolidone and about 0.25% (w/w) sodium deoxycholate as the surface stabilizer; and (b) about 5% (w/w) flake-like aggregation reducing agent; wherein the flake-like reducing agent comprises sucrose.