Claims for Patent: 9,974,746

Summary for Patent: 9,974,746

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:	15/130,255
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,974,746
Patent Claims:	1. An injectable nanoparticulate active agent composition produced by a method for reducing flake-like aggregates, wherein the method comprises: (a) preparing a dispersion of a nanoparticulate active agent and at least one surface stabilizer, wherein the dispersion comprises a nanoparticulate active agent having an effective average particle size of less than about 2000 nm, at least one surface stabilizer, and a liquid in which the active agent is poorly soluble; and (b) adding a flake-like aggregation reducing agent to the nanoparticulate active agent dispersion of step (a) to produce an injectable nanoparticulate active agent composition, wherein the flake-like aggregation reducing agent is selected from (i) a buffer selected from the group consisting of a phosphate buffer, an acetate buffer, a citrate buffer, a sodium phosphate buffer, a potassium phosphate buffer, and a sodium acetate buffer resulting in the composition having a pH above about 7.0, and (ii) a sugar selected from the group consisting of sucrose mannitol and dextrose, wherein the composition comprises no more than 6,000 active agent particles that are greater than 10 .mu.m in size and no more than 600 active agent particles that are greater than 25 .mu.m in size. 2. The nanoparticulate active agent composition of claim 1, wherein the flake-like aggregation reducing agent is a buffer selected from the group consisting of a phosphate buffer, an acetate buffer, a citrate buffer, a sodium phosphate buffer, a potassium phosphate buffer, and a sodium acetate buffer. 3. The nanoparticulate active agent composition of claim 1, wherein the flake-like aggregation reducing agent is a sugar selected from the group consisting of sucrose, mannitol and dextrose. 4. The nanoparticulate active agent composition of claim 1, wherein the active agent is meloxicam. 5. The nanoparticulate active agent composition of claim 1, wherein the active agent has an effective average particle size 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 150 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm. 6. The nanoparticulate active agent composition of claim 1, wherein the composition comprises no more than 3,000 active agent particles that are greater than 10 .mu.m in size and no more than 300 active agent particles that are greater than 25 .mu.m in size. 7. The nanoparticulate active agent composition of claim 1, wherein the composition has fewer than about 1000 active agent particles larger than 25 .mu.m, fewer than about 900 active agent particles larger than 25 .mu.m, fewer than about 800 active agent particles larger than 25 .mu.m, fewer than about 700 active agent particles larger than 25 .mu.m, fewer than about 600 active agent particles larger than 25 .mu.m, fewer than about 500 active agent particles larger than 25 .mu.m, fewer than about 400 active agent particles larger than 25 .mu.m, fewer than about 300 active agent particles larger than 25 .mu.m, fewer than about 250 active agent particles larger than 25 .mu.m, fewer than about 200 active agent particles larger than 25 .mu.m, fewer than about 150 active agent particles larger than 25 .mu.m, fewer than about 100 active agent particles larger than 25 .mu.m, or fewer than about 50 active agent particles larger than 25 .mu.m. 8. The nanoparticulate active agent composition of claim 1, wherein the composition has fewer than about 10,000 active agent particles larger than 10 .mu.m, fewer than about 9000 active agent particles larger than 10 .mu.m, fewer than about 8000 active agent particles larger than 10 .mu.m, fewer than about 7000 active agent particles larger than 10 .mu.m, fewer than about 6000 active agent particles larger than 10 .mu.m, fewer than about 5000 active agent particles larger than 10 .mu.m, fewer than about 4000 active agent particles larger than 10 .mu.m, fewer than about 3000 active agent particles larger than 10 .mu.m, fewer than about 2000 active agent particles larger than 10 .mu.m, or fewer than about 1000 active agent particles larger than 10 .mu.m. 9. The nanoparticulate active agent 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. 10. The nanoparticulate active agent 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 dodecylsulfate, 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, C.sub.12-15dimethyl hydroxyethyl ammonium chloride, C.sub.12-15dimethyl 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).sub.4 ammonium chloride, lauryl dimethyl (ethenoxy).sub.4 ammonium bromide, N-alkyl (C.sub.12-18)dimethylbenzyl ammonium chloride, N-alkyl (C.sub.14-18)dimethyl-benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C.sub.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.sub.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.sub.12 trimethyl ammonium bromides, C.sub.15 trimethyl ammonium bromides, C.sub.17 trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium 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. 11. The nanoparticulate active agent composition of claim 1, wherein the active agent is in a phase selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, and any combination thereof. 12. The nanoparticulate active agent composition of claim 1, wherein step (a) and step (b) of the method are performed simultaneously. 13. The nanoparticulate active agent composition of claim 1, wherein step (a) and step (b) of the method are performed sequentially. 14. The nanoparticulate active agent composition of claim 1, further comprising one or more excipients. 15. The nanoparticulate active agent composition of claim 14, wherein the one or more excipients are selected from the group consisting of binding agents, filling agents, lubricating agents, suspending agents, sweeteners, flavoring agents, preservatives, wetting agents and disintegrants.