REDUCTION OF FLAKE-LIKE AGGREGATION IN NANOPARTICULATE ACTIVE AGENT COMPOSITIONS

• US 20100316725A1
• Filed: 05/26/2010
• Published: 12/16/2010
• Est. Priority Date: 05/27/2009
• Status: Abandoned Application

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: Elan Pharma International Limited (Perrigo Company PLC)
• Inventors: Liu, Wei, Snyder, Peter, Slifer, David M., RYDE, Niels P.
• Application Number:
  US12/788,196
• Publication Number:
  US 20100316725A1
• Time in Patent Office: Days
• US Class Current: 424/489
• CPC Class Codes: A61K 31/5415 ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/28 Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1688 resulting in pure drug agglomerate optionally containing up to 5% of excipient
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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.

Claims

1. A nanoparticulate injectable composition comprising:

(a) an active agent having an effective average particle size of less than about 2000 nm;

(b) at least one surface stabilizer adsorbed on the surface of the active agent; and

(c) a flake-like aggregation reducing agent.

2. The composition of claim 1, wherein the active agent is meloxicam.

3. The 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.

4. The composition of claim 1, wherein the composition contains no more than 6,000 active agent particles that are greater than 10 μ

m in size and no more than 600 active agent particles that are greater than 25 μ

m in size.

5. The composition of claim 1, wherein the composition contains no more than 3,000 active agent particles that are greater than 10 μ

m in size and no more than 300 active agent particles that are greater than 25 μ

m in size.

6. The composition of claim 1, wherein the composition has fewer than about 1000 active agent particles larger than 25 μ

m, fewer than about 900 active agent particles larger than 25 μ

m, fewer than about 800 active agent particles larger than 25 μ

m, fewer than about 700 active agent particles larger than 25 μ

m, fewer than about 600 active agent particles larger than 25 μ

m, fewer than about 500 active agent particles larger than 25 μ

m, fewer than about 400 active agent particles larger than 25 μ

m, fewer than about 300 active agent particles larger than 25 μ

m, fewer than about 250 active agent particles larger than 25 μ

m, fewer than about 200 active agent particles larger than 25 μ

m, fewer than about 150 active agent particles larger than 25 μ

m, fewer than about 100 active agent particles larger than 25 μ

m, or fewer than about 50 active agent particles larger than 25 μ

m.

7. The composition of claim 1, wherein the composition has fewer than about 10,000 active agent particles larger than 10 μ

m, fewer than about 9000 active agent particles larger than 10 μ

m, fewer than about 8000 active agent particles larger than 10 μ

m, fewer than about 7000 active agent particles larger than 10 μ

m, fewer than about 6000 active agent particles larger than 10 μ

m, fewer than about 5000 active agent particles larger than 10 μ

m, fewer than about 4000 active agent particles larger than 10 μ

m, fewer than about 3000 active agent particles larger than 10 μ

m, fewer than about 2000 active agent particles larger than 10 μ

m, or fewer than about 1000 active agent particles larger than 10 μ

m.

8. The 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.

9. The 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 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-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_12-15dimethyl hydroxyethyl ammonium chloride, C_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)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, C₁₂ trimethyl ammonium bromides, C₁₅ trimethyl ammonium bromides, C₁₇ trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyl dimethyl ammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, POLYQUAT 10™

, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, MIRAPOL™

, ALKAQUAT™

, alkyl pyridinium salts;

amines, amine salts, amine oxides, imide azolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guar.

10. The composition of claim 1, wherein the flake-like aggregation reducing agent is a buffer.

11. The composition of claim 10, wherein the buffer is 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.

12. The composition of claim 10, wherein the buffer results in the composition having a pH selected from the group consisting of above about 7, above about 8, and above about 9.

13. The composition of claim 1, wherein the flake-like aggregation reducing agent is a sugar.

14. The composition of claim 13, wherein the sugar is selected from the group consisting of sucrose, mannitol and dextrose.

15. The composition of claim 1, further comprising one or more pharmaceutically acceptable excipients, carriers, or a combination thereof.

16. The composition of claim 1, further comprising one or more flake-like aggregation reducing agents.

17. The composition of claim 1, further comprising one or more active agents.

18. The 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, any combination thereof.

19. A method of reducing the flake-like aggregates in a nanoparticulate composition, comprising:

(a) preparing a nanoparticulate dispersion of an 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 dispersion of step (a).

20. The method of claim 19, wherein the flake-like aggregation reducing agent is a buffer.

21. The method of claim 20, wherein the buffer is 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.

22. The method of claim 19, wherein the flake-like aggregation reducing agent is a sugar.

23. The composition of claim 22, wherein the sugar is selected from the group consisting of sucrose, mannitol and dextrose.