Injectable nanoparticulate olanzapine formulations

• US 7,910,577 B2
• Filed: 11/16/2005
• Issued: 03/22/2011
• Est. Priority Date: 11/16/2004
• Status: Active Grant

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: Elan Pharma International Limited (Perrigo Company PLC)
• Inventors: Jenkins, Scott, Liversidge, Gary, Liversidge, Elaine Merisko
• Primary Examiner(s): Eyler; Yvonne L
• Assistant Examiner(s): GREENE, IVAN A
• Application Number:
  US11/274,887
• Publication Number:
  US 20060154918A1
• Time in Patent Office: 1,952 Days
• Field of Search: None
• US Class Current: 514/220
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• 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 9/145 with organic compounds
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/148 with compounds of unknown constitution, e.g. material from plants or animals with oils, fats, waxes, shellac A61K9/145
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/34 Tobacco-abuse
• CPC Class Codes: Y10S 977/902 Specified use of nanostructure
• CPC Class Codes: Y10S 977/904 for medical, immunological, body treatment, or diagnosis
• CPC Class Codes: Y10S 977/905 Specially adapted for travel through blood circulatory system
• CPC Class Codes: Y10S 977/906 Drug delivery
• CPC Class Codes: Y10S 977/915 Therapeutic or pharmaceutical composition

Abstract

Described are injectable formulations of nanoparticulate olanzapine that produce a prolonged duration of action upon administration, and methods of making and using such formulations. The injectable formulations comprise nanoparticulate olanzapine.

Claims

1. An injectable nanoparticulate olanzapine composition comprising:

(a) olanzapine nanoparticles having an effective average particle size that results in a therapeutic efficacy of about one week or greater;

(b) at least one surface stabilizer; and

(c) a pharmaceutically acceptable carrier, wherein said effective average particle size is between about 300 nm and about 5000 nm.

2. The composition of claim 1, wherein the composition is administered via intramuscular or subcutaneous injection so as to form a depot.

3. The composition of claim 2, wherein the depot releases the olanzapine at therapeutic levels for a period of time from about two to about six weeks.

4. The composition of claim 2, wherein the depot releases the olanzapine at therapeutic levels for a period of time from about two to about twelve weeks.

5. The composition of claim 2, wherein the depot releases the olanzapine at therapeutic levels for a period of time selected from one week to about two weeks, from about one week to about three weeks, from about one week to about four weeks, from about one week to about five weeks, from about one week to about six weeks, from about one week to about seven weeks, from about one week to about eight weeks, from about one week to about nine weeks, from about one week to about ten weeks, from about one week to about eleven weeks, or from about one week to about twelve weeks.

6. The composition of claim 1, wherein the olanzapine is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, and mixtures thereof.

7. The composition of claim 1, wherein the effective average particle size of the olanzapine particles is about 4900 nm, about 4800 nm, about 4700 nm, about 4600 nm, about 4500 nm, about 4400 nm, about 4300 mm, about 4200 nm, about 4100 nm, about 4 microns, about 3900 nm, about 3800 nm, about 3700 nm, about 3600 nm, about 3500 nm, about 3400 mm, about 3300 nm, about 3200 nm, about 3100 nm, about 3 microns, about 2900 mm, about 2800 nm, about 2700 nm, about 2600 nm, about 2500 nm, about 2400 nm, about 2300 nm, about 2200 nm, about 2100 nm, about 2000 nm, about 1900 nm, about 1800 nm, about 1700 nm, about 1600 nm, about 1500 nm, about 1400 nm, about 1300 nm, about 1200 nm, about 1100 nm, about 1000 nm, about 900 nm, about 800 nm, about 700 nm, about 600 nm, about 500 nm, about 400 nm, or about 300 nm.

8. The composition of claim 1, wherein:

(a) the olanzapine is present in an amount from about 99.5% to about 0.001%, from about 95% to about 0.1%, from about 90% to about 0.5%, and from about 5.0% to about 50%, by weight, based on the total combined weight of the olanzapine and at least one surface stabilizer, not including other excipients; and

(b) the at least one surface stabilizer is present in an amount selected from the group consisting of from about 0.5% to about 99.999% by weight, from about 5.0% to about 99.9% by weight, from about 10% to about 99.5%, or from about 0.1 to about 50%, by weight, based on the total combined dry weight of the olanzapine and at least one surface stabilizer, not including other excipients.

9. The composition of claim 1, wherein the surface stabilizer is a non-ionic surface stabilizer, an anionic surface stabilizer, a cationic surface stabilizer, or a zwitterionic surface stabilizer.

10. The composition of claim 1, wherein at least one surface stabilizer is 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 oils, 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, hypromello se 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 phospho lipid, 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-glucopyrano side;

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-cholesterols, PEG-vitamin A, random copolymers of vinyl acetate and vinyl pyrrolidone, cationic polymers, cationic biopolymers, cationic polysaccharides, cationic cellulosics, cationic alginates, cationic nonpolymeric compounds, cationic phospho lipids, 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, C₁₂ 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 (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, Polyquaternium-11 (MIRAPOL™

), stearyl -dimethylbenzylammonium chloride (ALKAQUAT™

), alkyl pyridinium salts;

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

11. The composition of claim 1, comprising a surface stabilizer selected from the group consisting of a polysorbate, benzalkonium chloride, dextrose, and a combination thereof.

12. The composition of claim 1, further comprising at least one additional olanzapine composition having an effective average particle size which is different than the effective average particle size of the olanzapine composition of claim 1.

13. The composition of claim 1, additionally comprising one or more non-olanzapine active agents.

14. The composition of claim 13, wherein at least one non-olanzapine agent is an antidepressant.

15. The composition of claim 14, wherein the antidepressant is fluoxetine.

16. The composition of claim 1, wherein the composition is syringeable with a 23 gauge needle.

17. The composition of claim 1, wherein the effective average particle size of the olanzapine particles is less than 4900 nm, less than 4800 nm, less than 4700 nm, less than 4600 nm, less than 4500 nm, less than 4400 nm, less than 4300 mm, 4200 nm, less than 4100 nm, less than 4 microns, less than 3900 nm, less than 3800 nm, less than 3700 nm, less than 3600 nm, less than 3500 nm, less than 3400 mm, less than 3300 nm, less than 3200 nm, less than 3100 nm, less than 3 microns, less than 2900 mm, less than 2800 nm, less than 2700 nm, less than 2600 nm, less than 2500 nm, less than 2400 nm, less than 2300 nm, less than 2200 nm, less than 2100 nm, less than 2000 nm, less than 1900 nm, less than 1800 nm, less than 1700 nm, less than 1600 nm, less than 1500 nm, less than 1400 nm, less than 1300 nm, less than 1200 nm, less than 1100 nm, less than 1000 nm, less than 900 nm, less than 800 nm, less than 700 nm, less than 600 nm, less than 500 nm, or less than 400 nm.