Nanoparticulate aripiprazole formulations

• US 20070148100A1
• Filed: 09/13/2006
• Published: 06/28/2007
• Est. Priority Date: 09/15/2005
• Status: Abandoned Application

• Current Assignee: Otsuka Pharmaceutical Company Limited (Otsuka Holdings Company Limited)
• Original Assignee: Elan Pharma International Limited (Perrigo Company PLC)
• Inventors: Jenkins, Scott
• Application Number:
  US11/520,058
• Publication Number:
  US 20070148100A1
• Time in Patent Office: Days
• US Class Current: 424/46
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• 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 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants

Abstract

The present invention is directed to compositions and methods comprising nanoparticulate aripiprazole, or salts or derivatives thereof, having improved bioavailability, faster rates of absorption and a faster onset of therapeutic effect. The nanoparticulate aripiprazole compositions are proposed to have an average effective particle size of less than about 2000 nm, and may be useful for the treatment of diseases and disorders of the central nervous system, including mental diseases and disorders.

Claims

1. A stable nanoparticulate aripiprazole, or salt or derivative thereof, composition comprising:

(a) particles of aripiprazole having an average effective particle size of less than about 2000 nm; and

(b) at least one surface stabilizer.

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

3. The composition of claim 1, wherein the effective average particle size of the aripiprazole particles 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.

4. The composition of claim 1, wherein the composition is formulated:

(a) for administration selected from the group consisting of parenteral, oral, pulmonary, intravenous, rectal, ophthalmic, colonic, intracistemal, intravaginal, intraperitoneal, ocular, otic, local, buccal, nasal, bioadhesive and topical administration;

(b) into a dosage form selected from the group consisting of liquid dispersions, gels, aerosols, ointments, creams, lyophilized formulations, tablets, capsules;

(c) into a dosage form selected from the group consisting of controlled release formulations, fast melt formulations, delayed release formulations, extended release formulations, pulsatile release formulations, mixed immediate release formulations, controlled release formulations;

or

(d) any combination of (a), (b), and (c).

5. The composition of claim 1, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers or a combination thereof.

6. The composition of claim 1, wherein

(a) the amount of aripiprazole is 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 aripiprazole and at least one surface stabilizer, not including other excipients;

(b) 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, and from about 10% to about 99.5% by weight, based on the total combined dry weight of aripiprazole and at least one surface stabilizer, not including other excipients;

or

(c) a combination of (a) and (b).

7. The composition of claim 1, further comprising at least one primary surface stabilizer and at least one secondary surface stabilizer.

8. The composition of claim 1, wherein the surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, a non-ionic surface stabilizer, and an ionic surface stabilizer.

9. The composition of claim 1, wherein at least one 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 (dioctyl sodium sulfosuccinate), dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonates, mixtures of sucrose stearate and sucrose distearate, C₁₈H₃₇CH₂C(O)N(CH₃)—

CH₂(CHOH)₄(CH₂OH)₂, 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

-Dthioglucoside;

n-hexyl β

-Dglucopyranoside;

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, PEG-vitamin E, lysozyme, 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, 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, alkyldimethylammonium 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 at least one surface stabilizer is selected from the group consisting of povidone, povidone polymer, Plasdone®

, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyvinyl pyrrolidone polymers, high molecular weight polyoxyalkylene ethers, Pluronic®

, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol phospholipids, dioxycholic acid, dioctylsulfosuccinate, sodium laurel sulphate, triblock copolymer surface modifiers such as B20-5000® and

B20-5000-sulfonated, tyloxapol, and lecithin.

11. The composition of claim 1 wherein the composition is formulated for subcutaneous or intramuscular injection.

12. The composition of claim 11, wherein the composition is formulated so as to form a depot upon injection.

13. The composition of claim 1, wherein the pharmacokinetic profile of said composition is not significantly affected by the fed or fasted state of a subject ingesting said composition.

14. The composition of claim 1, wherein the composition does not produce significantly different absorption levels when administered under fed as compared to fasting conditions.

15. The composition of claim 14, wherein the difference in absorption of the active agent composition of the invention, when administered in the fed versus the fasted state, is selected from the group consisting of less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, and less than about 3%.

16. The composition of claim 1, wherein administration of the composition to a subject in a fasted state is bioequivalent to administration of said composition to a subject in a fed state.

17. The composition of claim 16, wherein “

bioequivalency”

is established by;

(a) a 90% Confidence Interval of between 0.80 and 1.25 for both C_max and AUC;

or

(b) a 90% Confidence Interval of between 0.80 and 1.25 for AUC and a 90% Confidence Interval of between 0.70 to 1.43 for C_max.

18. The composition of claim 1, wherein:

(a) the T_max of the aripiprazole, when assayed in the plasma of a mammalian subject following administration, is less than the T_max for a non-nanoparticulate composition of the same aripiprazole, administered at the same dosage;

(b) the C_max of the aripiprazole, when assayed in the plasma of a mammalian subject following administration, is greater than the C_max for a non-nanoparticulate composition of the same aripiprazole, administered at the same dosage;

(c) the AUC of the aripiprazole, when assayed in the plasma of a mammalian subject following administration, is greater than the AUC for a non-nanoparticulate composition of the same aripiprazole, administered at the same dosage;

or

(d) any combination of (a), (b), and (c).

19. The composition of claim 18, wherein:

(a) the T_max is selected from the group consisting of not greater than about 90%, not greater than about 80%, not greater than about 70%, not greater than about 60%, not greater than about 50%, not greater than about 30%, not greater than about 25%, not greater than about 20%, not greater than about 15%, not greater than about 10%, and not greater than about 5% of the T_max exhibited by a non-nanoparticulate composition of the same aripiprazole, administered at the same dosage;

(b) the C_max is selected from the group consisting of at least about 50%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, at least about 500%, at least about 600%, at least about 700%, at least about 800%, at least about 900%, at least about 1000%, at least about 1100%, at least about 1200%, at least about 1300%, at least about 1400%, at least about 1500%, at least about 1600%, at least about 1700%, at least about 1800%, or at least about 1900% greater than the C_max exhibited by a non-nanoparticulate composition of the same aripiprazole, administered at the same dosage;

(c) the AUC is selected from the group consisting of at least about 25%, at least about 50%, at least about 75%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 200%, at least about 225%, at least about 250%, at least about 275%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, at least about 750%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, at least about 1000%, at least about 1050%, at least about 1100%, at least about 1150%, or at least about 1200% greater than the AUC exhibited by the non-nanoparticulate formulation of the same aripiprazole, administered at the same dosage;

or

(d) any combination of (a), (b), and (c).

20. The composition of claim 1, additionally comprising one or more active agents useful for the treatment of mental diseases or disorders.

21. The composition of claim 20, wherein said mental disease or disorder is selected from the group consisting of schizophreniform illness, schizophrenia, bipolar disorder and combinations thereof.

22. The composition of claim 20, wherein said one or more active agents is selected from the group consisting of chlorpromazine, fluphenazine, perphenazine and prochlorperazine, clozapine, olanzapine, quetiapine, ziprasidone and combinations thereof.

23. The composition claim 1, wherein:

(a) upon administration to a mammal the aripiprazole particles redisperse such that the particles have an effective average particle size selected from the group consisting of less than about 2 microns, 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;

(b) the composition redisperses in a biorelevant media such that the aripiprazole particles have an effective average particle size selected from the group consisting of less than about 2 microns, 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 mn;

or

(c) a combination of (a) and (b).

25. The method of claim 22, wherein contacting comprises a method selected from the group consisting of milling, homogenization, freezing, emulsion techniques, supercritical fluid particle generation techniques, precipitation, and combinations thereof.

24. A method of preparing a nanoparticulate aripiprazole, or a salt or derivative thereof, composition comprising:

contacting particles of aripiprazole with at least one surface stabilizer for a time and under conditions sufficient to provide a nanoparticulate aripiprazole composition having an effective average particle size of less than about 2000 nm.

26. A method for the treatment of schizophrenia, bipolar disorder, schizophreniform illnesses and related conditions in a subject comprising:

administering to a subject of an effective amount of a composition comprising,

(a) particles of aripiprazole or salt or derivative thereof having an average effective particle size of less than about 2000 nm; and

(b) at least one surface stabilizer.

27. The method of claim 26, further comprising one or more active agents useful for the treatment of schizophrenia, bipolar disorder and related condition.

28. The method of claim 27, wherein the related condition is selected from the group consisting of extrapyramidal symptoms, drug-induced Parkinsonism, acute dystonic reactions, akathisia, tardiv dyskinesia, tardive distonia and a combination thereof.

29. The composition of claim 26, wherein the composition is formulated for subcutaneous or intramuscular injection.

30. The method of claim 26, wherein the composition is in the form of an oral tablet.