PHARMACEUTICAL COMPOSITIONS COMPRISING SORBITAN ESTERS

• US 20120238552A1
• Filed: 03/19/2012
• Published: 09/20/2012
• Est. Priority Date: 03/18/2011
• Status: Active Grant

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Inventors: PERRY, Jason M., DEAVER, Daniel R., HICKEY, Magall B., REMENAR, Julius F., VANDIVER, Jennifer
• Granted Patent: US 9,034,867 B2
• Time in Patent Office: Days
• US Class Current: 514/220
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/4965 Non-condensed pyrazines
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• 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 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: A61P 25/00 Drugs for disorders of the nervous system
• 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 relates to a pharmaceutical composition comprising sorbitan esters of carboxylic acids that are useful for the delivery of anti-psychotic drugs.

Claims

1. A pharmaceutical composition comprising:

(a) a water-insoluble antipsychotic agent;

(b) sorbitan esters of a carboxylic acid, wherein the carboxylic acid comprises 4-20 carbon atoms;

(c) a polyoxyethylene derivative of a sorbitan ester of a carboxylic acid, wherein the carboxylic acid comprises 8-14 carbon atoms; and

(d) an aqueous vehicle;

wherein the composition forms an aqueous, flocculated, injectable suspension.

2. The pharmaceutical composition of claim 1, wherein the water-insoluble antipsychotic agent is aripiprazole, a compound of formula I, or a compound of formula II, or pharmaceutically acceptable salts, hydrates, or solvates thereof:

3. The pharmaceutical composition of claim 2, wherein the water-insoluble antipsychotic agent is Compound A-4 or Compound A-7:

5. The composition of claim 1, wherein the composition comprises components (b) and (c) at a ratio that results in flocs comprising component (a), wherein the flocs settle to greater than a predetermined sediment bed height, such that components (a), (b) and (c) can be resuspended for injection.

6. The composition of claim 5, wherein the bed height is comprised of at least a 20 to 80% increase in sediment height compared to a non flocculated composition after 24 hours of undisturbed sitting.

7. The composition of claim 5, wherein components (a), (b) and (c) can be resuspended for injection within 1-60 seconds of handshaking.

8. The composition of claim 1, wherein the ratio of components (b) to (c) is such that the composition can be injected using a 20 to 25 gauge needle.

9. The composition of claim 5, wherein (a), (b), and (c) form flocs having the following sizes:

Dv[10];

2-10 μ

m, Dv[50];

10-30 μ

m, and Dv[90];

less than 65 μ

mM.

10. The composition of claim 1, wherein the ratio of components (b) to (c) is approximately 5 to 2, by weight.

11. The composition of claim 1, wherein the sorbitan ester (b) is sorbitan laurate.

12. The composition of claim 11, wherein the polyoxyethylene derivative of a sorbitan ester (c) is polysorbate 20.

13. The composition of claim 11, comprising about 0.2-1 weight percent sorbitan laurate.

14. The composition of claim 11, comprising about 0.4-0.7 weight percent sorbitan laurate.

15. The composition of claim 11, comprising about 0.5 weight percent sorbitan laurate.

16. The composition of claim 12, comprising about 0.05-0.8 weight percent polysorbate 20.

17. The composition of claim 12, comprising about 0.1-0.3 weight percent polysorbate 20.

18. The composition of claim 12, comprising about 0.2 weight percent polysorbate 20.

19. The composition of claim 1, comprising approximately 15-35 weight percent aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or V (lurasidone), or pharmaceutically acceptable salts, hydrates, or solvates thereof.

20. The composition of any of the above claim 1, comprising approximately 20-30 weight percent aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or V, or pharmaceutically acceptable salts, hydrates, or solvates thereof.

21. The composition of claim 1, comprising approximately 20-26 weight percent aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or V, or pharmaceutically acceptable salts, hydrates, or solvates thereof.

34. A method for treating disorders of the central nervous system, comprising administering an effective amount of the composition of claim 1 to an individual in need of such treatment.

35. The method of claim 34, wherein the disorder is anxiety or depression.

36. The method of claim 34, wherein the disorder is bipolar disorder.

37. The method of claim 34, wherein the disorder is autism-related irritability.

38. The method of claim 34, wherein the disorder is a psychotic condition.

39. The method of claim 34, wherein the psychotic condition is schizophrenia or schizophreniform diseases.

40. The method of claim 34, wherein the psychotic condition is acute mania.

4. (canceled)

22. An injectable pharmaceutical composition comprising:

(a) aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or V, or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein component (a) is in a weight ratio of approximately 15-35%;

(b) sorbitan laurate in a weight ratio of approximately 0.2-1%

(c) polysorbate 20 in a weight ratio of approximately 0.05-0.8%; and

(d) an aqueous carrier.

23. The injectable pharmaceutical composition of claim 22 comprising

(a) in a weight ratio of approximately 20-26%;

(b) sorbitan laurate in a weight ratio of approximately 0.5%;

(c) polysorbate 20 in a weight ratio of approximately 0.2%; and

(d) an aqueous carrier.

24. An injectable composition comprising a water-insoluble antipsychotic agent and sorbitan esters of a carboxylic acid, wherein the carboxylic acid comprises 8-14 carbon atoms.

25. The composition of claim 24, wherein the sorbitan ester is sorbitan laurate.

26. The composition of claim 24, wherein the composition is formulated for modulating tissue reaction associated with the delivery of a water-insoluble antipsychotic agent.

27. The composition of claim 24, wherein the antipsychotic agent is aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or V.

28. The composition of claim 24, wherein the antipsychotic agent is selected from the group comprising compounds A-4 or A-7.

29. The composition of claim 26, wherein the modulation of the tissue reaction is a reduction in the irritation at the site of injection.

30. The composition of claim 25, wherein the composition further comprises a surfactant.

31. The composition of claim 30, wherein the surfactant is polysorbate 20.

32. The composition of claim 24, wherein the composition further comprises a buffer.

33. The composition of claim 32, wherein the buffer is a phosphate, citrate, tartrate or acetate buffer.