Pharmaceutical Compositions Comprising Sorbitan Esters

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:

wherein

R a is absent, and R b is —CH 2 OC(O)R 1 , —CH 2 OC(O)OR 1 , —CH 2 OC(O)N(R 1 ) 2 or —C(O)R 1 ;

or

R b is absent, and R a is —CH 2 OC(O)R 1 , —CH 2 OC(O)OR 1 , —CH 2 OC(O)N(R 1 ) 2 or —C(O)R 1 ;

R c is —CH 2 OC(O)R 1 , —CH 2 OC(O)OR 1 , —CH 2 OC(O)N(R 1 ) 2 or —C(O)R 1 ;

wherein each R 1 is independently selected from the group consisting of hydrogen, substituted or unsubstituted aliphatic, and substituted or unsubstituted aryl; and

wherein each R 2 is selected from the group consisting of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

wherein Y ⊖ is a pharmaceutically acceptable counterion; and

wherein represents a single or double bond.

3 . The pharmaceutical composition of any one of the above claims, wherein the water-insoluble antipsychotic agent is Compound A-4 or Compound A-7:

4 . The pharmaceutical composition of any one of the above claims, wherein the water-insoluble antipsychotic agent is olanzapine, a compound of formula III, or a compound of formula IV, or pharmaceutically acceptable salts, hydrates, or solvates thereof:

wherein

R 3 is —CH 2 OC(O)R 1 , —CH 2 OC(O)OR 1 , —CH 2 OC(O)N(R 1 ) 2 or —C(O)R 1 ;

R 4 is —CH 2 OC(O)R 1 , —CH 2 OC(O)OR 1 , —CH 2 OC(O)N(R 1 ) 2 or —C(O)R 1 ;

wherein each R 1 is independently selected from the group consisting of hydrogen, substituted or unsubstituted aliphatic, and substituted or unsubstituted aryl; and

wherein Y ⊖ is a pharmaceutically acceptable counterion.

5 . The composition of any one of the above claims, 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 any of the above claims, 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 μm, Dv[50]: 10-30 μm, and Dv[90]: less than 65 μmM.

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

11 . The composition of any of the above claims, 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 any of the above claims, 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 claims, 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 any of the above claims, 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.

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 any one of claims 25 - 29 , wherein the composition further comprises a surfactant.

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

32 . The composition of any one of claims 24 - 31 , wherein the composition further comprises a buffer.

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

34 . A method for treating disorders of the central nervous system, comprising administering an effective amount of the composition of any one of claims 1 - 33 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.