US2016038508A1PendingUtilityA1

Pharmaceutical compositions comprising sorbitan esters

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Assignee: ALKERMES PHARMA IRELAND LTDPriority: Mar 18, 2011Filed: Apr 16, 2015Published: Feb 11, 2016
Est. expiryMar 18, 2031(~4.6 yrs left)· nominal 20-yr term from priority
Inventors:Jason M. PerryDaniel R. DeaverMagali B. HickeyJulius F. RemenarJennifer Vandiver
A61P 25/24A61P 25/18A61P 25/00A61K 31/5513A61K 31/496A61K 9/0019A61K 47/26A61K 31/381A61K 9/10A61K 31/497A61K 31/4965A61K 31/551A61K 47/14A61K 2121/00A61K 47/30A61K 45/00
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Claims

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

exact text as granted — not AI-modified
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.

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