Compositions comprising spicamycin derivatives and methods of use thereof

Abstract

The present invention relates to compositions comprising spicamycin derivatives, methods of making such compositions, and their use in the treatment and/or prevention of pain, including neuropathic pain.

That which is claimed: 
     
         1 . A composition comprising:
 a) a spicamycin derivative of Formula II:   
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are different from each other and represent H or OH, and R represents a substituted or unsubstituted alkyl, alkenyl, alkynyl, or cycloalkyl;
 b) a biocompatible alcohol that solubilizes said spicamycin derivative; 
 c) glycerin or a glycol that is miscible with said biocompatible alcohol and solubilizes said spicamycin derivative; and 
 d) a surfactant soluble in a mixture of said biocompatible alcohol and said glycerin or glycol; 
 
       wherein said composition is substantially free of particulates, and is substantially free of mono-ethanolamine and N,N-dimethyl acetamide (DMAC), and wherein said composition is a single-phase solution. 
     
     
         2 . The composition of  claim 1 , further comprising an aqueous intravenous liquid or diluent. 
     
     
         3 . The composition of  claim 2 , wherein said aqueous intravenous liquid or diluent is selected from the group consisting of:
 a) 0.9% sodium chloride;   b) 5% dextrose; and   c) Lactated Ringers solution.   
     
     
         4 . The composition of  claim 1 , wherein said composition is substantially free of particulates. 
     
     
         5 . The composition of  claim 1 , wherein said composition is substantially free of particulates for about two weeks after said composition is formulated. 
     
     
         6 . The composition of  claim 1 , wherein said composition is substantially free of particulates for at least 1 year after said composition is formulated. 
     
     
         7 . The composition of  claim 1 , wherein said composition is essentially free of (DMAC), is essentially free of mono-ethanolamine, or is essentially free of both DMAC and mono-ethanolamine. 
     
     
         8 . The composition of  claim 1 , wherein said spicamycin derivative is a compound of Formula II and R is selected from the group consisting of:
 a) a linear alkenyl having 11-13 carbon atoms;   b) a linear, unsubstituted alkyl having 11-13 carbon atoms and no double or triple bonds;   c) a linear haloalkyl having 10-15 carbon atoms;   d) CH 3 (CH 2 ) n CH(OH)— or CH 3 (CH 2 ) n-1 CH(OH)CH 2 —, wherein n denotes an integer from 9-13;   e) an alkyl having 10-15 carbon atoms substituted with an azide group or a cyano group;   f) a linear alkyl having 10-13 carbon atoms substituted with a phenoxy group or a halogen-substituted phenoxy group;   g)   
       
         
           
           
               
               
           
         
         wherein m denotes an integer from 0-2 and p denotes an integer from 9-14; 
         h) 
       
       
         
           
           
               
               
           
         
         wherein m denotes an integer from 0-2 and p denotes an integer from 8-13; 
         i) 
       
       
         
           
           
               
               
           
         
         wherein m denotes an integer from 0-2 and p denotes an integer from 10-15; 
         j) CH 3 (CH 2 ) m SO 2 O(CH 2 ) p —, wherein m denotes an integer from 0-3 and p denotes an integer from 9-14; 
         k) 
       
       
         
           
           
               
               
           
         
         wherein m denotes an integer from 0-3 and p denotes an integer from 10-15; 
         l) CH 3 Si(CH 2 ) 10 — or CH 3 Si—C═C—(CH 2 ) 8 —; 
         m) 
       
       
         
           
           
               
               
           
         
         n) 
       
       
         
           
           
               
               
           
         
         o) 
       
       
         
           
           
               
               
           
         
       
       and
 p) a linear alkadienyl having 11-13 carbon atoms. 
 
     
     
         9 . The composition of  claim 8 , wherein R 1  is H and R 2  is OH. 
     
     
         10 . The composition of  claim 8 , wherein said spicamycin derivative is 6-[4-deoxy-4-[(2E,4E)-tetradecadienoylglycyl]amino-L-glycero-β-L-manno heptopyranosyl]amino-9H-purine (KRN5500) and has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The composition of  claim 1 , wherein said spicamycin derivative is present in an amount of from about 0.01 mg/mL to about 10 mg/mL. 
     
     
         12 . The composition of  claim 1 , wherein said spicamycin derivative is present in an amount of from about 0.1 mg/mL to about 5 mg/mL. 
     
     
         13 . The composition of  claim 1 , wherein said spicamycin derivative is present in an amount of from about 2 mg/mL to about 4 mg/mL. 
     
     
         14 . The composition of  claim 1 , wherein:
 a) said spicamycin derivative is present in an amount of from about 2 mg/mL to about 4 mg/mL;   b) said biocompatible alcohol is present in an amount of from about 250 mg/mL to about 350 mg/mL;   c) said glycerin or glycol is present in an amount of from about 600 mg/mL to about 700 mg/mL; and   d) said surfactant is present in an amount of from about 20 mg/mL to about 100 mg/mL.   
     
     
         15 . The composition of  claim 1 , wherein:
 a) said spicamycin derivative is present in an amount of from about 0.01 mg/mL to about 0.03 mg/mL;   b) said biocompatible alcohol is present in an amount of from about 2 mg/mL to about 3 mg/mL;   c) said glycerin or glycol is present in an amount of from about 4 mg/mL to about 7 mg/mL; and   d) said surfactant is present in an amount of from about 0.2 mg/mL to about 0.5 mg/mL.   
     
     
         16 . The composition of  claim 1 , wherein said biocompatible alcohol is selected from the group consisting of:
 a) ethanol; and   b) t-butanol.   
     
     
         17 . The composition of  claim 1 , wherein said glycol is selected from the group consisting of:
 a) propylene glycol;   b) polyethylene glycol; and   c) polypropylene glycol.   
     
     
         18 . The composition of  claim 1 , wherein said surfactant is selected from the group consisting of:
 a) polysorbate;   b) a poloxmer;   c) n-dodecyl-b-maltoside;   d) tocopheryl-polyethylene glycol succinate;   e) polyethylene glycol;   f) a polyoxyl;   g) Solutol;   h) Pluronics;   i) sodium dodecyl sulfate;   j) SPAN; and   k) octoxynol-9.   
     
     
         19 . The composition of  claim 1 , wherein said composition comprises:
 a) KRN5500 in an amount of about 4 mg/mL;   b) ethanol in an amount of about 293 mg/mL;   c) propylene glycol in an amount of about 618 mg/mL; and   d) polysorbate 80 in an amount of about 40 mg/mL.