Antimalarial compositions and uses thereof

Abstract

Provided herein are compounds, compositions and method of using thereof to treat or prevent malaria.

We claim: 
     
         1 . A method for the treatment or prevention of malaria in a subject comprising administering to the subject a pharmaceutical suspension comprising nanoparticles or microparticles of a crystalline compound of Formula (III) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 
       
         
           
           
               
               
           
         
         wherein: R 11  is C 1 -C 6  alkyl. 
       
     
     
         2 . The method according to  claim 1 , wherein R 11  is C 6  alkyl. 
     
     
         3 . The method according to  claim 1 , wherein the compound of Formula (III) is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 
       
     
     
         4 . The method according to  claim 1 , wherein the suspension comprises microparticles of a crystalline compound of Formula (III) with average particle size in the range of about 1 μm to about 50 μm. 
     
     
         5 . The method according to  claim 1 , wherein the suspension comprises microparticles of a crystalline compound of Formula (III) with average particle size in the range of about 10 μm to about 20 μm. 
     
     
         6 . The method according to  claim 1 , wherein the suspension further comprises a pharmaceutically acceptable excipient selected from surfactants, solubilizers, emulsifiers, preservatives, isotonicity agents, dispersing agents, wetting agents, fillers, solvents, buffers, stabilizers, lubricants, thickening agents, suspending agents, and any combinations thereof. 
     
     
         7 . The method according to  claim 1 , wherein the suspension further comprises Synperonic® F108, dodecyl sodium sulfate (SLS), D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), hydroxypropyl methylcellulose (HPMC), and any combinations thereof. 
     
     
         8 . The method according to  claim 1 , wherein the wherein the concentration of the crystalline compound of Formula (III) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is between about 20 mg/mL and about 300 mg/mL. 
     
     
         9 . The method according to  claim 1 , wherein the pharmaceutical suspension is administered by subcutaneous or intramuscular injection. 
     
     
         10 . The method according to  claim 1 , wherein the pharmaceutical suspension is effective for sustained or controlled release. 
     
     
         11 . The method according to  claim 1 , wherein the compound of Formula (III) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is released from the pharmaceutical suspension over a period of at least about twelve weeks after administration. 
     
     
         12 . The method according to  claim 1 , wherein the compound of Formula (III) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is released from the pharmaceutical suspension at a rate providing an average concentration of trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione in the blood plasma of said subject of at least about 200 nM or at least about 1000 nM over about 13 weeks. 
     
     
         13 . The method according to  claim 1 , wherein the compound of Formula (III) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered with an additional antimalarial agent. 
     
     
         14 . The method according to  claim 13 , wherein the additional antimalarial agent is selected from the group consisting of artemisinin, artemisinin derivatives, proguanil, quinine, chloroquine, amodiaquine, pyrimethamine, doxycycline, clindamycin, mefloquine, primaquine, pyronaridine, halofantrine, and ELQ-300. 
     
     
         15 . A compound of Formula (III) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 11  is C 6  alkyl.