Deuterated forms of acetaminophen and uses thereof

Abstract

The present disclosure provides compositions comprising deuterated forms of acetaminophen. When administered to human subjects, such compositions form less of the toxic metabolite NAPQI, and therefore are useful in methods of treating various diseases and conditions with a reduced risk of liver injury or other side effects associated with non-deuterated forms of acetaminophen.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein each Y is independently hydrogen or deuterium; and 
         at least one Y is deuterium. 
       
     
     
         2 . The composition of  claim 1 , wherein the composition is suitable for oral administration. 
     
     
         3 . The composition of  claim 1 , wherein the composition is suitable for intravenous (IV) administration. 
     
     
         4 . The composition of  claim 1 , wherein the composition is suitable for topical administration. 
     
     
         5 . The composition of  claim 1 , wherein the composition is a solid dose composition. 
     
     
         6 . The composition of  claim 1 , wherein the composition is used to treat pain. 
     
     
         7 . The composition of  claim 1 , wherein the composition is used to reduce fever. 
     
     
         8 . The composition of any one of  claims 1 - 7 , wherein at least two instances of Y are deuterium. 
     
     
         9 . The composition of any one of  claims 1 - 7 , wherein at least three instances of Y are deuterium. 
     
     
         10 . The composition of any one of  claims 1 - 7 , wherein at least four instances of Y are deuterium. 
     
     
         11 . The composition of any one of  claims 1 - 7 , wherein at least five instances of Y are deuterium. 
     
     
         12 . The composition of any one of  claims 1 - 7 , wherein at least six instances of Y are deuterium. 
     
     
         13 . The composition of any one of  claims 1 - 7 , wherein at least seven instances of Y are deuterium. 
     
     
         14 . The composition of any one of  claims 1 - 7 , wherein at least eight instances of Y are deuterium. 
     
     
         15 . The composition of any one of  claims 1 - 7 , wherein each Y is deuterium. 
     
     
         16 . The composition of any one of  claims 1 - 15 , further comprising a pharmaceutically acceptable carrier. 
     
     
         17 . The composition of  claim 5 , wherein the solid dose composition is a tablet, caplet, capsule, granule, powder, sachet, rapidly disintegrating tablet, or chewable. 
     
     
         18 . The composition of  claim 4 , wherein the topical composition is a cream, foam, gel, lotion, ointment, transdermal patch, tincture, or paste. 
     
     
         19 . The composition of any one of  claims 1 - 18 , further comprising one or more additional agents. 
     
     
         20 . The composition of  claim 19 , wherein each additional agent is independently an anti-inflammatory agent, opioid analgesic, cough suppressant, antihistamine, decongestant, caffeine, sleep agent, or a combination thereof. 
     
     
         21 . The composition of  claim 20 , wherein the anti-inflammatory agent is a cyclooxygenase-2 (COX-2) inhibitor. 
     
     
         22 . The composition of  claim 21 , wherein the COX-2 inhibitor is rofecoxib, celecoxib, valdecoxib, or etoricoxib. 
     
     
         23 . The composition of  claim 20 , wherein the anti-inflammatory agent is an NSAID. 
     
     
         24 . The composition of  claim 19 , wherein the additional agents are an NSAID and caffeine. 
     
     
         25 . The composition of  claim 19 , wherein the additional agent is caffeine. 
     
     
         26 . The composition of  claim 24 , wherein the NSAID and/or caffeine include at least one deuterium atom. 
     
     
         27 . The composition of  claim 23  wherein the NSAID is aspirin, ibuprofen, naproxen, sulindac, ketoprofen, tolmetin, etodolac, fenoprofen, diclofenac, flurbiprofen, piroxicam, ketorolac, indomethacin, nabumetone, oxaprozin, mefanamic acid, or diflunisal. 
     
     
         28 . The composition of  claim 20 , wherein the opioid analgesic is codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, tramadol, or oxycodone. 
     
     
         29 . A method for treating pain in a subject, the method comprising administering to the subject a pharmaceutical composition according to any one of  claims 1 - 28 . 
     
     
         30 . A method for reducing fever in a subject, the method comprising administering to the subject a pharmaceutical composition according to any one of  claims 1 - 28 . 
     
     
         31 . A method for treating pain in a subject while avoiding one or more side effects associated with the administration of acetaminophen in a non-deuterated form, the method comprising administering to the subject a pharmaceutical composition according to any one of  claims 1 - 28 . 
     
     
         32 . A method for reducing fever in a subject while avoiding one or more side effects associated with the administration of acetaminophen in a non-deuterated form, the method comprising administering to the subject a pharmaceutical composition according to any one of  claims 1 - 28 . 
     
     
         33 . The method of any one of  claims 29 - 32 , wherein the method reduces the level of NAPQI in the subject by at least 5%, 10%, 15%, 25%, 30%, 35%, 40%, 45%, or 50% when compared to the administration of the same or an equivalent amount of acetaminophen in a non-deuterated form. 
     
     
         34 . The method of any one of  claims 29 - 33 , wherein the method reduces the risk of serious liver injury in the subject when compared to the administration of the same or an equivalent amount of acetaminophen in a non-deuterated form. 
     
     
         35 . The method of any one of  claims 29 - 34 , wherein the method reduces the risk of serious liver injury as measured by one or more Liver Function Tests (LFTs) in the subject when compared to the administration of the same or an equivalent amount of acetaminophen in a non-deuterated form. 
     
     
         36 . The method of any one of  claims 29 - 35 , wherein the maximum daily dose of the compound is up to 6,000 mg, 8,000 mg, or 12,000 mg per day. 
     
     
         37 . Use of a pharmaceutical composition according to any one of  claims 1 - 28  for treating pain. 
     
     
         38 . Use of a pharmaceutical composition according to any one of  claims 1 - 28  for reducing fever. 
     
     
         39 . The use of any one of  claims 37 - 38 , wherein the method reduces the level of NAPQI in the subject by at least 5%, 10%, 15%, 25%, 30%, 35%, 40%, 45%, or 50% when compared to the administration of the same or an equivalent amount of acetaminophen in a non-deuterated form. 
     
     
         40 . The use of any one of  claims 37 - 38 , wherein the method reduces the risk of serious liver injury in the subject when compared to the administration of the same or an equivalent amount of acetaminophen in a non-deuterated form. 
     
     
         41 . The use of any one of  claims 37 - 40 , wherein the method reduces the risk of serious liver injury as measured by one or more Liver Function Tests (LFTs) in the subject when compared to the administration of the same or an equivalent amount of acetaminophen in a non-deuterated form. 
     
     
         42 . The use of any one of  claims 37 - 41 , wherein the maximum daily dose of the compound is up to 6,000 mg, 8,000 mg, or 12,000 mg per day. 
     
     
         43 . A kit comprising a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof;
 wherein each Y is independently hydrogen or deuterium; and 
 at least one Y is deuterium; 
 
         and a container. 
       
     
     
         44 . The kit of  claim 43 , further comprising an additional agent in a second container.