Formulations for the treatment of pain

Abstract

Formulations and methods are provided for the treatment of pain, and neuropathic pain in particular. The formulations are eutectic mixtures of a capsaicinoid and a local anesthetic agent and/or an anti-pruritic agent.

1 . A substantially nonaqueous therapeutic formulation comprising a binary eutectic mixture of: 
 (a) a capsaicinoid having the structure of formula (I)                          wherein R 1  is hydrogen, hydroxyl or methoxy, R 2  is hydroxyl or C 2 -C 6  alkoxycarbonyl, X is selected from                          and R is selected from C 5 -C 11 alkyl, C 5 -C 11  alkenyl, C 11 -C 23  cis-alkenyl, C 11 -C 23  alkynyl, and C 11 -C23 alkadienyl; and    (b) a second active agent effective to decrease at least one side effect associated with capsaicin monotherapy, said second agent existing as a solid at 25° C.    
   
   
       2 . The formulation of  claim 1 , wherein the capsaicinoid is selected from resiniferatoxin, N-vanillyl-alkadienamides, N-vanillyl-alkanedienyls, N-vanillyl-monounsaturated alkenamides, N-vanillylsulfonamides, and hydroxyphenylacetamides.  
   
   
       3 . The formulation of  claim 2 , wherein the capsaicinoid is an N-vanillyl-monounsaturated alkenamide.  
   
   
       4 . The formulation of  claim 3 , wherein the capsaicinoid is capsaicin.  
   
   
       5 . The formulation of any one of claims  1 , 2, 3, and 4, wherein the second active agent is a local anesthetic agent.  
   
   
       6 . The formulation of  claim 5 , wherein the local anesthetic agent is selected from amylocaine, articaine, benzocaine, bupivacaine, butacaine, 2-chloroprocaine, cinchocaine, dexivacaine, diamocaine, dibucaine, etidocaine, ketocaine, lidocaine, mepivacaine, oxybuprocaine, parethoxycaine, prilocaine, procaine, propanocaine, proparacaine, propoxycaine, pyrrocaine, risocaine, rodocaine, ropivacaine, tetracaine, and combinations thereof.  
   
   
       7 . The formulation of  claim 6 , wherein the local anesthetic agent is lidocaine.  
   
   
       8 . The formulation of  claim 6 , wherein the local anesthetic agent is tetracaine.  
   
   
       9 . The formulation of  claim 5 , wherein the capsaicinoid represents about 10 wt. % to about 70 wt. % of the formulation.  
   
   
       10 . The formulation of  claim 9 , wherein the capsaicinoid represents about 40 wt. % to about 70 wt. % of the formulation.  
   
   
       11 . The formulation of  claim 5 , wherein the second active agent is an anti-pruritic agent.  
   
   
       12 . The formulation of  claim 11 , wherein the anti-pruritic agent is selected from menthol, camphor, phenol, and combinations thereof.  
   
   
       13 . The formulation of  claim 12 , wherein the capsaicinoid represents 10 wt. % to about 70 wt. % of the formulation.  
   
   
       14 . The formulation of  claim 13 , wherein the capsaicinoid represents about 40 wt. % to about 70 wt. % of the formulation.  
   
   
       15 . A substantially nonaqueous therapeutic formulation comprising a ternary eutectic mixture of: 
 (a) a capsaicinoid having the structure of formula (I)                          wherein R 1  is hydrogen, hydroxyl or methoxy, R 2  is hydroxyl or C 2 -C 6  alkoxycarbonyl, X is selected from                          and R is selected from C 5 -C 11  alkyl, C 5 -C 11  alkenyl, C 11  -C 23  cis-alkenyl, C 11  -C 23  alkynyl, and C 11  -C 23  alkadienyl;    (b) a second active agent effective to decrease at least one side effect associated with capsaicin monotherapy; and    (c) a third active agent effective to decrease at least one side effect associated with capsaicin monotherapy, said second and third active agents both existing as a solid at 25° C.    
   
   
       16 . The formulation of  claim 15 , wherein the capsaicinoid is selected from resiniferatoxin, N-vanillyl-alkadienamides, N-vanillyl-alkanedienyls, N-vanillyl-monounsaturated alkenamides, N-vanillylsulfonamides, and hydroxyphenylacetamides.  
   
   
       17 . The formulation of  claim 16 , wherein the capsaicinoid is an N-vanillyl-monounsaturated alkenamide.  
   
   
       18 . The formulation of  claim 17 , wherein the capsaicinoid is capsaicin.  
   
   
       19 . The formulation of any one of claims  15 ,  16 ,  17 , and  18 , wherein the second active agent is a local anesthetic agent.  
   
   
       20 . The formulation of  claim 19 , wherein the local anesthetic agent is selected from amylocaine, articaine, benzocaine, bupivacaine, butacaine, 2-chloroprocaine, cinchocaine, dexivacaine, diamocaine, dibucaine, etidocaine, ketocaine, lidocaine, mepivacaine, oxybuprocaine, parethoxycaine, prilocaine, procaine, propanocaine, proparacaine, propoxycaine, pyrrocaine, risocaine, rodocaine, ropivacaine, tetracaine, and combinations thereof.  
   
   
       21 . The formulation of  claim 20 , wherein the local anesthetic agent is lidocaine.  
   
   
       22 . The formulation of  claim 20 , wherein the local anesthetic agent is tetracaine.  
   
   
       23 . The formulation of any one of claims  15 ,  16 ,  17 , and  18 , wherein the third active agent is an anti-pruritic agent.  
   
   
       24 . The formulation of  claim 23 , wherein the anti-pruritic agent is selected from menthol, camphor, phenol, and combinations thereof.  
   
   
       25 . The formulation of  claim 12 , wherein the capsaicinoid represents 10 wt. % to about 50 wt. % of the formulation.  
   
   
       26 . The formulation of  claim 25 , wherein the second and third active agents are present in a weight ratio of about 1:1.  
   
   
       27 . The method of  claim 12 , wherein the eutectic mixture is administered by injection.  
   
   
       28 . A method for treating a patient suffering from pain, comprising administering to the patient a therapeutically effective amount of the formulation of  claim 1  or  claim 15 .  
   
   
       29 . The method of  claim 28 , wherein the formulation is administered topically.  
   
   
       30 . The method of  claim 29 , wherein the pain is caused by inflammation of joints, tends, nerves, or muscle.  
   
   
       31 . The method of  claim 30 , wherein the pain is caused by arthritis.  
   
   
       32 . The method of  claim 28 , wherein the pain is back pain.  
   
   
       33 . The method of  claim 28 , wherein the pain is headache pain.  
   
   
       34 . The method of  claim 28 , wherein the pain is caused by cancer.  
   
   
       35 . The method of  claim 28 , wherein the pain is neuropathic pain.  
   
   
       36 . The method of  claim 35 , wherein the neuropathic pain is post-herpetic neuralgia.  
   
   
       37 . The method of  claim 35 , wherein the neuropathic pain is the result of HIV—associated neuropathy.  
   
   
       38 . The method of  claim 35 , wherein the neuropathic pain is associated with diabetic neuropathy.  
   
   
       39 . The method of  claim 20 , wherein the neuropathic pain is trigeminal neuralgia.