Treatment of ophthalmic disorders using urea and urea derivatives

Abstract

Methods for treating disorders of the eye and/or disorders of a nerve in a human or veterinary patient by delivering to the patient a therapeutically effective amount of a compound selected from the group of; urea, urea derivatives, thiourea, thiourea derivatives, guanidine, guanidine derivatives and compounds having General Formula I as set forth herein. For ophthalmic applications, the compound may be delivered by intravitreal injection such that the compound causes vitreal liquefaction, posterior vitreoretinal detachment and other affects.

1 - 28 . (canceled)  
   
   
       29 . A method for treating optic neuropathy or optic nerve damage in a human or animal subject, said method comprising the step of: 
 intravitreally injecting a therapeutically effective an substantially non-toxic amount of a preparation containing an organic acid in combination with at least one agent selected from the group consisting of: 
 urea;  
 urea derivatives;  
 thiourea;  
 thiourea derivatives;  
 guanidine;  
 guanidine derivatives; and,  
 compounds having the general formula:  
                     
   wherein R is hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C6 alkylphenyl or hydroxyl protecting group; R1 and R2 are each independently hydrogen, C1-C6 alkyl, C3-C8 cycloalky, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkenyl, —S(O)q(C1-C6 alkenyl) or                          wherein A is —CH2—, —O—, —S—, —S(O)— or —S(O)2—: W1 and W2 are each independently hydrogen, halo, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, C2-C4 alkenyl, or, C2-C4 alkynyl; R3 is hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, or, C1-C6 alkylphenyl; X is O, S, or NR4; R4 is hydrogen, C1-C6 alkyl, C1-C4 alkylphenyl or, C1-C6 alkoxy; R5 is hydrogen, C3-C8 cycloalkyl or C1-C8 alkyl; Y is selected from                          wherein Z1 and Z2 are each independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, hydroxyl, C2-C4 alkenyl, C2-C6 alkyl, C1-C6 alkythio, halo, trifluoromethyl or —NR6R7; R6 and R7 are each independently hydrogen, C3-C8 cycloalkyl, C1-C6 alkyl, C1-C4 alkylphenyl; n is 1 to 6 all inclusive; m and p are each independently 0 to 6 inclusive and q is 0, 1 or 2;    and pharmaceutical salts thereof.    
   
   
       30 . A method according to  claim 29  wherein the organic acid comprises citric acid.  
   
   
       31 . A method according to  claim 30  wherein the preparation has the formulation:  
     
       
         
               
               
               
             
                   
                   
               
                   
                   
               
                   
                 Ingredient 
                 Quantity 
               
                   
                   
               
                   
               
               
               
               
               
             
                   
                 Urea 
                 0.01%-30.0% 
                 by weight 
               
                   
                 Citric Acid 
                 0.00001%-1.0% 
                 by weight 
               
                   
                 Sodium Chloride 
                 0.05%-3.6% 
                 by weight 
               
                   
                 Sterile water for Injection USP 
                 Q.S 100% 
                 by weight 
               
                   
                   
               
                   
                   
               
           
              
              
              
              
             
             
              
             
          
           
              
              
              
              
              
              
             
          
         
       
     
   
   
       32 . A method according to  claim 29 ,  30  or  31  wherein the preparation contains urea in a concentration of from about 0.003 mg urea per 50 μl to about 15 mg urea per 50 μl.  
   
   
       33 . A method according to  claim 32  wherein the concentration of urea is from 0.005 mg urea per 50 μl to 7.5 mg urea per 50 μl.  
   
   
       34 . A method according to  claim 29 ,  30  or  31  wherein the preparation contains citric acid in a concentration of from about 0.00001% to about 1.0%.  
   
   
       35 . A method according to  claim 34  wherein the concentration of citric acid is from 0.00007% to 0.007%.  
   
   
       36 . A method according to  claim 29 ,  30  or  31  wherein the preparation contains sodium chloride in a concentration of 0.05% to 3.6%.  
   
   
       37 . A method according to  claim 36  wherein the concentration of sodium chloride is between 0.9% and 1.8%.  
   
   
       38 . A method according to  claim 29  wherein the preparation contains: 
 urea in an amount between about 0.005 mg per 50 μl to 7.5 mg per 50 μl;    citric acid in an amount between 0.00007% and 0.007%; and    sodium chloride in an amount from 0.9% to about 1.8%.    
   
   
       39 . A method according to  claim 29  wherein the preparation has a pH from about 4.0 to about 9.0.  
   
   
       40 . A method according to  claim 29  wherein the preparation has a pH of is less than 7.0.  
   
   
       41 . A method according to  claim 40  wherein the preparation has a pH in the range of 4.0 to 6.5.  
   
   
       42 . A method according to any of claims  29 ,  30  or  31  wherein the preparation further comprises one or more buffers.  
   
   
       43 . A method according to  claim 42  wherein the preparation contains at least one buffer selected from the group consisting of phosphate buffers, acetate, and glycine.