Corneal epithelial migration promoter

Abstract

Based on research for compounds that can display a corneal epithelial migration promoting effect in ophthalmology, the present invention provides P2Y receptor agonist corneal epithelial migration promoters, such as phosphoric acid compounds having an adenosyl group, uridyl group, xanthosyl group, guanosyl group, or thymidyl group, or their salts, with excellent corneal epithelial migration promoting effects.

1 . A method of promoting epithelial migration in the cornea or conjunctiva, said method comprising: 
 administering to the eye of a subject an epithelial migration promoter formulation comprising a P2Y receptor agonist in an amount effective to promote epithelial migration in the cornea or conjunctiva, wherein said P2Y receptor agonist is a compound of formula I or its pharmacologically tolerated salts:                          wherein n is an integer of 1-4; X is hydrogen, and R 1  is a uracil group, thymine group, adenine group, hypoxanthine group, or guanine group.    
   
   
       2 . The method according to  claim 1 , wherein said promoting epithelial migration is to repair epithelial defects.  
   
   
       3 . The method according to  claim 1 , wherein said promoting epithelial migration to repair epithelial defects is such that the epithelium extends to cover a damaged portion of the cornea or conjunctiva.  
   
   
       4 . The method according to  claim 3 , wherein said damaged portion of the cornea or conjunctiva results from corneal disease.  
   
   
       5 . The method according to  claim 4 , wherein said corneal disease is selected from the group consisting of corneal ulcers, exfoliation of corneal epithelium, and keratitis.  
   
   
       6 . The method according to  claim 1 , wherein said epithelial migration promoter formulation contains an effective amount of said P2Y receptor agonist or its pharmacologically tolerated salt together with a pharmacologically tolerated additive.  
   
   
       7 . The method according to  claim 16 , wherein said uracil group, thymine group, adenine group, hypoxanthine group, or guanine group is a substituted uracil, thymine, adenine, hypoxanthine, or guanine group.  
   
   
       8 . The method according to  claim 7 , wherein said substituted uracil, thymine, adenine, hypoxanthine, or guanine group is substituted with a group selected from the group consisting of: halogens, C 1-6  straight-chain or branched lower alkyl groups, C 1-6  straight-chain or branched lower alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, hydroxyl group, amino groups, and protecting groups.  
   
   
       9 . The method according to  claim 8 , wherein said protecting groups are selected from the groups consisting of C 2-6  lower alkanoyl groups and arylcarbonyl groups.  
   
   
       10 . The method according to  claim 1 , wherein said pharmacologically tolerated salts are selected from the group consisting of alkali metal salts, alkaline earth metal salts, ammonia salts, organic amine salts, hydrochloric acid salts, sulfuric acid salts, phosphoric acid salts, lactic acid salts, maleic acid salts, fumaric acid salts, oxalic acid salts, methanesulfonic acid salts, and para-toluenesulfonic acid salts.  
   
   
       11 . The method according to  claim 10 , wherein said pharmacologically tolerated salts are selected from the group consisting of sodium, potassium, calcium, ammonia, diethylamine, triethanolamine, hydrochloric acid, sulfuric acid, phosphoric acid, lactic acid, maleic acid, fumaric acid, oxalic acid, methanesulfonic acid, and para-toluenesulfonic acid salts.  
   
   
       12 . The method according to  claim 1 , wherein said amount of the P2Y receptor agonist effective to promote epithelial migration in the cornea or conjunctiva is in the range of 0.0001% to 15%.  
   
   
       13 . The method according to  claim 1 , wherein said epithelial migration promoter formulation is in the form selected from the group consisting of eye drops and eye ointments.  
   
   
       14 . The method according to  claim 1 , wherein said formulation comprises at least one additive selected from the group consisting of isotonic agents, buffers, stabilizers, preservatives, pH adjustors, and base agents.  
   
   
       15 . The method according to  claim 14 , wherein said additive is selected from the group consisting of: sodium chloride, potassium chloride, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium edetate, benzalconium chloride, sorbic acid, sodium hydroxide, dilute hydrochloric acid, white Vaseline, and fluidic paraffin.  
   
   
       16 . The method according to  claim 1 , wherein said P2Y receptor agonist uridine 5′-diphosphoric acid, adenosine 5′-diphosphoric acid, uridine 5′-triphosphoric acid, adenosine 5′-triphosphoric acid, or the salts thereof.