Methods and compositions for treating meibomian gland disease

Abstract

A method for treating a patient having meibomian gland disease, ocular irritation associated with delayed tear clearance, or recurrent corneal epithelial erosion, is disclosed. Preferably, the method concerns treatment of a patient with topical tetracycline, a derivative or analogue of tetracycline, or a chemically modified tetracycline (CMT). Oral administration of a CMT is also disclosed as part of the method for treating meibomian gland disease, ocular irritation associated with delayed tear clearance, or recurrent corneal epithelial erosion.

1 . A method of treating a patient having meibomian gland disease, aqueous tear deficiency, delayed tear clearance or recurrent comeal epithelial erosion, said method comprising:
 topically administering an effective amount of tetracycline to an eye of the patient.   
     
     
         2 . The method of  claim 1 , wherein said tetracycline is an antimicrobial tetracycline. 
     
     
         3 . The method of  claim 2 , wherein said antimicrobial tetracycline is oxytetracycline. 
     
     
         4 . The method of  claim 2 , wherein said antimicrobial tetracycline is doxycycline. 
     
     
         5 . The method of  claim 1 , wherein said tetracycline is a non-antimicrobial tetracycline. 
     
     
         6 . The method of  claim 5 , wherein said non-antimicrobial is a member selected from the group consisting of 4-dedimethylaminotetracycline, 4-dedimethylamino-5-oxytetracycline, 4-dedimethylamino-7-chlorotetracycline, 4-hydroxy-4-dedimethylaminotetracycline, 4-dedimethylamino-12a-deoxytetracycline, 4-dedimethylamino-11-hydroxy-12a-deoxytetracycline, 4-dedimethylamino-7-dimethylaminotetracycline, 6-dimethyl-6-deoxy-4-dedimethylaminotetracycline, 6-o-deoxy-5-hydroxy-4-dedimethylaminotetracycline, 11a-chlortetracycline, 12a-deoxytetracycline and 2-nitrilo analogs of tetracycline. 
     
     
         7 . The method of  claim 1 , wherein said treatment increases tear clearance in the eye of the patient. 
     
     
         8 . The method of  claim 1 , wherein said treatment comprises inhibiting a member selected from the group consisting of matrix metalloproteinase activity in tear fluid, synthesis and activation of interleukin-1 β, conversion of precursor interleukin-1 βto mature interleukin-1β, ocular surface inflammation and reactive oxygen species in tear fluid and ocular surface epithelium. 
     
     
         9 . The method of  claim 8 , wherein said matrix metalloproteinase comprises matrix metalloproteinase-9. 
     
     
         10 . The method of  claim 1 , wherein said treatment comprises increasing production of interleukin-1 receptor antagonist by corneal epithelium. 
     
     
         11 . The method of  claim 1 , wherein said treatment comprises reducing interleukin-1-α concentration in tear fluid. 
     
     
         12 . A method of treating a patient having meibomian gland disease, aqueous tear deficiency, delayed tear clearance or recurrent corneal epithelial erosion, said method comprising:
 orally administering an effective amount of tetracycline to an eye of the patient.   
     
     
         13 . The method of  claim 12 , wherein said tetracycline is an antimicrobial tetracycline. 
     
     
         14 . The method of  claim 13 , wherein said antimicrobial tetracycline is oxytetracycline. 
     
     
         15 . The method of  claim 13 , wherein said antimicrobial tetracycline is doxycycline. 
     
     
         16 . The method of  claim 12 , wherein said tetracycline is a non-antimicrobial tetracycline. 
     
     
         17 . The method of  claim 16 , wherein said non-antimicrobial is a member selected from the group consisting of 4-dedimethylaminotetracycline, 4-dedimethylamino-5-oxytetracycline, 4-dedimethylamino-7-chlorotetracycline, 4-hydroxy-4-dedimethylaminotetracycline, 4-dedimethylamino-12a-deoxytetracycline, 4-dedimethylamino-11-hydroxy-12a-deoxytetracycline, 4-dedimethylamino-7-dimethylaminotetracycline, 6-dimethyl-6-deoxy-4-dedimethylaminotetracycline, 6-o-deoxy-5-hydroxy-4-dedimethylaminotetracycline, 11a-chlortetracycline, 12a-deoxytetracycline and 2-nitrilo analogs of tetracycline. 
     
     
         18 . The method of  claim 12 , wherein said treatment increases tear clearance in the eye of the patient. 
     
     
         19 . The method of  claim 12 , wherein said treatment comprises inhibiting a member selected from the group consisting of matrix metalloproteinase activity in tear fluid, synthesis and activation of interleukin-1 β, conversion of precursor interleukine-1 β to mature interleukin-1 β, ocular surface inflammation and reactive oxygen species in tear fluid and ocular surface epithelium. 
     
     
         20 . The method of  claim 19 , wherein said matrix metalloproteinase comprises matrix metalloproteinase-9. 
     
     
         21 . The method of  claim 12 , wherein said treatment comprises increasing production of an interleukin-1 receptor antagonist by corneal epithelium. 
     
     
         22 . The method of  claim 12 , wherein said treatment comprises reducing interleukin-1-α concentration in tear fluid. 
     
     
         23 . A composition for treating a patient having meibomian gland disease, said composition comprising an antimicrobial tetracycline or a non-antimicrobial tetracycline as an active ingredient in a balanced salt solution. 
     
     
         24 . The composition of  claim 23 , wherein said active ingredient has a final concentration of between about 0.001% to about 1.0%. 
     
     
         25 . The composition of  claim 23 , wherein said active ingredient has a final concentration of about 0.025%. 
     
     
         26 . The composition of  claim 23 , wherein said active ingredient is doxycyc line. 
     
     
         27 . The composition of  claim 23 , wherein said antimicrobial tetracycline comprises a member selected from the group consisting of a topical ointment, a gel and a sustained-release preparation. 
     
     
         28 . An ophthalmic preparation comprising an aqueous solution containing one or more tetracycline compounds in an amount sufficient to treat an ocular disease characterized by eye surface inflammation. 
     
     
         29 . The ophthalmic preparation of  claim 15  wherein said tetracycline compound is tetracycline hydrochloride. 
     
     
         30 . The ophthalmic preparation of  claim 16  wherein said tetracycline hydrochloride is present at a concentration of about 0.125% to 2% when the solution is isotonic or attains isotonicity.