Cyclosporin compositions

Abstract

Disclosed herein are therapeutic methods, compositions, and medicaments related to cyclosporine.

What is claimed is: 
     
         1 . A composition comprising cyclosporin A at a concentration of from about 0.0001% (w/v) to less than about 0.05% (w/v). 
     
     
         2 . The composition of  claim 1  which is an aqueous solution. 
     
     
         3 . The concentration of  claim 1  wherein the concentration of cyclosporin A is from about 0.02% (w/v) to about 0.04% (w/v). 
     
     
         4 . The composition of  claim 2  wherein the concentration of cyclosporin A is from about 0.02% (w/v) to about 0.04% (w/v). 
     
     
         5 . The composition of  claim 2  containing no ethanol. 
     
     
         6 . The composition of  claim 2  containing no hyaluronic acid. 
     
     
         7 . The composition of  claim 2  containing no cyclodextrin A. 
     
     
         8 . The composition of  claim 6  containing no cyclodextrin. 
     
     
         9 . The composition of  claim 8  containing no ethanol. 
     
     
         10 . The composition of  claim 9  containing no vitamin E TPGS. 
     
     
         11 . The composition of  claim 9  containing no hyaluronic acid. 
     
     
         12 . The composition  claim 1  wherein topical administration of one 35 μL drop of said composition to each eye of a female New Zealand white rabbit provides to the corneas of said rabbit at least about 500 ng of cyclosporin A per gram of cornea of said rabbit at 30 minutes after said topical administration. 
     
     
         13 . The composition of  claim 1  wherein topical administration of one 35 μL drop of said composition to each eye of a female New Zealand white rabbit provides to the corneas of said rabbit at least about 1000 ng of cyclosporin A per gram of cornea of said rabbit at 30 minutes after said topical administration. 
     
     
         14 . The composition of  claim 1  wherein topical administration of one 35 μL drop of said composition to each eye of a female New Zealand white rabbit provides to the corneas of said rabbit at least about 1400 ng of cyclosporin A per gram of cornea of said rabbit at 30 minutes after said topical administration. 
     
     
         15 . The composition of  claim 1  wherein topical administration of one 35 μL drop of said composition to each eye of a female New Zealand white rabbit provides to the corneas of said rabbit at least about 17000 ng·hr of cyclosporin A per gram of cornea of said rabbit over a period of 24 hours after said topical administration. 
     
     
         16 . The composition of  claim 2  wherein topical administration of one 35 μL drop of said composition to each eye of a female New Zealand white rabbit provides to the conjunctivas of said rabbit at least about 3300 ng·hr of cyclosporin A per gram of conjunctiva of said rabbit over a period of 24 hours after said topical administration. 
     
     
         17 . The composition of  claim 2  wherein said composition is an aqueous solution containing from 0.005% (w/v) to about 0.04% (w/v) cyclosporin A, wherein topical administration of one 35 μL drop of said composition to each eye of a New Zealand rabbit provides at least about 17000 ng·hr of cyclosporin A per gram of cornea to the corneas of said rabbit as determined by:
 topically administering said composition to each eye of each of 15 female New Zealand white rabbit test subjects; and 
 determining the amount of cyclosporin A in the corneas of three subjects at times of about 0.5 hours, about 2 hours, about 6 hours, about 12 hours, and about 24 after administration to said subject; 
 wherein the amount of cyclosporin A in the cornea is determined only once for each subject. 
 
     
     
         18 . The composition of  claim 2  wherein said composition is an aqueous solution containing from 0.005% (w/v) to about 0.04% (w/v) cyclosporin A, wherein topical administration of one 35 μL drop of said composition to each eye of a New Zealand rabbit provides at least about 6000 ng of cyclosporin A per gram of conjunctiva to the conjunctivas of said rabbit as determined by:
 topically administering said composition to each eye of each of 15 female New Zealand white rabbit test subjects; and 
 determining the amount of cyclosporin A in the conjunctivas of three subjects at times of about 0.5 hours, about 2 hours, about 6 hours, about 12 hours, and about 24 after administration to said subject; 
 wherein the amount of cyclosporin A in the conjunctiva is determined only a single time for each subject. 
 
     
     
         19 . The composition of  claim 1  further comprising a surfactant. 
     
     
         20 . The composition of  claim 1  further comprising a preservative. 
     
     
         21 . A method comprising topically administering a composition according to  claim 1  to an eye of a mammal in need thereof to enhance or restore lacrimal gland tearing. 
     
     
         22 . The method of  claim 21 , wherein said method increases tear production in a tear-deficient eye. 
     
     
         23 . The method of  claim 21 , wherein said method is effective in treating keratoconjunctivitis sicca. 
     
     
         24 . The method of  claim 21 , wherein said method is effective in treating dry eye disease. 
     
     
         25 . The method of  claim 21  wherein the mammal is a human patient, and wherein less than 10% of human patients suffer burning or stinging when said composition is administered only once a day for a period of three months. 
     
     
         26 . The method of  claim 21  wherein the mammal is a human patient, and wherein less than 10% of human patients suffer ocular burning when said composition is administered only once a day for a period of three months. 
     
     
         27 . The method of  claim 21  wherein the composition is administered only once a day. 
     
     
         28 . An aqueous solution comprising cyclosporin A at a concentration of from 0.01% (w/v) to 0.019% (w/v). 
     
     
         29 . The composition of  claim 28  wherein the concentration of cyclosporin A is about 0.015% (w/v). 
     
     
         30 . An aqueous solution comprising cyclosporin A at a concentration of from 0.01% (w/v) to 0.02% (w/v) and more than 95% (w/w) water. 
     
     
         31 . An aqueous solution comprising cyclosporin A at a concentration of from 0.01% (w/v) to 0.02% (w/v) and does not contain sodium hyaluronate at a concentration of 0.05% (w/v). 
     
     
         32 . The aqueous solution of  claim 31  which contains no sodium hyaluronate. 
     
     
         33 . An aqueous solution comprising cyclosporin A at a concentration of from 0.01% (w/v) to 0.02% (w/v) and does not contain polysorbate 80 at a concentration of 0.05% (w/v). 
     
     
         34 . The aqueous solution of  claim 31  which contains from 0.1% to 1% polysorbate 80. 
     
     
         35 . An kit comprising a container comprising an aqueous solution comprising cyclosporin A at a concentration of from 0.005% (w/v) to 0.03% (w/v), wherein said container is capable of dispensing eye drops, and wherein said composition has been stored in said container for at least two months. 
     
     
         36 . A composition comprising cyclosporin A at a concentration of from 0.01% (w/v) to 0.02% (w/v) and a preservative. 
     
     
         37 . The composition of  claim 36  wherein the concentration of cyclosporin A is about 0.015% (w/v). 
     
     
         38 . The composition of  claim 2  wherein the cyclosporin A concentration is about 0.04% (w/v). 
     
     
         39 . The composition of  claim 2  wherein the cyclosporin A concentration is about 0.005% (w/v).