Ocular delivery of drugs

Abstract

The present invention relates to an aqueous composition comprising a macrolide immunosuppressant drug at a concentration of less than 2% w/v and an amphiphilic carbohydrate compound having a molecular weight in the range 1-50 kDa, for use in treatment of an eye disorder by topical application to the eye, wherein the amphiphilic carbohydrate compound is present at a concentration below 10% w/v of the composition. A preferred carbohydrate compound is quaternary ammonium palmitoyl glycol chitosan (GCPQ). Pharmaceutical compositions and methods of treatment are also provided. The treatment may be for instance dry eye syndromes (DES), vernal keratoconjunctivitis (VKC), eczema, atopic keratoconjunctivitis (AKC), Sjögren syndrome, post-operative refractive surgery, corneal transplant or contact lens intolerance.

1 - 14 . (canceled) 
     
     
         15 . A method of treating an eye disorder, comprising topically applying an aqueous composition to the eye of a subject in need thereof,
 wherein the aqueous composition comprises an immunosuppressant drug at a concentration of less than 2% w/v and an amphiphilic carbohydrate compound having a molecular weight in the range 1-50 kDa,   wherein the amphiphilic carbohydrate compound is present at a concentration below 10% w/v of the composition, and is represented by the general formula:   
       
         
           
           
               
               
           
         
         wherein a+b+c+d=1.000 and 
         a is between 0.00 and 0.84 
         b is between 0.01 and 0.40, 
         c is between 0.00 and 0.84, and 
         d is between 0.05 and 0.50; and 
         wherein: 
         X is a hydrophobic group; 
         R 1 , R 2  and R 3  are independently selected from a substituted or unsubstituted alkyl group; 
         R 4 , R 5 , R 6  and R 10  are independently selected from hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, or a substituted or unsubstituted alkene group; 
         R 7  may be present or absent and, when present, is an unsubstituted or substituted alkyl group, an unsubstituted or substituted amine group or a substituted or unsubstituted amide group; 
         R 8  and R 9  are independently selected from hydrogen and either a substituted or unsubstituted alkyl group, a substituted or unsubstituted ether group, or a substituted or unsubstituted alkene group; 
         or a salt thereof. 
       
     
     
         16 . The method according to  claim 15 , wherein the immunosuppressant drug is selected from the group consisting of sirolimus, cyclosporine A, tacrolimus and everolimus. 
     
     
         17 . The method according to  claim 15 , wherein the composition does not comprise lipids. 
     
     
         18 . The method according to  claim 15 , wherein the eye disorder comprises dry eye syndromes (DES), vernal keratoconjunctivitis (VKC), eczema, atopic keratoconjunctivitis (AKC), Sjogren syndrome, post-operative refractive surgery, corneal transplant or contact lens intolerance. 
     
     
         19 . The method according to  claim 15 , wherein the aqueous composition comprises the drug is encapsulated by the amphiphilic carbohydrate compound. 
     
     
         20 . The method according to  claim 15 , wherein the aqueous composition comprises aggregates having a mean particle size between 10 nm and 20 μm. 
     
     
         21 . The method according to  claim 15 , wherein the carbohydrate compound is quaternary ammonium palmitoyl glycol chitosan (GCPQ). 
     
     
         22 . The method according to  claim 21 , wherein the palmitoylation level, d, is in the range 0.08-0.25. 
     
     
         23 . The method according to  claim 21 , wherein the quaternisation level, b, is in the range 0.02 to 0.20. 
     
     
         24 . The method according to  claim 15 , wherein drug is present in the aqueous composition at a concentration in the range 0.001-1% w/v. 
     
     
         25 . The method according to  claim 15 , wherein the ratio of amphiphilic carbohydrate compound to the drug in the aqueous composition is greater than 5:1. 
     
     
         26 . The method according to  claim 15 , wherein the ratio of amphiphilic carbohydrate compound to the drug in the aqueous composition is greater than 7.5:1. 
     
     
         27 . The method according to  claim 15 , wherein the amphiphilic carbohydrate compound in the aqueous composition is quaternary ammonium palmitoyl glycol chitosan (GCPQ), and the GCPQ has a palmitoylation level between 10 mole % and 40 mole %. 
     
     
         28 . The method according to  claim 15 , wherein the amphiphilic carbohydrate compound in the aqueous composition is quaternary ammonium palmitoyl glycol chitosan (GCPQ), and the GCPQ has a quaternization level between 6 mole % and 20 mole %. 
     
     
         29 . The method according to  claim 15 , wherein the amphiphilic carbohydrate compound in the aqueous composition is quaternary ammonium palmitoyl glycol chitosan (GCPQ), and wherein the GCPQ has a palmitoylation level between 16 mole % and 32 mole %. 
     
     
         30 . The method according to  claim 15 , wherein the amphiphilic carbohydrate compound in the aqueous composition is quaternary ammonium palmitoyl glycol chitosan (GCPQ), and wherein the GCPQ has a quaternization level between 11 mole % and 19 mole %. 
     
     
         31 . The method according to  claim 15 , wherein the pH of the aqueous composition is from 6.5 to 7.4. 
     
     
         32 . The method according to  claim 15 , wherein the drug is cyclosporine A. 
     
     
         33 . The method according to  claim 15 , wherein the drug is cyclosporine A and is present in the aqueous composition at a concentration of 0.05%, 0.08%, or 0.1% w/v. 
     
     
         34 . The method according to  claim 15 , wherein the drug is tacrolimus.