Compositions and Methods for Treating Ocular Diseases

Abstract

The present invention relates to the treatment of ocular diseases in a human subject. In particular, the invention relates to an intracameral administration of a sustained release biodegradable intracameral implant.

What is claimed is: 
     
         1 . An intracameral implant comprising:
 biodegradable hydrogel comprising (i) a polymer network comprising one or more units of polyalkylene glycol, and (ii) sustained release travoprost particles,   the sustained release travoprost particles comprising travoprost and at least one biodegradable polymer,   the sustained release travoprost particles dispersed within the hydrogel,   wherein the implant is suitable for intracameral implantation and has a length of about 1 mm to about 2.5 mm in its dry state, a diameter of not more than 0.3 mm in its dried state and a total weight of about 20 μg to about 110 μg in its dry state, wherein travoprost is the sole active agent in the implant and wherein the travoprost particles are a blend of at least two travoprost particles selected from   1) first travoprost particles comprising:   travoprost and   biodegradable polymer comprising a polylactide or polylactides having an acid end group and an inherent viscosity ranging from about 0.05 to less than about 0.5 dl/g measured in 0.5% w/v chloroform at 30° C.,   wherein the first particles comprise from about 40 wt.-% to about 50 wt.-% travoprost, based on the total mass of the first particles;   2) second travoprost particles comprising:   travoprost and   biodegradable polymer comprising a polylactide or polylactides having an acid end group and an inherent viscosity specification ranging from about 0.5 to less than about 0.80 dl/g measured in 0.5% w/v chloroform at 30° C.,   wherein the second particles comprise from about 40 wt.-% to about 50 wt.-% travoprost, based on the total mass of the second particles;   3) third travoprost particles comprising:   travoprost and   biodegradable polymer comprising a polylactide or polylactides having an acid end group and an inherent viscosity specification ranging from about 0.8 to about 1.7 dl/g measured in 0.5% w/v chloroform at 30° C.,   wherein the third particles comprise from about 40 wt.-% to about 50 wt.-% travoprost based on the total mass of the third particles;   4) fourth travoprost particles comprising:   travoprost and   biodegradable polymer comprising a polylactide or polylactides having an ester end group and an inherent viscosity ranging from about 0.05 to about 1.7 dl/g measured in 0.1% w/v chloroform at 25° C.,   wherein the fourth particles comprise from about 40 wt.-% to about 50 wt.-% travoprost based on the total mass of the fourth particles.   
     
     
         2 . The intracameral implant according to  claim 1 , wherein the implant has a diameter of less than 0.5 mm after 24 hours of hydration in vitro in phosphate-buffered saline at a pH of 7.4 at 37° C. 
     
     
         3 . The intracameral implant according to  claim 2 , wherein the implant has a diameter ranging from about 0.3 mm to 0.49 mm after 24 hours of hydration in vitro in phosphate-buffered saline at a pH of 7.4 at 37° C. 
     
     
         4 . The intracameral implant according to  claim 1 , wherein a ratio of the diameter of the implant after 24 hours of hydration in vitro in phosphate-buffered saline at a pH of 7.4 at 37° C. to the diameter of the implant in its dried state is less than 2.5. 
     
     
         5 . The intracameral implant according to  claim 1 , wherein the implant contains a dose of about 2 μg to about 30 μg of travoprost 
     
     
         6 . (canceled) 
     
     
         7 . The intracameral implant according to  claim 1 , wherein the biodegradable polymer comprises a polylactide and the hydrogel comprises a polymer network comprising one or more units of polyethylene glycol. 
     
     
         8 . The intracameral implant according to  claim 1 , wherein the hydrogel comprises a polymer network comprising one or more units of polyethylene glycol. 
     
     
         9 . The intracameral implant according to  claim 1 , wherein the implant is in the form of a fiber. 
     
     
         10 . The intracameral implant according to  claim 1 , wherein the implant has a total weight of about 30 μg to about 105 μg in its dried state. 
     
     
         11 . The intracameral implant according to  claim 1 , wherein the implant shows a burst of less than 15%, based on the total weight of travoprost in the intracameral implant, on day 1 measured in vitro under simulated physiological sink conditions in 50 mL of 1×PBS, 0.5% castor oil, 0.01% sodium fluoride buffer at pH 7.2-7.4 at 37° C. 
     
     
         12 . The intracameral implant according to  claim 1 , wherein the total mass of the biodegradable polymer in the implant is less than 34 μg. 
     
     
         13 . The intracameral implant according to  claim 1 , wherein the travoprost in the implant is less than 25 μg. 
     
     
         14 . The intracameral implant according to  claim 1 , wherein the total mass of the implant is less than 103 μg in its dried state. 
     
     
         15 . The intracameral implant according to  claim 1 , wherein the travoprost particles have a diameter ranging from 1 to 100 μm determined by sieving or have an average diameter ranging from 1 to 100 μm determined by laser diffraction. 
     
     
         16 . The intracameral implant according to  claim 1 , wherein the polymer network comprises an 8-arm-polyethylene glycols being cross-linked including a group represented by the following formula 
       
         
           
           
               
               
           
         
         wherein m is 2 or 6. 
       
     
     
         17 . The intracameral implant according to  claim 1 , wherein the hydrogel dissolves within 2 to 4 months when implanted into the eye. 
     
     
         18 . The intracameral implant according to  claim 1 , wherein the hydrogel dissolves within 6 to 8 months when implanted into the eye. 
     
     
         19 . (canceled) 
     
     
         20 . The intracameral implant according to  claim 16 , wherein the implant contains a dose of about 5 μg of travoprost comprises an 8-arm-polyethylene glycol being cross-linked including a group represented by the following formula 
       
         
           
           
               
               
           
         
         wherein m is 2. 
       
     
     
         21 . The intracameral implant according to  claim 16 , wherein the implant contains a dose of about 15 μg of travoprost and comprises an 8-arm-polyethylene glycols being cross-linked including a group represented by the following formula 
       
         
           
           
               
               
           
         
         wherein m is 2. 
       
     
     
         22 . The intracameral implant according to  claim 16 , wherein the implant contains a dose of about 15 μg of travoprost and comprises an 8-arm-polyethylene glycols being cross-linked including a group represented by the following formula 
       
         
           
           
               
               
           
         
         wherein m is 6. 
       
     
     
         23 . The intracameral implant according to  claim 16 , wherein the implant contains a dose of about 26 μg of travoprost and comprises an 8-arm-polyethylene glycols being cross-linked including a group represented by the following formula 
       
         
           
           
               
               
           
         
         wherein m is 6. 
       
     
     
         24 . The intracameral implant according to  claim 1 , wherein the implant has a length of about 1.5 mm to about 2.5 mm in its dried state; and a diameter of about 0.14 mm to about 0.29 mm in its dried state. 
     
     
         25 . The intracameral implant according to  claim 1 , wherein the travoprost particles comprise a blend of particles comprising
 first travoprost particles comprising a mixture of travoprost and the biodegradable polymer comprises a polylactide or polylactides having an acid end group and an inherent viscosity ranging from about 0.05 to less than about 0.5 dl/g measured in 0.5% w/v chloroform at 30° C., wherein the first particles contain from about 40 wt.-% to about 50 wt.-%, travoprost, based on the total mass of the first particles; and   second travoprost particles comprising a mixture of travoprost and the biodegradable polymer comprising a polylactide or polylactides having an acid end group and an inherent viscosity ranging from about 0.5 to less than about 0.80 dl/g measured in 0.5% w/v chloroform at 30° C., wherein the second particles contain from about 40 wt.-% to about 50 wt.-% travoprost, based on the total mass of the second particles,
 wherein the blend comprises based on the total amount of the blend, about 35 wt.-% to about 55 wt.-% particles of the first particles and about 35 wt.-% to about 55 wt.-% particles of the of particles. 
   
     
     
         26 . The intracameral implant according to  claim 1 , wherein the travoprost particles comprise a blend of particles comprising
 first particles comprising a mixture of travoprost and the biodegradable polymer comprising a polylactide or polylactides having an acid end group and an inherent viscosity ranging from about 0.05 to less than about 0.5 dl/g measured in 0.5% w/v chloroform at 30° C. wherein the first particles contains from about 40 wt.-% to about 50 wt.-% travoprost, based on the total mass of the first particles,   a second type of travoprost particles comprising a mixture of travoprost and the biodegradable polymer comprising a polylactide or polylactides having an acid end group and an inherent viscosity ranging from about 0.5 to less than about 0.80 dl/g measured in 0.5% w/v chloroform at 30° C. wherein the second particle contains from about 40 wt.-% to about 50 wt.-% travoprost, based on the total mass of the second particles, and   a third type of travoprost particles comprising a mixture of travoprost and the biodegradable polymer comprising a polylactide or polylactides having an acid end group and an inherent viscosity ranging from about 0.8 to about 1.7 dl/g measured in 0.5% w/v chloroform at 30° C. wherein the third particles contains from about 40 wt.-% to about 50 wt.-% travoprost, based on the total mass of the third particles,   wherein the blend comprises, based on the total amount of blend, about 20 wt.-% to about 35 wt.-% particles of the first particles and about 30 wt.-% to about 50 wt.-% particles of the second particles and about 25 wt.-% to about 45 wt.-% of particles of the third particles.   
     
     
         27 . The intracameral implant according to  claim 1 , wherein the travoprost particles comprise a blend of particles comprising
 first particles comprising a mixture of travoprost and the biodegradable polymer comprising a polylactide or polylactides having an acid end group and an inherent viscosity ranging from about 0.05 to less than about 0.5 dl/g measured in 0.5% w/v chloroform at 30° C. wherein the first particles contains from about 40 wt.-% to about 50 wt.-% travoprost, based on the total mass of the first particles,   second particles comprising a mixture of travoprost and the biodegradable polymer comprising a polylactide or polylactides having an acid end group and an inherent viscosity ranging from about 0.5 to less than about 0.80 dl/g measured in 0.5% w/v chloroform at 30° C. wherein the second particles contains from about 40 wt.-% to about 50 wt.-% travoprost, based on the total mass of the second particles,   third particles comprising travoprost and the biodegradable polymer comprising a polylactide or polylactides having an acid end group and an inherent viscosity ranging from about 0.8 to about 1.7 dl/g measured in 0.5% w/v chloroform at 30° C. wherein the third particles contain from about 40 wt.-% to about 50 wt.-% travoprost, based on the total mass of the third particles, and   fourth particles comprising travoprost and the biodegradable polymer comprising a polylactide or polylactides having an ester end group and an inherent viscosity ranging from about 0.05 to about 1.7 dl/g measured in 0.1% w/v chloroform at 25° C. wherein the fourth particles contains from about 40 wt.-% to about 50 wt.-% travoprost, based on the total mass of the fourth particles,   wherein the blend contains, based on the total amount of blend, about 15 wt.-% to about 25 wt.-% particles of the first particles and about 15 wt.-% to about 25 wt.-% particles of the second particles and about 5 wt.-% to about 15% of the third particles and about 40 wt.-% to about 60 wt.-% of particles of the fourth particles.   
     
     
         28 . An intracameral implant comprising:
 biodegradable hydrogel comprising (i) a polymer network comprising one or more units of polyalkylene glycol, and (ii) sustained release travoprost particles,   the sustained release travoprost particles comprising travoprost and at least one biodegradable polymer,   the sustained release travoprost particles dispersed within the hydrogel,   wherein the implant is suitable for intracameral implantation and has a length of about 1 mm to about 2.5 mm in its dry state, a diameter of not more than 0.3 mm in its dried state and a total weight of about 20 μg to about 110 μg in its dry state, wherein travoprost is the sole active agent in the implant and wherein the travoprost particles are a blend of at least two travoprost particles selected from   1) first travoprost particles comprising:   travoprost and   biodegradable polymer comprising a polylactide or polylactides having an acid end group and an inherent viscosity ranging from about 0.05 to less than about 0.5 dl/g measured in 0.5% w/v chloroform at 30° C.;   2) second travoprost particles comprising:   travoprost and   biodegradable polymer comprising a polylactide or polylactides having an acid end group and an inherent viscosity ranging from about 0.5 to less than about 0.80 dl/g measured in 0.5% w/v chloroform at 30° C.;   3) third travoprost particles comprising:   travoprost and   biodegradable polymer comprising a polylactide or polylactides having an acid end group and an inherent viscosity ranging from about 0.8 to about 1.7 dl/g measured in 0.5% w/v chloroform at 30° C.;   4) fourth travoprost particles comprising:   travoprost and   biodegradable polymer comprising a polylactide or polylactides having an ester end group and an inherent viscosity ranging from about 0.05 to about 1.7 dl/g measured in 0.1% w/v chloroform at 25° C.   
     
     
         29 . An intracameral implant comprising:
 biodegradable hydrogel comprising (i) a polymer network comprising one or more units of polyalkylene glycol, and (ii) sustained release travoprost particles,   the sustained release travoprost particles comprising travoprost and at least one biodegradable polymer,   the sustained release travoprost particles dispersed within the hydrogel,   wherein the implant is suitable for intracameral implantation and has a length of about 1 mm to about 2.5 mm in its dry state, a diameter of not more than 0.3 mm in its dried state and a total weight of about 20 μg to about 110 μg in its dry state, wherein travoprost is the sole active agent in the implant and wherein the travoprost particles are a blend of at least two travoprost particles, wherein each travoprost particles comprise from about 40 wt.-% to about 50 wt.-% travoprost, based on the total mass of the particles, wherein each travoprost particles comprise travoprost and a biodegradable polymer comprising a polylactide or polylactides and wherein the polylactide or polylactides of each travoprost particles have a different inherent viscosity.