Intracameral drug delivery depots

Abstract

Methods of treating an eye for an ocular condition such as placing a composite depot comprising a xerogel with embedded degradable particles into an anterior chamber of an eye to deliver a therapeutic agent. The xerogel is a hydrogel after exposure to intraocular fluid and is degradable. The degradable particles comprise the therapeutic agent and hydrolytically degrade in the anterior chamber to provide a controlled release of the therapeutic agent into the eye. Materials and processes for making depots are provided as well as alternative methods of their use.

1 . A composite depot comprising:
 a xerogel adapted for placement in the intracameral site of an eye for treatment of an ocular condition, the xerogel comprising a cross-linked matrix having crosslinked moieties with 4-10 arms each with polyethylene glycol terminated with an end group formed by the amidization of a functional group selected from one or more succinimidyl succinate, succinimidyl adipate, succinimidyl azelate and succinimidyl glutarate, wherein the xerogel is converted to a hydrolytically degradable hydrogel after exposure to intraocular fluid;   hydrolytically degradable particles having diameters less than or equal to 100 microns embedded in the xerogel, the hydrolytically degradable particles comprising one or more of polylactic acid (PLA), polyglycolic acid (PGA), or a copolymer of PLA and PGA; and   a therapeutic agent encapsulated by the hydrolytically degradable particles, wherein the therapeutic agent comprises travoprost,   wherein the composite depot is rod-shaped.   
     
     
         2 . The composite depot of  claim 1 , wherein the cross-linked matrix is conjugated with a fluorescent imaging agent. 
     
     
         3 . The composite depot of  claim 2 , wherein the fluorescent imaging agent comprises fluorescein. 
     
     
         4 . The composite depot of  claim 3 , wherein the fluorescein is not visible without a machine aid. 
     
     
         5 . The composite depot of  claim 1 , wherein the cross-linked matrix comprises no more than about 5 wt % fluorescein. 
     
     
         6 . The composite depot of  claim 1 , wherein the cross-linked matrix is made by reacting a polyethylene glycol precursor with a fluorescein-conjugated trilysine. 
     
     
         7 . The composite depot of  claim 1 , wherein the composite depot is visible with fluorescence after placement in the intracameral site of an eye and wherein the degradation of the hydrogel can be determined by an absence of fluorescence. 
     
     
         8 . The composite depot of  claim 1 , wherein the length of the composite depot is from 0.1 mm to 10 mm. 
     
     
         9 . The composite depot of  claim 1 , wherein the diameter of the composite depot at equilibrium water content is less than 1 mm. 
     
     
         10 . The composite depot of  claim 1 , wherein the composite depot has a volume from 0.1 μL to 1000 μL. 
     
     
         11 . The composite depot of  claim 1 , wherein the amount of the travoprost in the composite depot has a dry weight from 10 μg to 100 μg. 
     
     
         12 . The composite depot of  claim 1 , wherein the composite depot is adapted for delivery into the intracameral site of the eye using a needle smaller than, or equal to, 25 gauge. 
     
     
         13 . The composite depot of  claim 1 , wherein the cross-linked matrix comprises crosslinked moieties with 4-8 arms. 
     
     
         14 . The composite depot of  claim 1 , wherein the cross-linked matrix comprises crosslinked moieties with 4 arms. 
     
     
         15 . The composite depot of  claim 1 , wherein the cross-linked comprises crosslinked moieties with 8 arms. 
     
     
         16 . The composite depot of  claim 1 , wherein the composite depot is adapted to release a therapeutically effective dose of the travoprost for at least three months and no more than 8 months. 
     
     
         17 . A composite depot comprising:
 a xerogel adapted for placement in the intracameral site of an eye for treatment of an ocular condition, the xerogel comprising a cross-linked matrix, wherein the xerogel is converted to a hydrolytically degradable hydrogel after exposure to intraocular fluid;   hydrolytically degradable particles, the hydrolytically degradable particles comprising one or more of polylactic acid (PLA), polyglycolic acid (PGA), or a copolymer of PLA and PGA; and   a therapeutic agent encapsulated by the hydrolytically degradable particles, wherein the therapeutic agent comprises travoprost,   wherein the composite depot is rod-shaped, and wherein the length of the composite depot is from 0.1 mm to 10 mm.   
     
     
         18 . The composite depot of  claim 17 , wherein the cross-linked matrix is conjugated with a fluorescent imaging agent. 
     
     
         19 . The composite depot of  claim 17 , wherein the diameter of the composite depot at equilibrium water content is less than 1 mm. 
     
     
         20 . The composite depot of  claim 17 , wherein the composite depot has a volume from 0.1 μL to 1000 μL. 
     
     
         21 . The composite depot of  claim 17 , wherein the amount of the travoprost in the composite depot has a dry weight from 10 μg to 100 μg. 
     
     
         22 . The composite depot of  claim 17 , wherein the composite depot is adapted for delivery into the intracameral site of the eye using a needle smaller than, or equal to, 25 gauge. 
     
     
         23 . The composite depot of  claim 17 , wherein the cross-linked matrix is formed by cross-linking 4-8 arm polyethylene glycol. 
     
     
         24 . The composite depot of  claim 17 , wherein the cross-linked matrix is formed by cross-linking 4 arm polyethylene glycol. 
     
     
         25 . The composite depot of  claim 17 , wherein the cross-linked matrix is formed by cross-linking 8 arm polyethylene glycol. 
     
     
         26 . The composite depot of  claim 17 , wherein the composite depot is adapted to release a therapeutically effective dose of the travoprost for at least three months and no more than 8 months. 
     
     
         27 . A composite depot comprising:
 a xerogel adapted for placement in the intracameral site of an eye for treatment of an ocular condition, the xerogel comprising a cross-linked matrix comprising 4-10 arm polyethylene glycol terminated with an end group selected from one or more succinimidyl succinate, succinimidyl adipate, succinimidyl azelate and succinimidyl glutarate, and wherein the xerogel is converted to a hydrolytically degradable hydrogel after exposure to intraocular fluid;   hydrolytically degradable particles having diameters less than or equal to 100 microns embedded in the xerogel, the hydrolytically degradable particles comprising one or more of polylactic acid (PLA), polyglycolic acid (PGA), or a copolymer of PLA and PGA; and   a therapeutic agent encapsulated by the hydrolytically degradable particles, wherein the therapeutic agent comprises travoprost, and wherein the travoprost has a dry weight in the composite depot from 10 μg to 100 μg,   wherein the composite depot is rod-shaped, wherein the length of the composite depot is from 0.1 mm to 10 mm, wherein the diameter of the composite depot at equilibrium water content is less than 1 mm, wherein the composite depot has a volume from 0.1 μL to 1000 μL, and wherein the composite depot is adapted to release a therapeutically effective dose of the therapeutic agent for at least three months and no more than 8 months.   
     
     
         28 . The composite depot of  claim 27 , wherein the cross-linked matrix is conjugated with a fluorescent imaging agent and wherein the hydrogel degrades about 2 to about 4 months after placement as determined by an absence of fluorescence.