Ocular therapeutic agent delivery devices and methdos for making and using such devices

Abstract

Ocular implant devices ( 10, 20, 121 ) for the delivery of a therapeutic agent to an eye ( 101, 301 ) in a controlled and sustained manner. Dual mode and single mode drug delivery devices ( 10, 20, 121 ) are illustrated and described. Implants ( 10, 20 ) suitable for subconjunctival placement are described. Implants ( 121, 10, 20 ) suitable for intravitreal placement also are described. The invention also includes fabrication and implementation techniques associated with the unique ocular implant devices ( 10, 20, 121 ) that are presented herein.

1 - 52 . (canceled) 
     
     
         53 . A method of delivering a therapeutic agent to an eye in need of treatment thereof, comprising attaching an implant comprising a therapeutic agent to eye tissues in which the implant releases the therapeutic agent continuously to the eye by initial delivery of a loading dose to the eye followed by a period of time in which delivery of the therapeutic agent to the eye occurs via a substantially constant release rate. 
     
     
         54 . The method according to  claim 53  wherein the period of time of substantially constant release rate being approximately three months or more. 
     
     
         55 . The method according to  claim 53  wherein the eye tissues comprise subconjunctival tissues or intravitreal tissues. 
     
     
         56 . An ocular implant providing sustained-release of a first therapeutic agent to the eye for a prolonged period of time, comprising:
 a composite material matrix layer comprising:   (i) a first therapeutic agent, and   (ii) a polymeric matrix material into which the first therapeutic agent is dispersed, including (1) a bioerodible polymer permeable to the therapeutic agent, and (2) a water-soluble polymer having greater water solubility than the permeable polymer.   
     
     
         57 . The ocular implant according to  claim 56  wherein a discrete solid core comprising the first or a second therapeutic agent, and where the solid core is embedded within the composite material matrix layer. 
     
     
         58 . The ocular implant according to  claim 57  wherein the composite material matrix layer containing about 5 to about 50 wt % of the permeable polymer, about 0.05 to about 90 wt % of the water-soluble polymer, and about 1.0 to about 50 wt % of the first therapeutic agent. 
     
     
         59 . An ocular implant providing sustained-release of a therapeutic agent to the eye for a prolonged period of time, comprising:
 (a) a composite material matrix layer comprising:   (i) a first therapeutic agent, and   (ii) a polymeric matrix material into which the first therapeutic agent is dispersed, including poly(ethylene vinyl) acetate and a cellulose ether polymer, and   (b) optionally, a discrete solid core comprising an additional amount of the first therapeutic agent or a second different therapeutic agent, wherein the solid core being embedded within the composite material matrix layer.   
     
     
         60 . A method of making an implant useful for providing sustained-release of a therapeutic agent to the eye for a prolonged period of time, comprising:
 (a) forming a premixture by mixing and dispersing a therapeutic agent with a cellulose ether polymer in an aqueous medium effective to provide a suspension of the therapeutic agent;   (b) combining the premixture of step (a) with superhydrolyzed polyvinyl alcohol with mixing effective to form a substantially uniform mixture;   (c) applying the substantially uniform mixture upon a flat surface as a coating layer;   (d) optionally embedding a pellet of therapeutic agent within the coating layer;   (e) drying the coating layer to provide a composite material matrix layer including a polymer matrix;   (f) cutting out a section of the dried coating layer to provide an ocular implant.   
     
     
         61 . A method of delivering a therapeutic agent to an eye in need of treatment thereof, comprising:
 attaching an implant comprising a therapeutic agent to the eye, in which the implant comprises a composite material matrix layer including a therapeutic agent, and a polymeric matrix material into which the therapeutic agent is dispersed including a superhydrolyzed polyvinyl alcohol permeable to the therapeutic agent and a cellulose ether polymer, and, optionally, a discrete solid core comprising an additional therapeutic agent and embedded within the composite material matrix layer, effective to deliver the therapeutic agent to the eye.   
     
     
         62 . The method of  claim 61  wherein the implant is attached to a subconjunctival region of the eye or an intravitreal region of the eye. 
     
     
         63 . The method of  claim 61  wherein the discrete solid core is included, and delivery of the therapeutic agent proceeds as an initial loading dose delivery followed by sustained release of a lower, relatively constant rate of infusion. 
     
     
         64 . The method of  claim 61  wherein the therapeutic agent in the composite material matrix layer and the pellet comprise cyclosporine. 
     
     
         65 . An intraocular reservoir implant comprising a first therapeutic agent reservoir subassembly comprising an inner core comprising a therapeutic agent for the eye covered by and substantially radially centered within a polymeric layer including silicone material permeable to the therapeutic agent, and an ocular attachment means affixed to the polymeric layer of the subassembly. 
     
     
         66 . The intraocular implant according to  claim 65 , wherein the polymeric layer additionally comprises a dispersion of therapeutic agent. 
     
     
         67 . The intraocular implant according to  claim 65  wherein the attachment means comprises a suture stub. 
     
     
         68 . The intraocular implant according to  claim 65  wherein the attachment means comprises a crosslinked polyvinyl alcohol member. 
     
     
         69 . A method of making an implant for intraocular delivery of therapeutic substances to the eye, comprising:
 providing a mold comprising an upper surface region including at least one impression provided therein including lateral and depth dimensions sufficient to receive a drug pellet and an upright rigid post fixed in location at a side of the impression, in which the upper surface region includes polytetrafluoroethylene;   introducing flowable silicone fluid into the impression, in which the silicone optionally contains a dispersion of therapeutic drug;   submerging a drug pellet in the silicone fluid;   centering the drug pellet, in which the pellet is surrounded at all exposed peripheral sides and top surface thereof by the silicone fluid;   optionally spinning the mold via centrifugation sufficient to degas the silicone fluid;   optionally passing a polyester mesh down the post until submerged in the flowable silicone fluid;   hardening the silicone fluid to form an integral silicone/pellet subassembly;   separating the silicone-pellet subassembly from the upper surface region of the mold.   
     
     
         70 . A method of delivering a therapeutic agent to an eye in need of treatment thereof, comprising:
 attaching an implant comprising a therapeutic agent in the vitreous tissues of the eye, in which the implant comprises a therapeutic agent reservoir subassembly comprising an inner core comprising a therapeutic agent for the eye covered by and substantially radially centered within a polymeric layer including silicone material permeable to the therapeutic agent, and an ocular attachment means affixed to the polymeric layer, effective to deliver the therapeutic agent intravitreally.