Drug Delivery Methods, Structures, and Compositions for Nasolacrimal System

Abstract

An implant for insertion into a punctum of a patient comprises a body. The body has a distal end, a proximal end, and an axis therebetween. The distal end of the body is insertable distally through the punctum into the canalicular lumen. The body comprises a therapeutic agent included within an agent matrix drug core. Exposure of the agent matrix to the tear fluid effects an effective therapeutic agent release into the tear fluid over a sustained period. The body has a sheath disposed over the agent matrix to inhibit release of the agent away from the proximal end. The body also has an outer surface configured to engage luminal wall tissues so as to inhibit expulsion when disposed therein. In specific embodiments, the agent matrix comprises a non-bioabsorbable polymer, for example silicone in a non-homogenous mixture with the agent.

1 - 53 . (canceled) 
     
     
         54 . A drug insert adapted for disposition within an implant, the implant being adapted for insertion into or adjacent to an eye of a patient, for providing sustained release of a therapeutic agent to the eye or surrounding tissues or both, the insert comprising a drug core and a sheath body partially covering the drug core, the drug core comprising a therapeutic agent contained in a polymer, the sheath body being disposed over a portion of the drug core to inhibit release of the agent from said portion and so as to define at least one exposed surface of the drug core adapted to release the agent to the eye or surrounding tissues, or both, when the implant is inserted into the patient. 
     
     
         55 . The drug insert of  claim 54 , wherein the therapeutic agent is selected from the group consisting of latanoprost, bimatoprost, timolol maleate and cyclosporin. 
     
     
         56 . The drug insert of  claim 54 , wherein the drug core comprises inclusions of the therapeutic agent in the polymer. 
     
     
         57 . The drug insert of  claim 56 , wherein the inclusions comprise droplets and the therapeutic agent is latanoprost. 
     
     
         58 . The drug insert of  claim 56 , wherein the inclusions comprise solid particles and the therapeutic agent is bimatoprost. 
     
     
         59 . The drug insert of  claim 56 , wherein the inclusions are from about 1 micrometer to about 100 micrometers in size. 
     
     
         60 . The drug insert of  claim 55  wherein about 3 micrograms to about 135 micrograms of latanoprost or bimatoprost is present in the drug insert. 
     
     
         61 . The drug insert of  claim 55  wherein about 3.5 micrograms, about 7 micrograms or about 14 micrograms latanoprost is present in the drug insert. 
     
     
         62 . The drug insert of  claim 54 , wherein the polymer comprises a non-biodegradable polymer. 
     
     
         63 . The drug insert of  claim 62 , wherein the non-biodegradable polymer is selected from the group consisting of silicone, an acrylate, a polyethylene, polyurethane, polyester, and Nusil 6385. 
     
     
         64 . The drug insert of  claim 54 , wherein the concentration of therapeutic agent in the drug insert is selected from the group consisting of about 5%, about 10% and about 20%. 
     
     
         65 . The drug insert of  claim 54 , wherein the drug core comprises a non-homogenous mixture of silicone and the therapeutic agent. 
     
     
         66 . The drug insert of  claim 54 , wherein the insert has a diameter selected from the group consisting of about 0.006 inches, about 0.012 inches and about 0.025 inches. 
     
     
         67 . The drug insert of  claim 54 , wherein the drug core further comprises one or more additives to increase or decrease solubility of the therapeutic agent for control of the release of the therapeutic agent. 
     
     
         68 . The drug insert of  claim 67 , wherein the one or more additives is selected from the group consisting of surfactants, tinuvin, salts and water. 
     
     
         69 . The drug insert of  claim 54 , wherein the sheath is comprised of at least one of polyimide or polyethylene terephthalate. 
     
     
         70 . A method of manufacturing a drug insert for an implant body adapted for insertion within or adjacent to an eye of a patient,
 the insert comprising a drug core and a sheath body partially covering the drug core, the drug core comprising a therapeutic agent contained in a matrix, the sheath body being disposed over a portion of the drug core to inhibit release of the agent from said portion and so as to define at least one exposed surface of the drug core adapted to release the agent to the eye or surrounding tissues, or both, when the implant is inserted into the patient, the method comprising:   injecting into a tube a mixture comprising the therapeutic agent and a polymer such that the tube is substantially filled therewith, the tube being substantially impermeable to the agent;   curing the mixture within the tube to form a tube filled with the drug core; and   cutting the tube filled with the drug core to form a plurality of drug inserts therefrom, each of the plurality of drug inserts being of substantially the same length, each insert being adapted to fit within a respective implant body and to release, through the exposed surface of the insert, therapeutic quantities of the agent to tear liquid, when the drug insert is contained within an implant that is in contact with tear liquid.   
     
     
         71 . The method of  claim 70  wherein the drug insert provides sustained release of a therapeutic agent to the eye or surrounding tissues, or both, 
     
     
         72 . The method of  claim 70 , further comprising sealing one end of the drug insert to provide an exposed surface at the other end thereof. 
     
     
         73 . The method of  claim 70 , wherein the tube is comprised of at least one of polyimide or polyethylene terephthalate. 
     
     
         74 . The method of  claim 70 , further comprising adding a catalyst into the tube prior to injecting the therapeutic agent and the polymer. 
     
     
         75 . The method of  claim 70 , wherein the polymer comprises silicone. 
     
     
         76 . The method of  claim 70 , wherein the plurality of drug inserts are between about 0.80 millimeters and 0.95 millimeters in length. 
     
     
         77 . The method of  claim 70 , wherein the therapeutic agent is selected from the group consisting of latanoprost, bimatoprost, timolol maleate and cyclosporin. 
     
     
         78 . A drug core comprising a therapeutic agent contained in a matrix for disposition into or as a drug insert or an implant, the drug insert or the implant being adapted for disposition within or adjacent to an eye of a patient for providing sustained release of the therapeutic agent to the eye or surrounding tissues or both, wherein the therapeutic agent is dissolved in the matrix or constitutes inclusions in the matrix. 
     
     
         79 . The drug core of  claim 78 , wherein the matrix comprises inclusions of liquid latanoprost oil and Nusil 6385 polymer. 
     
     
         80 . The drug core of  claim 78 , wherein the matrix comprises cyclosporin and a polyurethane. 
     
     
         81 . The drug core of  claim 78  disposed within a sheath body. 
     
     
         82 . An implant configured for insertion in or adjacent to an eye of a patient, the implant body comprising a channel therein adapted to receive a drug insert, configured such that an exposed surface of the insert will be exposed to tear liquid when the insert is disposed within the implant and the implant is disposed in or adjacent to the eye, the drug insert comprising a drug core and a sheath body partially covering the drug core, the drug core comprising a therapeutic agent contained in a matrix, the sheath body being disposed over a portion of the drug core to inhibit release of the agent from said portion and so as to define at least one exposed surface of the drug core adapted to release the agent to the eye or surrounding tissues, or both, when the implant is inserted into the patient. 
     
     
         83 . The implant of  claim 82 , wherein the implant body comprises a channel therein adapted to receive a drug core. 
     
     
         84 . The implant of  claim 82 , wherein the implant is configured for use as a punctal plug. 
     
     
         85 . The implant of  claim 82 , wherein:
 a) the therapeutic agent is latanoprost or bimatoprost and   b) about 5 nanograms to about 500 nanograms of latanoprost or bimatoprost is released each day from the implant.   
     
     
         86 . The implant of  claim 82  wherein the therapeutic agent is timolol maleate and wherein about 270 micrograms to about 1350 micrograms timolol maleate is present in the implant and wherein the implant is configured to release about 20 micrograms to about 135 micrograms timolol maleate each day. 
     
     
         87 . The implant of  claim 82  wherein the therapeutic agent is cyclosporin and wherein the implant is configured to release about 50 nanograms to about 100 nanograms cyclosporin each day. 
     
     
         88 . The implant of  claim 82 , wherein the implant is configured for delivery of therapeutic agent for a period of at least 3 months. 
     
     
         89 . The implant of  claim 82 , wherein the sheath is comprised of at least one of polyimide or polyethylene terephthalate. 
     
     
         90 . The implant of  claim 82 , wherein the implant body is configured for use in ocular tissues selected from the group consisting of: the punctum, the canaliculus, the conjunctival tissue layer of the eye, above the sclera tissue layer, and partially within the scleral tissue layer so as not to penetrate the scleral tissue. 
     
     
         91 . The implant of  claim 82 , wherein the matrix comprises a non-biodegradable polymer selected from the group consisting of silicone, an acrylate, a polyethylene, polyurethane, and polyester. 
     
     
         92 . The implant of  claim 91 , wherein the non-biodegradable polymer is Nusil 6385. 
     
     
         93 . The implant of  claim 82 , wherein the drug core comprises a non-homogenous mixture of silicone and the therapeutic agent. 
     
     
         94 . The implant of  claim 82 , wherein the drug insert has a diameter selected from the group consisting of about 0.006 inches, about 0.012 inches and about 0.025 inches. 
     
     
         95 . A method of delivering a therapeutic agent to an eye, the method comprising:
 placing an implant in a structure of the eye, the implant comprising:   an implant body comprising a channel therein adapted to receive a drug insert, configured such that an exposed surface of the insert will be exposed to tear liquid when the insert is disposed within the implant and the implant is disposed in or adjacent to the eye, the drug insert comprising a drug core and a sheath body partially covering the drug core, the drug core comprising a therapeutic agent contained in a matrix, the sheath body being disposed over a portion of the drug core to inhibit release of the agent from said portion and so as to define at least one exposed surface of the drug core adapted to release the agent to the eye or surrounding tissues, or both, when the implant is inserted into the patient, and wherein a release rate of therapeutic agent from the insert to the eye is dependent upon the exposed surface of the drug core;   and releasing the therapeutic agent to the eye over an extended period of time.   
     
     
         96 . The method of  claim 95 , wherein the implant body comprises a channel therein adapted to receive a drug core. 
     
     
         97 . The method of  claim 95 , wherein the extended period of time is at least three months. 
     
     
         98 . The method of  claim 95 , wherein the therapeutic agent is selected from the group consisting of latanoprost, bimatoprost, timolol maleate and cyclosporin. 
     
     
         99 . The method of  claim 95 , wherein the therapeutic agent is latanoprost or bimatoprost and wherein about 3 micrograms to about 135 micrograms of latanoprost or bimatoprost is present in the implant and wherein about 5 nanograms to about 500 nanograms of latanoprost or bimatoprost is released each day from the drug core. 
     
     
         100 . The method of  claim 95 , wherein the therapeutic agent is timolol maleate, wherein about 270 micrograms to about 1350 micrograms timolol maleate is present in the implant, and wherein about 20 micrograms to about 135 micrograms timolol maleate is released each day from the drug core. 
     
     
         101 . The method of  claim 95 , wherein the therapeutic agent is cyclosporin and wherein about 50 nanograms to about 100 nanograms cyclosporin is released each day from the drug core. 
     
     
         102 . The method of  claim 95 , wherein the implant is configured for use as a punctal plug. 
     
     
         103 . The method of  claim 95 , wherein the drug core comprises a matrix that contains inclusions of the therapeutic agent. 
     
     
         104 . The method of  claim 103 , wherein
 a) the inclusions comprise droplets of an oil of the therapeutic agent, and the therapeutic agent is latanoprost, or   b) the inclusions comprise solid particles of the therapeutic agent and the therapeutic agent is bimatoprost.   
     
     
         105 . The method of  claim 103 , wherein the inclusions are from about 1 micrometer to about 100 micrometers in size. 
     
     
         106 . The method of  claim 95 , wherein the sheath is comprised of at least one of polyimide or polyethylene terephthalate. 
     
     
         107 . The method of  claim 95 , wherein the implant is configured for use in ocular tissues selected from the group consisting of: the punctum, the canaliculus, the conjunctival tissue layer of the eye, above the sclera tissue layer, and partially within the scleral tissue layer so as not to penetrate the scleral tissue. 
     
     
         108 . The method of  claim 95 , wherein the matrix comprises a non-biodegradable polymer selected from the group consisting of silicone, an acrylate, a polyethylene, polyurethane, and polyester. 
     
     
         109 . The method of  claim 108 , wherein the non-biodegradable polymer is Nusil 6385. 
     
     
         110 . The method of  claim 95 , wherein the drug insert has a diameter selected from the group consisting of about 0.006 inches, about 0.012 inches and about 0.025 inches. 
     
     
         111 . The method of  claim 95 , wherein the drug core comprises a non-homogenous mixture of silicone and the therapeutic agent. 
     
     
         112 . The method of  claim 95 , wherein the drug core further comprises one or more additives to increase or decrease solubility of the therapeutic agent for control of the release of the therapeutic agent. 
     
     
         113 . The method of  claim 112 , wherein the one or more additives is selected from the group consisting of surfactants, tinuvin, salts and water. 
     
     
         114 . A method of treating a condition of the eye in a patient in need thereof, comprising: disposing within or adjacent to an eye of the patient a drug core, the drug core comprising a therapeutic agent contained in a matrix, wherein the therapeutic agent is dissolved in the matrix or constitutes inclusions in the matrix, for providing release of the therapeutic agent to the eye or surrounding tissues or both over an extended period of time, wherein the rate of release of therapeutic agent is dependent upon the area of the exposed surface of the drug core, wherein the therapeutic agent is adapted to treat the condition. 
     
     
         115 . The method of  claim 114 , wherein the extended period of time is at least three months. 
     
     
         116 . The method of  claim 114 , wherein the therapeutic agent is selected from the group consisting of latanoprost, bimatoprost, timolol maleate and cyclosporin. 
     
     
         117 . The method of  claim 114 , wherein the therapeutic agent is latanoprost or bimatoprost and wherein about 3 micrograms to about 135 micrograms of latanoprost or bimatoprost is present in the implant and wherein about 5 nanograms to about 500 nanograms of latanoprost or bimatoprost is released each day from the drug core. 
     
     
         118 . The method of  claim 114 , wherein the therapeutic agent is timolol maleate, wherein about 270 micrograms to about 1350 micrograms timolol maleate is present in the implant, and wherein about 20 micrograms to about 135 micrograms timolol maleate is released each day from the drug core. 
     
     
         119 . The method of  claim 114 , wherein the therapeutic agent is cyclosporin and wherein about 50 nanograms to about 100 nanograms cyclosporin is released each day from the drug core. 
     
     
         120 . The method of  claim 114 , wherein the drug core is configured for use as a punctal plug. 
     
     
         121 . The method of  claim 114 , wherein the drug core comprises a matrix that contains inclusions of the therapeutic agent. 
     
     
         122 . The method of  claim 121 , wherein
 a) the inclusions comprise droplets of an oil of the therapeutic agent, and the therapeutic agent is latanoprost, or   b) the inclusions comprise solid particles of the therapeutic agent and the therapeutic agent is bimatoprost.   
     
     
         123 . The method of  claim 121 , wherein the inclusions are from about 1 micrometer to about 100 micrometers in size. 
     
     
         124 . The method of  claim 114 , wherein the drug core is configured for use in ocular tissues selected from the group consisting of: the punctum, the canaliculus, the conjunctival tissue layer of the eye, above the sclera tissue layer, and partially within the scleral tissue layer so as not to penetrate the scleral tissue. 
     
     
         125 . The method of  claim 114 , wherein the matrix comprises a non-biodegradable polymer selected from the group consisting of silicone, an acrylate, a polyethylene, polyurethane, and polyester. 
     
     
         126 . The method of  claim 125 , wherein the non-biodegradable polymer is Nusil 6385. 
     
     
         127 . The method of  claim 114 , wherein the drug core comprises a non-homogenous mixture of silicone and the therapeutic agent. 
     
     
         128 . The method of  claim 114 , wherein the drug core further comprises one or more additives to increase or decrease solubility of the therapeutic agent for control of the release of the therapeutic agent. 
     
     
         129 . The method of  claim 128 , wherein the one or more additives is selected from the group consisting of surfactants, tinuvin, salts and water.