Patent Publication Number: US-2010114309-A1

Title: Drug delivery implants for inhibition of optical defects

Description:
CROSS-REFERENCES TO RELATED APPLICATIONS 
     This application claims the benefit of under 35 U.S.C. §109(e) of U.S. Provisional Patent Application No. 60/871,867 filed on Dec. 26, 2007, the disclosure of which is incorporated herein by reference. 
    
    
     BACKGROUND OF THE INVENTION 
     The present invention is directed to the treatment of optical defects of the eye with implants that release one or more therapeutic agents. 
     Pathological conditions that degrade vision can be debilitating. Optical defects of the eye that interfere with one&#39;s ability to see can range in severity from nearly imperceptible to blindness. One common form of optical defect of the eye is refractive error of the eye, with typical refractive errors including nearsightedness or myopia, farsightedness or hyperopia, and astigmatism. Refractive error of the eye generally results from imperfection in the physical properties of the ocular tissues of the eye so that an image formed on the retina is less than ideal. The eye includes an anterior corneal surface and intermediate crystalline lens, both of which refract light to form an image on the retina. Imperfections in either the cornea or the crystalline lens can result in refractive error of the eye. The positions of the cornea and crystalline lens in relation to each other and in relation to the retina can also effect image quality and refractive error. For example, if the distance from the crystalline lens to the retina is too long, a patient can suffer from myopia. Current eye research and treatments are also directed to the diagnosis and correction of additional refractive errors of the eye such as spherical aberration and coma. 
     Refractive errors of the eye can be corrected by treatments that include eye glasses, intraocular lenses, contact lenses and laser surgery. Although these treatments are generally effective, each treatment modality has limitations and may not be suitable for everyone. For example, eyeglasses and contact lenses are not a permanent form of correction and are only effective while worn. Thus, many people suffer from significant degradation in their vision when these lenses are not worn. Intraocular lenses are invasive and require surgery, so that the use of intraocular lenses is often limited to the treatment of cataracts. Although laser eye surgery is effective this elective surgery can occasionally result in complications, so that many people choose to live the inconvenience and limitations of eyeglasses and/or contact lenses. In addition to the above limitations, these therapies generally attempt to correct optical defects of an eye after the defect has developed. 
     There have been proposals to control the progression of refractive error. For example, the application of atropine eye drops to children has been shown to control the progression of myopia. However, the application of liquid drops with atropine can result in side effects and may involve applying liquid drops regularly for an extended time. In addition, the eye drop format can be difficult to instill in children making compliance a significant issue in treatment. As such, since compliance to the drop regimen may be determinative to the desired clinical outcome, missing doses can lead to further disease progression. 
     In light of the above, what is needed are treatments for optical defects of the eye that eliminate at least some of the above short comings of the current therapies. 
     BRIEF SUMMARY OF THE INVENTION 
     The present invention is directed to the treatment of optical defects of the eye with implants that release a therapeutic agent. 
     In a first aspect, the present invention provides an implant for use with an eye. The implant comprises an implantable structure and a therapeutic agent. The therapeutic agent is deliverable from the structure into the eye so as to therapeutically effect and/or stabilize a refractive property of the eye. 
     In many embodiments, the refractive property of the eye may comprise at least one of myopia, hyperopia or astigmatism. The therapeutic agent can comprise a composition that therapeutically effects or stabilizes the refractive property of the eye when delivered into at least one of a sclera, a vitreous humor, an aqueous humor or a ciliary muscle of the eye. The therapeutic agent may comprise at least one of a mydriatic or a cycloplegic drug. For example, the therapeutic agent may include a cycloplegic that comprises at least one of atropine, cyclopentolate, succinylcholine, homatropine, scopolamine, or tropicamide. 
     In many embodiments, a retention element can be attached to the structure to retain the structure along a natural tissue surface of or adjacent to the eye. The retention element can be shaped to retain the structure in or adjacent at least one of a punctual duct, a scleral tissue, or a conjunctival tissue. The structure can be shaped to retain the structure adjacent at least one of a punctual duct, a scleral tissue, or a conjunctival tissue. The structure may have at least one surface and release a therapeutic quantity of the therapeutic agent into tear or tear film fluid of the eye throughout a time period of at least one week when the implant is implanted with the at least one surface exposed to the tear or tear film fluid. For example, the structure can be adapted to release the therapeutic agent in therapeutic amounts over a period of time from about one to twelve months after the structure is inserted into the eye, and the structure may comprise at least one of a reservoir, a matrix, a solution, a surface coating or a bioerodable material. The structure may comprise a drug core and a layer disposed over the drug core to inhibit release of the therapeutic agent through the layer, and the layer may comprise an opening formed therein to release the drug through the opening. The structure may comprise particles of the agent, and the particles may independently release the agent therefrom when the structure is implanted to provide a substantially uniform release rate. 
     In specific embodiments, at least a portion of the structure may be bioerodable, and the therapeutic agent can be released while the structure erodes. 
     Many embodiments may comprise a counteractive agent to avoid a side effect of the therapeutic agent, and the counteractive agent may comprise at least one of an anti-glaucoma drug or a miotic drug. For example, the anti-glaucoma drug may comprise at least one of a sympathomimetic, a parasympathomimetic, a beta blocking agent, a carbonic anhydrase inhibitor, or prostaglandin analogue. In specific embodiments, the anti-glaucoma drug may comprise at least one of Apraclonidine, Brimonidine, Clonidine, Dipivefrine, Epinephrine, Aceclidine, Acetylcholine, Carbachol, Demecarium, Echothiophate, Fluostigmine, Neostigmine, Paraoxon, Physostigmine, Pilocarpine, Acetazolamide, Brinzolamide, Diclofenamide, Dorzolamide, Methazolamide, Befunolol, Betaxolol, Carteolol, Levobunolol, Metipranolol, Timolol, Bimatoprost, Latanoprost, Travoprost, Unoprostone, Dapiprazole or Guanethidine. 
     In specific embodiments, a therapeutic implant comprises a structure, a punctal plug and a therapeutic agent. The punctual plug retains the structure adjacent to an eye. The therapeutic agent may comprises atropine deliverable from the structure into the eye to therapeutically effect and/or stabilize refractive properties of the eye. The refractive property of the eye may comprise at least one of myopia, astigmatism or hyperopia. 
     In another aspect a method of treating an optical defect of an eye with a therapeutic agent is provided. The method comprises implanting a structure into a tissue of or near the eye. A therapeutic agent is released from the implanted structure so that the therapeutic agent effects and/or stabilizes a refractive property of the eye. 
     In some embodiments, the refractive property of the eye comprises at least one of a myopia, a hyperopia or an astigmatism. The therapeutic agent can be released in therapeutic amounts over a period of time from about one to twelve months after the structure is inserted into the eye. For example, the period of time can be from about six to twelve months. The therapeutic agent can be continuously released over the period of time. 
     In many embodiments, the structure can be implanted in at least one of a sclera, a punctum or a conjunctiva of the eye. For example, the structure may be anchored to the punctum and release the therapeutic agent into a tear or tear film of the eye. In addition or in combination, the structure may be anchored to the sclera and release the therapeutic agent into at least one of a vitreous humor, an aqueous humor or a ciliary muscle of the eye. The structure may be anchored to the conjunctiva and release the therapeutic agent into at least one of a vitreous humor, an aqueous humor or a ciliary muscle of the eye. The structure may be covered by the conjunctiva and release the therapeutic agent into at least one of a vitreous humor, an aqueous humor or a ciliary muscle of the eye. For example, the structure is placed between the conjunctiva and the sclera. 
     In many embodiments, the therapeutic agent effects accommodation of the eye. In specific embodiments, the therapeutic agent can comprise a cycloplegic, such as at least one of atropine, cyclopentolate, succinylcholine, homatropine, scopolamine, or tropicamide. The therapeutic agent can comprise atropine. 
     In some embodiments a counteractive agent can be released from the implanted structure and/or another structure to counteract a side effect of the therapeutic agent. The counteractive agent may comprise at least one of an anti-glaucoma drug or a miotic drug. In specific embodiments, the anti-glaucoma drug may comprise at least one of a sympathomimetic, a parasympathomimetic, a beta blocking agent, a carbonic anhydrase inhibitor, or prostaglandin analogue. 
     In some embodiments the therapeutic agent can be released with a profile that corresponds to a kinetic order of therapeutic agent release and the order can be within a range from about zero to about one. In specific embodiments, the range is from about zero to about one half, for example from about zero to about one quarter. The therapeutic agent may released with a profile that corresponds to a kinetic order of therapeutic agent release and the order is within a range from about zero to about one half for at least about a month after the structure is inserted, for example the order can be within the range at least about 3 months after the structure is inserted. 
     In some embodiments, a method of treating an optical defect of an eye comprises treating the eye with at least one of an anti-glaucoma drug and/or a miotic drug to avoid a side effect of a therapeutic agent used to treat the optical defect of the eye. Children and/or adolescents may treated, and the optical defect of the eye may comprise at least one of a myopia, a hyperopia or an astigmatism. The anti-glaucoma drug may comprise at least one of a sympathomimetic, a parasympathomimetic, a beta blocking agent, a carbonic anhydrase inhibitor, or prostaglandin analogue. In specific embodiments, the anti-glaucoma drug comprises at least one of Apraclonidine, Brimonidine, Clonidine, Dipivefrine, Epinephrine, Aceclidine, Acetylcholine, Carbachol, Demecarium, Echothiophate, Fluostigmine, Neostigmine, Paraoxon, Physostigmine, Pilocarpine, Acetazolamide, Brinzolamide, Diclofenamide, Dorzolamide, Methazolamide, Befunolol, Betaxolol, Carteolol, Levobunolol, Metipranolol, Timolol, Bimatoprost, Latanoprost, Travoprost, Unoprostone, Dapiprazole or Guanethidine. In many embodiments, the anti-glaucoma drug is capable of a miotic effect. The miotic drug can comprise at least one of echothiophate, pilocarpine, physostigmine salicylate, diisopropylfluorophosphate, carbachol, methacholine, bethanechol, epinephrine, dipivefrin, neostigmine, echothiopateiodide or demecium bromide. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIGS. 1-1  and  1 - 2  show anatomical tissue structures of the eye suitable for use with implants, according to embodiments of the present invention; 
         FIG. 1A  shows a top cross sectional view of a sustained release implant to treat an optical defect of an eye, according to an embodiment of the present invention; 
         FIG. 1B  shows a side cross sectional view of the sustained release implant of  FIG. 1A ; 
         FIG. 1C  shows a perspective view of a sustained release implant with a coil retention element, according to an embodiment of the present invention; 
         FIG. 1D  shows a perspective view of a sustained release implant with a retention element comprising struts, according to an embodiment of the present invention; 
         FIG. 1E  shows a perspective view of a sustained release implant with a cage retention element, according to an embodiment of the present invention; 
         FIG. 1F  shows a perspective view of a sustained release implant comprising a core and sheath, according to an embodiment of the present invention; 
         FIG. 2A  shows a cross sectional view of a sustained release implant with core comprising an enlarged exposed surface area, according to an embodiment of the present invention; 
         FIG. 2B  shows a cross sectional view of a sustained release implant with a core comprising an enlarged exposed surface area, according to an embodiment of the present invention; 
         FIGS. 2C and 2D  show perspective view and cross sectional views, respectively, of a sustained release implant with a core comprising a reduced exposed surface area, according to an embodiment of the present invention; 
         FIG. 2E  shows a cross sectional view of a sustained release implant with a core comprising an enlarged exposed surface area with castellation, according to an embodiment of the present invention; 
         FIG. 2F  shows a perspective view of a sustained release implant comprising a core with redundant surface area according to an embodiment of the present invention; 
         FIG. 2G  shows a perspective view of a sustained release implant with a core comprising a channel with an internal porous surface, according to an embodiment of the present invention; 
         FIG. 2H  shows a perspective view of a sustained release implant with a core comprising porous channels to increase drug migration, according to an embodiment of the invention; 
         FIG. 2I  shows a perspective view of a sustained release implant with a convex exposed drug core surface, according to an embodiment of the present invention; 
         FIG. 2J  shows a side view of a sustained release implant with a core comprising an exposed surface area with several soft protrusions, tendrils, cilia type members extending therefrom, according to an embodiment of the present invention; 
         FIG. 2K  shows a side view of a sustained release implant with a drug core comprising a convex exposed surface and a retention element, according to an embodiment of the present invention. 
         FIG. 3A  shows a perspective view of a punctual plug with a reservoir, according to an embodiment of the present invention; 
         FIG. 3B  shows a schematic representation of a preferred configuration of medication within the reservoir and its contact with the external tear flow, according to an embodiment of the present invention; 
         FIG. 4  shows a retention element that encompass a tube, for example a tube used to form a punctual plug, and a structure to release therapeutic agents that encompass a drug reservoir enclosed with a permeable layer, according to an embodiment of the present invention; 
         FIG. 5  show a retention elements that encompasses a punctual plug, and a structure to release therapeutic agents that encompasses a drug reservoir enclosed with a material permeable to the drug, according to an embodiment of the present invention; 
         FIG. 6  shows a punctual plug having materials to release therapeutic agents (e.g. coatings and/or biodegradable polymers) according to embodiments of the present invention; 
         FIG. 7  shown an implant for complete insertion into the canaliculus of the human eye with medication, according to an embodiment of the present invention; 
         FIG. 8A  shows a plan view, with representative dimensions, of a punctal plug according to an embodiment of the present invention; 
         FIG. 8B  shows a plan view, with representative dimensions, of a punctal plug, according to an embodiment of the present invention; 
         FIG. 9  shows a retention element that encompasses a punctual plug and a retention element that encompasses a hollow implant, and structures to release therapeutic agents that encompass coatings applied to the retention elements, according to an embodiment of the present invention; and 
         FIGS. 10A to 10C  show deployment of a sustained release implant, according to an embodiment of the present invention; 
         FIG. 11  shows sustained release therapeutic agent implants and implant locations on or near an eye, according to embodiments of the present invention; 
         FIG. 12A  shows a device for treating optical defects of the eye that comprises a sustained release implant that releases a therapeutic agent to treat the optical defect of the eye and additional sustained release implants to counteract side effects of the therapeutic agent; and 
         FIG. 12B  shows a sustained release implant that releases a therapeutic agent to treat an optical defect of the eye and releases counteractive agents that counteracts a side effect of the therapeutic agent, according to embodiments of the present invention. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       FIGS. 1-1  and  1 - 2  show anatomical tissue structures of an eye  2  suitable for treatment with implants, according to an embodiment of the present invention. Eye  2  includes a cornea  4  and an iris  6 . A sclera  8  surrounds cornea  4  and iris  6  and appears white. A conjunctival layer  9  is substantially transparent and disposed over sclera  8 . A crystalline lens  5  is located within the eye. A retina  7  is located near the back of eye  2  and is generally sensitive to light. Retina  7  includes a fovea  7 F that provides high visual acuity and color vision. Cornea  4  and lens  5  refract light to form an image on fovea  7 F and retina  7 . The optical power of cornea  4  and lens  5  contribute to the formation of images on fovea  7 F and retina  7 . The relative locations of cornea  4 , lens  5  and fovea  7 F are also important to image quality. For example, if the axial length of eye  2  from cornea  4  to retina  7 F is large, eye  2  can be myopic. Also, during accommodation, lens  5  moves toward cornea  4  to provide good near vision of objects proximal to the eye. 
     The anatomical tissue structures shown in  FIG. 1-1  also include the lacrimal system, which includes an upper canaliculus  10  and a lower canaliculus  12 , collectively the canaliculae, and the naso-lacrimal duct or sac  14 . The upper and lower canaliculae terminate in an upper punctum  11  and a lower punctum  13 , also referred to as punctal apertures. The punctal apertures are situated on a slight elevation at the medial end of the lid margin at the junction  15  of the ciliary and lacrimal portions near the medial canthus  17 . The punctal apertures are round or slightly ovoid openings surrounded by a connective ring of tissue. Each of the punctal openings  11 ,  13  leads into a vertical portion  10   a ,  12   a  of the respective canaliculus before turning horizontally to join its other canaliculus at the entrance of a lacrimal sac  14 . The canaliculae are tubular and lined by stratified squamous epithelium surrounded by elastic tissue which permits the canaliculus to be dilated. 
     As the eye is an optical system, the interrelationship of the optical components of the eye can contribute to a refractive defect of the eye (e.g. myopia, hyperopia and/or astigmatism). In some instances, if the eye attains an axial length that is too long, the eye can be myopic. Also, if the cornea and/or the lens have excessive optical power relative to the length of the eye, the eye may be myopic. If the cornea and/or lens have insufficient optical power relative to the width of the eye, hyperopia can occur (i.e. the axial length of the eye is too short relative to the width of the eye). The position of the crystalline lens within the eye may also contribute to the refractive condition of the eye as well. 
     Growth and development of the eye during childhood and adolescence can effect the optical properties of the eye, and many people undergo a progressive worsening of refractive error of the eye during childhood and adolescence. For example, myopic school age children can undergo a progressive worsening of myopia as the eye develops and grows. As this progression of myopia is associated with development of the eye during childhood and adolescence it can be referred to as developmental myopia. Also, as moderate to severe myopia can be associated with astigmatism, treatment of the progressive worsening of myopia can also treat the progressive worsening of astigmatism. 
     In preferred embodiments, the progression of a refractive defect of the eye is treated with a therapeutic agent to attenuate the worsening of the refractive defect. The therapeutic agent can be a cycloplegic, for example atropine, that is used to attenuate the progression of myopia. Although such treatments may not entirely eliminate refractive defects of the eye, early detection and intervention can limit the severity of the refractive defect. 
       FIG. 1A  shows a top cross sectional view of a sustained release implant  100  to treat an optical defect of an eye, according to embodiments of the present invention. Implant  100  includes a drug core  110 . Drug core  110  is an implantable structure that retains a therapeutic agent. Drug core  110  comprises a matrix  170  that contains particles  160  of therapeutic agent. Particles  160  will often comprise a concentrated form of the therapeutic agent, for example a solid form such as a crystalline form and/or liquid form such as an oil form of the therapeutic agent, and the therapeutic agent may over time dissolve into matrix  170  of drug core  110 . Matrix  170  can comprise a silicone matrix or the like. 
     Drug core  110  is surrounded by a sheath body  120 . Sheath body  120  is can be substantially impermeable to the therapeutic agent, so that the therapeutic agent is often released from an exposed surface on an end of drug core  110  that is not covered with sheath body  120 . A retention element  130  is connected to drug core  110  and sheath body  120 . Retention element  130  is shaped to retain the implant in a hollow tissue structure, for example, a punctum of a canaliculus as described above. 
     An occlusive element  140  is disposed on and around retention element  130 . Occlusive element  140  is impermeable to tear flow and occludes the hollow tissue structure and may also serve to protect tissues of the tissue structure from retention element  130  by providing a more benign tissue-engaging surface. Sheath body  120  includes a sheath body portion  150  that connects to retention element  130  to retain sheath body  120  and drug core  110 . Sheath body portion  150  also acts as a stop to limit movement of sheath body  120  and drug core  110 . 
       FIG. 1B  shows a side cross sectional view of the sustained release implant of  FIG. 1A . Drug core  110  is cylindrical and shown with a circular cross-section. Sheath body  120  comprises an annular portion disposed on drug core  110 . Retention element  130  comprises several longitudinal struts  131 . Longitudinal struts  131  are connected together near the ends of the retention element. Although longitudinal struts are show, circumferential struts can also be used. Occlusive element  140  is supported by and disposed over longitudinal struts  131  of retention element  130  and may comprise a radially expandable membrane or the like. 
     The drug core comprises the therapeutic agent and materials to provide sustained release of the therapeutic agent. The therapeutic agent, for example atropine, migrates from the drug core to the target tissue, for example ciliary muscles of the eye. The therapeutic agent may optionally be only slightly soluble in the matrix so that the release rate remains “zero order” for the lifetime of the release of the therapeutic agent when dissolved in the matrix and available for release from the surface of drug core  110 . As the therapeutic agent diffuses from the exposed surface of the core to the tear or tear film, the rate of migration from the core to the tear or tear film is related to the concentration of therapeutic agent dissolved in the matrix. In some embodiments, the concentration of therapeutic agent dissolved in the drug core may be controlled to provide the desired rate of release of the therapeutic agent. The therapeutic agent included in the core can include liquid, solid, solid gel, solid crystalline, solid amorphous, solid particulate, and/or dissolved forms of the therapeutic agent. In some embodiments, the drug core comprises a silicone matrix containing the therapeutic agent. An exemplary therapeutic agent comprises solid atropine particles dispersed in the silicone matrix. 
     The drug core can be made from any biocompatible material capable of providing a sustained release of the therapeutic agent. Although the drug core is described above with respect to an embodiment comprising a matrix with a substantially non-biodegradable silicone matrix with particles of the drug located therein that dissolve, the drug core can include any structure that provides sustained release of the therapeutic agent, for example biodegradable matrix, a porous drug core, liquid drug cores and solid drug cores. The structures can be adapted to release the therapeutic agent in therapeutic amounts over a period of time from about one to twelve months after the structure is inserted into the eye. A matrix that contains the therapeutic agent can be formed from either biodegradable or non-biodegradable polymers. Examples of biodegradable polymers may include poly(L-lactic acid) (PLLA), poly(L-glycolic acid) (PLGA), polyglycolide, poly-L-lactide, poly-D-lactide, poly(amino acids), polydioxanone, polycaprolactone, polygluconate, polylactic acid-polyethylene oxide copolymers, modified cellulose, collagen, polyorthoesters, polyhydroxybutyrate, polyanhydride, polyphosphoester, poly(alpha-hydroxy acid), collagen matrices and combinations thereof. The devices of the present invention may be fully or partially biodegradable or non-biodegradable. Examples of non-biodegradable materials are various commercially available biocompatible polymers including but not limited to silicone, polyethylene terephthalate, acrylates, polyethylenes, polyolefins, including ultra high molecular weight polyethylene, expanded polytetrafloroethylene, polypropylene, polycarbonate urethane, polyurethanes, polyamides, sheathed collagen. In some embodiments the drug core may comprise a hydrogel polymer, either degradable or non-degradable. In some embodiments, the therapeutic agent can be comprised in a drug eluting material used as a coating, such as those commercially available from Surmodics of Eden Prairie, Minn., and Angiotech Pharmaceuticals of British Columbia, Canada, and the like. 
     The therapeutic agent can comprise any substance, for example a drug, that effects the optical properties of the eye. Suitable drugs to effect the optical properties of the eye may include cycloplegics, for example atropine, cyclopentolate, succinylcholine, homatropine, scopolamine, and/or tropicamide. Other drugs may be used to effect pupil dilation and/or other optical properties of the eye include neostigmine, phentolamine, phospholine iodide and pilocarpine. Additional drugs such as miotics can be used, including echothiophate, pilocarpine, physostigmine salicylate, diisopropylfluorophosphate, carbachol, methacholine, bethanechol, epinephrine, dipivefrin, neostigmine, echothiopateiodide and demecium bromide. Other suitable therapeutic agents include mydriatics such as hydroxyamphetamine, ephedrine, cocaine, tropicamide, phenylephrine, cyclopentolate, oxyphenonium and eucatropine. In addition, anti-cholinergics may be employed such as, pirenzepine. Examples of applicable therapeutic agents may be found in United States Patent Applications 20060188576 and 20030096831, hereby incorporated by reference in their entirety. 
     In addition to the therapeutic agent used to treat the optical defect of the eye, additional therapeutic agents can be provided to counteract possible side effects of the therapeutic agent. The additional counteractive therapeutic agent(s) can be comprised within the core that releases the therapeutic agent that treats the optical defect of the eye, or additional drug cores can be provided to separately release the additional counteractive therapeutic agent(s). 
     One possible side effect of a cycloplegic therapeutic agent is pupil dilation that can result in photophobia. Therefore, in some embodiments, a miotic therapeutic agent is released into the eye to counteract the pupil dilation caused by the cycloplegic. 
     Another potential side effect of cycloplegic therapeutic agents is glaucoma, possibly related to the dilation of the pupil. Therefore, in some embodiments an anti-glaucoma therapeutic agent(s) may be released to counteract a possible glaucoma inducing side effect of the therapeutic agent used to treat the optical defect of the eye. Suitable anti-glaucoma therapeutic agents include: sympathomimetics such as Apraclonidine, Brimonidine, Clonidine, Dipivefrine, and Epinephrine; parasympathomimetics such as Aceclidine, Acetylcholine, Carbachol, Demecarium, Echothiophate, Fluostigmine, Neostigmine, Paraoxon, Physostigmine, and Pilocarpine; carbonic anhydrase inhibitors such as Acetazolamide, Brinzolamide, Diclofenamide, Dorzolamide, and Methazolamide, beta blocking agents such as Befunolol, Betaxolol, Carteolol, Levobunolol, Metipranolol, and Timolol; prostaglandin analogues such as Bimatoprost, Latanoprost, Travoprost, and Unoprostone; and other agents such as Dapiprazole, and Guanethidine. In a preferred embodiment, atropine is released as a therapeutic agent to treat developmental myopia in children, and bimatoprost and/or latanoprost is released as an anti-glaucoma treatment. 
     It should be noted that some therapeutic agents will have more than one effect on the eye. For example, anti-glaucoma therapeutic agents can also cause pupil constriction. Thus in some embodiments, an additional therapeutic agent can be added to counteract more than one side effect of the therapeutic agent that is released to correct the optical defect of the eye. 
     The therapeutic agent is released at therapeutic levels to provide a desired treatment response when implant  100  is implanted in a tissue or near the eye. For example, with the drug atropine as used to treat myopia, the atropine is released from the drug core at therapeutic rate that delivers the lowest effective dose. The drug is preferably released at a uniform rate, for example a rate that corresponds to zero order kinetics, although the drug can be released at rates that correspond to other orders of reaction kinetics, for example first order. In many embodiments, the kinetic order of the reaction will vary from zero order to first order as the drug is released. Thus, the therapeutic agent is released with a profile that corresponds to a range of kinetic orders that varies from about zero to about one. Ideally, the drug core is removed before the rate at which the therapeutic agent is released changes significantly so as to provide uniform delivery of the therapeutic agent. As a uniform rate of delivery is desired, it may be desirable to remove and/or replace the drug core before the reaction kinetics transition entirely to first order. In other embodiments, first or higher order release kinetics may be desirable during some or all of the treatment, so long as the therapeutic agent release profile remains within a safe and effective range. In some embodiments the drug core may release at an effective rate for the period of 1 week to 5 years, more particularly in the range of 3-24 months. 
     The rate of release of the therapeutic agent can be related to the concentration of therapeutic agent dissolved in the drug core. In many embodiments, the drug core comprises non-therapeutic agents that are selected to provide a desired solubility of the therapeutic agent in the drug core. The non-therapeutic agent of the drug core can comprise polymers as described above and additives. A polymer of the core can be selected to provide the desired solubility of the therapeutic agent in the matrix. For example, the core can comprise hydrogel that may promote solubility of hydrophobic treatment agent. In some embodiments, functional groups can be added to the polymer to modulate the release kinetics of the therapeutic agent in the matrix. For example, functional groups can be attached to silicone polymer. 
     In some embodiments, additives may be used to control the concentration of therapeutic agent by increasing or decreasing solubility of the therapeutic agent in the drug core. The solubility may be controlled by providing appropriate molecules and/or substances that increase and/or decrease the solubility of the dissolved form of the therapeutic agent to the matrix. The solubility of the dissolved form of the therapeutic agent may be related to the hydrophobic and/or hydrophilic properties of the matrix and therapeutic agent. For example, surfactants, salts, hydrophilic polymers can be added to the matrix to modulate the release kinetics. In addition, oils and hydrophobic molecules can be added to the matrix to modulate the release kinetics of the matrix. 
     Instead or in addition to controlling the rate of migration based on the concentration of therapeutic agent dissolved in the matrix, the surface area of the drug core can also be controlled to attain the desired rate of drug migration from the core to the target site. For example, a larger exposed surface area of the core will increase the rate of migration of the treatment agent from the drug core to the target site, and a smaller exposed surface area of the drug core will decrease the rate of migration of the therapeutic agent from the drug core to the target site. The exposed surface area of the drug core can be increased in any number of ways, for example by making the exposed surface tortuous or porous, thereby increasing the surface area available to the core. 
     The sheath body comprises appropriate shapes and materials to control migration of the therapeutic agent from the drug core. The sheath body houses the core and can fit snugly against the core. The sheath body is made from a material that is substantially impermeable to the therapeutic agent so that the rate of migration of the therapeutic agent may be largely controlled by the exposed surface area of the drug core that is not covered by the sheath body. Typically, migration of the therapeutic agent through the sheath body will be about one tenth of the migration of the therapeutic agent through the exposed surface of the drug core, or less, often being one hundredth or less. In other words, the migration of the therapeutic agent through the sheath body is at least about an order of magnitude less that the migration of the therapeutic agent through the exposed surface of the drug core. Suitable sheath body materials include polyimide, polyethylene terephthalate” (hereinafter “PET”). The sheath body has a thickness, as defined from the sheath surface adjacent the core to the opposing sheath surface away from the core, from about 0.00025″ to about 0.0015″. The total diameter of the sheath that extends across the core ranges from about 0.2 mm to about 1.2 mm. The core may be formed by dip coating the core in the sheath material. Alternatively, the sheath body can be a tube and the core introduced into the sheath as a liquid or slid into the sheath body tube. 
     The sheath body can be provided with additional features to facilitate clinical use of the implant. For example, the sheath may replaceable receive a drug core that is exchangeable while the retention element and sheath body remain implanted in the patient. The sheath body is often rigidly attached to the retention element as described above, and the core is exchangeable while the retention element retains the sheath body. For example, the sheath body can be provided with external protrusions that apply force to the sheath body when squeezed and eject the core from the sheath body. Another drug core can then be positioned in the sheath body. 
     The retention element comprises an appropriate material that is sized and shaped so that the implant can be easily positioned in the desired tissue location, for example the punctum or canaliculus. The retention element is mechanically deployable and typically expands to a desired cross sectional shape, for example with the retention element comprising a superelastic shape memory alloy such as Nitinol™. Other materials in addition to Nitinol™ can be used, for example resilient metals or polymers, plastically deformable metals or polymers, shape memory polymers and the like for example spring stainless steel, Eligloy®, tantalum, titanium, cobalt chromium to provide the desired expansion. The retention element may be bio-degradable or non-biodegradable depending on the desired treatment time and whether the patient requires physician follow up. This expansion capability permits the implant to fit in hollow tissue structures of varying sizes, for example canaliculae ranging from 0.3 mm to 1.2 mm (i.e. one size fits all). Although a single retention element can be made to fit canaliculae from 0.3 to 1.2 mm across, a plurality of alternatively selectable retention elements can be used to fit this range if desired, for example a first retention element for canaliculae from 0.3 to 0.9 mm and a second retention element for canaliculae from 0.9 to 1.2 mm. The retention element has a length appropriate to the anatomical structure to which the retention element attaches, for example a length of about 3 mm or less for a retention element positioned near the punctum of the canaliculus. 
     Although the sheath body and drug core are attached to one end of the retention element as described above, in many embodiments the other end of retention element is not attached to drug core and sheath body so that the retention element can slide over the sheath body and drug core while the retention element expands. This sliding capability on one end is desirable as the retention element will typically shrink in length as the retention element expands in width to assume the desired cross sectional width. In addition, the core of the device may be replaceable with the sheath body remaining in place. Alternatively, the sheath body may be replaceable within the retention element to provide for exchange of a the drug core to replenish the supply of therapeutic agent to the device. 
     The occlusive element comprises an appropriate material that is sized and shaped so that the implant can at least partially inhibit, even block, the flow of fluid through the hollow tissue structure, for example lacrimal fluid through the canaliculus. The occlusive material shown is a thin walled membrane of a biocompatible material, for example silicone, that can expand and contract with the retention element. The occlusive element is formed as a separate thin tube of material that is slid over the end of the retention element and anchored to one end of the retention element as described above. Alternatively, the occlusive element can be formed by dip coating the retention element in a biocompatible polymer, for example silicone polymer. The thickness of the occlusive element can be in a range from about 0.03 mm to about 0.15 mm, and often from about 0.05 mm to 0.1 mm. 
       FIG. 1C  shows a perspective view of a sustained release implant  102  with a coil retention element  132 , according to an embodiment of the present invention. Retention element  132  comprises a coil and retains a drug core  112 . Drug core  112  is partially covered. The sheath body comprises a first component  122 A that covers a first end of drug core  112  and a second component  122 B that covers a second end of the drug core. An occlusive element can be placed over the retention element or the retention element can be dip coated as described above. 
       FIG. 1D  shows a perspective view of a sustained release implant  104  with a retention element  134  comprising struts, according to an embodiment of the present invention. Retention element  134  comprises longitudinal struts and retains a drug core  114 . Drug core  114  is covered with a sheath body  124  over most of drug core  114 . The drug core releases therapeutic agent through an exposed end and sheath body  124  is annular over most of the drug core as described above. An occlusive element can be placed over the retention element or the retention element can be dip coated as described above. 
       FIG. 1E  shows a perspective view of a sustained release implant  106  with a cage retention element  136 , according to an embodiment of the present invention. Retention element  136  comprises several connected strands of metal (such as a mesh or lattice, or helical structure) and retains a drug core  116 . Drug core  116  is covered with a sheath body  126  over most of drug core  116 . The drug core releases therapeutic agent through an exposed end and sheath body  126  is annular over most of the drug core as described above. An occlusive element can be placed over the retention element or the retention element can be dip coated as described above. 
       FIG. 1F  shows a perspective view of a sustained release implant comprising a core and sheath, according to an embodiment of the present invention. Drug core  118  is covered with a sheath body  128  over most of drug core  118 . The drug core releases therapeutic agent through an exposed end and sheath body  128  is annular over most of the drug core as described above. The rate of therapeutic agent release is controlled by the surface area of the exposed drug core and materials comprised within drug core  118 . Such an implant can be implanted in ocular tissues, for example below conjunctival tissue layer  9  of the eye and either above sclera tissue layer  8 , as shown in  FIG. 1F , or only partially within the scleral tissue layer so as not to penetrate the scleral tissue. It should be noted that drug core  118  can be used with any of the retention elements and occlusive elements as described herein. In an embodiment, the drug core is implanted between sclera  8  and conjunctiva  9  without sheath body  128 . In this embodiment without the sheath body, the physical characteristics of the drug core can be adjusted to compensate for the increased exposed surface of drug core, for example by reducing the concentration of dissolved atropine in the drug core matrix as described herein. 
     The cores and sheath bodies described herein can be implanted in a variety of tissues in several ways. Many of the cores and sheaths described herein, in particular the structures described with reference to  FIGS. 2A to 2J  can be implanted alone as punctal plugs. Alternatively, many of the cores and sheath bodies described herein can comprise a drug core, sheath body, and/or the like so as to be implanted with the retention elements and occlusive elements described herein. 
       FIG. 2A  shows a cross sectional view of a sustained release implant  200  with core comprising an enlarged exposed surface area, according to an embodiment of the present invention. A drug core  210  is covered with a sheath body  220 . Sheath body  220  includes an opening  220 A. Opening  220  has a diameter that approximates the maximum cross sectional diameter of drug core  210 . Drug core  210  includes an exposed surface  210 E, also referred to as an active surface. Exposed surface  210 E includes 3 surfaces: an annular surface  210 A, a cylindrical surface  210 B and an end surface  210 C. Annular surface  210 A has an outer diameter that approximates the maximum cross sectional diameter of core  210  and an inner diameter that approximates the outer diameter of cylindrical surface  210 B. End surface  210 C has a diameter that matches the diameter of cylindrical surface  210 B. The surface area of exposed surface  210 E is the sum of the areas of annular surface  210 A, cylindrical surface  210 B and end surface  210 C. The surface area may be increased by the size of cylindrical surface area  210 B that extends longitudinally along an axis of core  210 . 
       FIG. 2B  shows a cross sectional view of a sustained release implant  202  with a core  212  comprising an enlarged exposed surface area  212 A, according to an embodiment of the present invention. A sheath body  222  extends over core  212 . The treatment agent can be released from the core as described above. Exposed surface area  212 A is approximately conical, can be ellipsoidal or spherical, and extends outward from the sheath body to increase the exposed surface area of drug core  212 . 
       FIGS. 2C and 2D  show perspective and cross sectional views, respectively, of a sustained release implant  204  with a drug core  214  comprising a reduced exposed surface area  214 A, according to an embodiment of the present invention. Drug core  214  is enclosed within a sheath body  224 . Sheath body  22  includes an annular end portion  224 A that defines an opening through which drug core  214  extends. Drug core  214  includes an exposed surface  214 A that releases the therapeutic agent. Exposed surface  214 A has a diameter  214 D that is less than a maximum dimension, for example a maximum diameter, across drug core  214 . 
       FIG. 2E  shows a cross sectional view of a sustained release implant  206  with a drug core  216  comprising an enlarged exposed surface area  216 A with castellation extending therefrom, according to an embodiment of the present invention. Drug core  216  includes an indentation  2161 . The castellation includes several fingers  216 F extending from the indentation. Core  216  is covered with a sheath body  226 . Sheath body  226  is open on one end to provide an exposed surface  216 A on drug core  216 . Indentation  2161  has the shape of an inverted cone. Several fingers  216 F extend outward from indentation  2161  to provide an increase in surface area of exposed surface  216 A. Sheath body  226  also includes fingers and has a castellation pattern that matches core  216 . 
       FIG. 2F  shows a perspective view of a sustained release implant  250  comprising a core with folds, according to an embodiment of the present invention. Implant  250  includes a core  260  and a sheath body  270 . Core  260  has an exposed surface  260 A on the end of the core that permits drug migration to the surrounding tear or tear film fluid. Core  260  also includes folds  260 F. Folds  260 F increase the surface area of core that contains the drug to be delivered within the volume of the implant. With this increase in exposed surface area, folds  260 F increase migration of the therapeutic agent from core  260  into the tear or tear film fluid and target treatment area. Folds  260 F are formed so that a channel  260 C is formed in core  260 . Channel  260 C connects to the end of the core to an opening in exposed surface  260 A and provides for the migration of treatment agent. Thus, the total exposed surface area of core  260  includes exposed surface  260 A that is directly exposed to the tear or tear film fluid and the surfaces of folds  260 F that are exposed to the tear or tear film fluids via connection of channel  260 C with exposed surface  260 A and the tear or tear film fluid. 
       FIG. 2G  shows a perspective view of a sustained release implant with a core comprising a channel with a series of protrusions and/or cavities extending from the central axis, according to an embodiment of the present invention. Implant  252  includes a core  262  and sheath body  272 . Core  262  has an exposed surface  262 A on the end of the core that permits drug migration to the surrounding tear or tear film fluid. Core  262  also includes a channel  262 C. Channel  262 C increases the surface area of the channel with a porous internal surface  262 P formed on the inside of the channel against the core. Channel  262 C extends to the end of the core near exposed surface  262 A of the core. The surface area of core that is exposed to the surrounding fluid tear or tear film fluid can include the inside of core  262  that is exposed to channel  262 C. This increase in exposed surface area can increase migration of the therapeutic agent from core  262  into the tear or tear film fluid and target treatment area. Thus, the total exposed surface area of core  262  can include exposed surface  260 A that is directly exposed to the tear or tear film fluid and porous internal surface  262 P that is exposed to the tear or tear film fluids via connection of channel  262 C with exposed surface  262 A and the tear or tear film fluid. 
       FIG. 2H  shows a perspective view of a sustained release implant  254  with a core  264  comprising porous channels to increase drug migration, according to an embodiment of the invention. Implant  254  includes core  264  and sheath body  274 . Exposed surface  264 A is located on the end of core  264 , although the exposed surface can be positioned at other locations. Exposed surface  264 A permits drug migration to the surrounding tear or tear film fluid. Core  264  also includes porous channels  264 C. Porous channels  264 C extend to exposed surface  264 . Porous channels  264 C are large enough that tear or tear film fluid can enter the porous channels and therefore increase the surface area of core  264  that is in contact with tear or tear film fluid. The surface area of the core that is exposed to the surrounding fluid tear or tear film fluid includes the inner surfaces of channels  264 C. With this increase in exposed surface area, porous channels  264 C increase migration of the therapeutic agent from core  264  into the tear or tear film fluid and target treatment area. Thus, the total exposed surface area of core  264  includes exposed surface  264 A that is directly exposed to the tear or tear film fluid and internal surface that is exposed to the tear or tear film fluids via connection of porous channel  262 C with exposed surface  264 A and the tear or tear film fluid. 
       FIG. 2I  shows a perspective view of a sustained release implant  256  with a drug core  266  comprising a convex exposed surface  266 A, according to an embodiment of the present invention. Drug core  266  is partially covered with a sheath body  276  that extends at least partially over drug core  266  to define convex exposed surface  266 A. Sheath body  276  comprises a shaft portion  276 S. Convex exposed surface  266 A provides an increased exposed surface area above the sheath body. A cross sectional area of convex exposed surface  266 A is larger than a cross sectional area of shaft portion  276 S of sheath body  276 . In addition to the larger cross sectional area, convex exposed surface  266 A has a larger surface area due to the convex shape which extends outward from the core. Sheath body  276  comprises several fingers  276 F that support drug core  266  in the sheath body and provide support to the drug core to hold drug core  266  in place in sheath body  276 . Fingers  276 F are spaced apart to permit drug migration from the core to the tear or tear film fluid between the fingers. Protrusions  276 P extend outward on sheath body  276 . Protrusions  276 P can be pressed inward to eject drug core  266  from sheath body  276 . Drug core  266  can be replaced with another drug core after an appropriate time, for example after drug core  266  has released most of the therapeutic agent. 
       FIG. 2J  shows a side view of a sustained release implant  258  with a core  268  comprising an exposed surface area with several soft brush-like members  268 F, according to an embodiment of the present invention. Drug core  268  is partially covered with a sheath body  278  that extends at least partially over drug core  268  to define exposed surface  268 A. Sheath body  278  comprises a shaft portion  278 S. Soft brush-like members  268 F extend outward from drug core  268  and provide an increased exposed surface area to drug core  268 . Soft brush-like members  268 F are also soft and resilient and easily deflected such that these members do not cause irritation to neighboring tissue. Although drug core  268  can be made of many materials as explained above, silicon is a suitable material for the manufacture of drug core  268  comprises soft brush like members  268 F. Exposed surface  268 A of drug core  268  also includes an indentation  2681  such that at least a portion of exposed surface  268 A is concave. 
       FIG. 2K  shows a side view of a sustained release implant  259  with a drug core  269  comprising a convex exposed surface  269 A, according to an embodiment of the present invention. Drug core  269  is partially covered with a sheath body  279  that extends at least partially over drug core  269  to define convex exposed surface  269 A. Sheath body  279  comprises a shaft portion  279 S. Convex exposed surface  269  provides an increased exposed surface area above the sheath body. A cross sectional area of convex exposed surface  269 A is larger than a cross sectional area of shaft portion  279 S of sheath body  279 . In addition to the larger cross sectional area, convex exposed surface  269 A has a larger surface area due to the convex shape that extends outward on the core. A retention element  289  comprising a coil of wire is attached to sheath body  279 . Retention element  289  can be dip coated to make retention element  289  biocompatible. 
       FIGS. 3A to 3C  show retention elements that encompass punctual plugs and structures to release therapeutic agents that encompass reservoirs, according to embodiments of the present invention. Structures suitable for incorporation with the present invention are described in U.S. Pat. No. 6,196,993, entitled “Ophthalmic insert and method for sustained release of medication to the eye”, issued in the name of Cohan on Mar. 6, 2001, the full disclosure of which is incorporated herein by reference. The reservoir can include any of the therapeutic agents described herein to treat optical defects of the eye, for example atropine to treat myopia of the eye. The migration of the drug from the reservoir may occur by diffusion, although other migration mechanisms are possible. 
       FIG. 3A  shows a perspective view of a punctual plug with a reservoir, according to an embodiment of the present invention. An ophthalmic insert  332  is shown in the form of a punctal occluder with a reservoir  334  designed to store and release therapeutic agent onto the surface of the eye in a continuous, long-term manner. Ophthalmic insert  332  can be molded or otherwise formed from a flexible material, such as silicone, that is impermeable to the therapeutic agent, which will fill the reservoir  334 . Reservoir  334  is formed by a channel through the interior of a body portion  336  of insert  332 . Preferably, body portion  336  is flexible, and may even be accordion-shaped to provide the capability of lengthwise expansion as it is filled with the therapeutic agent. 
     Still referring to  FIG. 3A , a collarette  340  anchors the insert  332  to the exterior of the lacrimal punctum and is provided with a pore  342  in fluid communication with reservoir  334 . In order to control the delivery of a specific therapeutic agent, the geometry of pore  342  may be customized as explained in U.S. Pat. No. 6,196,993, previously incorporated herein by reference. Through pore  342 , therapeutic agent is deployed from reservoir  334  into the tears of the lacrimal lake where the therapeutic agent mixes, as eye drops do, with the tears and penetrates the eye to have the intended pharmacological effect. Although not required, an enlarged bulb portion  238  may be provided to help secure the insert  332  within the canaliculus and also to provide additional volume for reservoir  334  as shown. 
       FIG. 3B  shows a schematic representation of a preferred configuration of medication within the reservoir and its contact with the external tear flow, according to an embodiment of the present invention. The reservoir  334  includes a region (a) containing the most concentrated form of the medication, in either a solid or liquid state. The medication diffuses from region (a) into an adjacent region (b), nearest the pore  342 , comprising a saturated solution of the medication. The rate-controlling pore  342  can be formed with desired dimensions at the time the insert  332  is made, or pore  342  could be sized appropriately by retrofitting insert  332  with an apertured cap of appropriate geometry fit over reservoir  334 . In an alternative embodiment, pore  342  could be provided in the form of an imperforate material placed over the collarette  340  that is permeable to the passage of the medication. 
       FIG. 4  shows a retention element that encompass a tube, for example a tube used to form a punctual plug, and a structure to release therapeutic agents that encompass a drug reservoir at least partially enclosed with a permeable layer, according to an embodiment of the present invention. Structures suitable for incorporation with the present invention are described in U.S. Pat. App. Pub. No. 2004/0208910, entitled “Sustained release device and method for ocular delivery of adrenergic agents”, published in the name of Ashton on Oct. 21, 2004, the full disclosure of which is incorporated herein by reference. The reservoir can include any of the therapeutic agents described herein to treat optical defects of the eye, for example atropine to treat myopia of the eye. The retention element comprises any of the structures described in the &#39;910 publication used to retain the drug reservoir at the intended location near the eye. 
       FIG. 4  schematically illustrates an enlarged cross-sectional illustration of a sustained release drug delivery device with a reservoir and a permeable plug. A device  300  includes a permeable outer layer  310 , a substantially impermeable inner tube  312 , a reservoir  314 , a substantially impermeable cap  316 , and a permeable plug  318 . A port  320  communicates plug  318  with the exterior of the device, as described above with respect to port  224  and plug  216 . Inner tube  312  and cap  316  can be formed separately and assembled together, or the inner tube and the cap can be formed as a single, integral, monolithic element. The provision of permeable outer layer  310  allows the therapeutic agent(s) in reservoir or drug core  314  to flow through the outer layer in addition to port  320 , and thus assists in raising the overall delivery rate. The material out of which outer layer  310  is formed can be specifically chosen for its ability to adhere to the underlying structures, cap  316 , tube  312 , and plug  318 , and to hold the entire structure together. Optionally, a hole or holes  322  can be provided through inner tube  312  to increase the flow rate of the therapeutic agent(s) from reservoir  314 . 
       FIG. 5  shows a retention elements that encompasses a punctual plug, and a structure to release therapeutic agents that encompasses a drug reservoir enclosed with a material permeable to the drug, according to an embodiment of the present invention. Structures suitable for incorporation with the present invention are described in U.S. Pat. App. Pub. Nos. 2004/0020253, entitled “Implantable device having controlled release of medication and method of manufacturing the same”, published in the name of Prescott on Jan. 26, 2006; and U.S. App. Pub. No. 2006/0020248, entitled “Lacrimal insert having reservoir with controlled release of medication and method of manufacturing the same”, published in the name of Prescott on Jan. 26, 2006, the full disclosures of which are incorporated herein by reference. The reservoir can include any of the therapeutic agents described herein to treat optical defects of the eye, for example medications to treat optical defects of the eye. 
       FIG. 5  schematically illustrates a lacrimal insert in the shape of a punctum plug  510  for insertion into a lacrimal puncta. The punctum plug  510  includes a body  512  defining a reservoir  514 , a neck portion  516 , a flared portion  518 , and a tapered portion  520  terminating in a tip  522 . A non-porous head  524  is provided over the neck portion  516  of the body  512 , and these enclose the reservoir. A medication  526  is provided in the reservoir. In accord with one aspect of the invention, the body  512  and head  524  are made of different materials, with the body  512  being made from a biocompatible, preferably soft and flexible first material which is relatively impermeable to the medication, and the head  524  being made from a biocompatible, preferably soft and flexible second material which is permeable to the medication. 
       FIG. 6  shows a punctual plug having materials to release therapeutic agents (e.g. coatings and/or biodegradable polymers) according to embodiments of the present invention. Structures suitable for use with the present invention are described in PCT/US2005/023848 published as International Pub. No. WO 2006/014434, entitled “TREATMENT MEDIUM DELIVERY DEVICE AND METHODS FOR DELIVERY OF SUCH TREATMENT MEDIUMS TO THE EYE USING SUCH A DELIVERY DEVICE”, in the name of Lazar on Feb. 9, 2006. The biodegradable polymer can include any of the therapeutic agents described herein to treat optical defects of the eye, for example a treatment medium such as atropine to treat myopia of the eye. 
       FIG. 6  shows a treatment medium delivery device  600  according an embodiment of the present invention. The treatment medium delivery device  600  includes a first body portion  610  and a second body portion  620 . The second body portion  620  is generally configured and arranged so as to include the therapeutic agent or treatment medium that is to be dispensed. 
     The first body portion  610  is sized, configured and arranged so as to be removably inserted and secured in an opening provided in the eye, more particularly, a portion of the body proximal the eye. More particularly, the first body portion  610  is sized, configured and arranged such that when the first body portion is inserted into the opening it is secured within the opening so it does not fall or come out as a result of normal and expected bodily function, such as for example, blinking of the eyelids and any laxity of the eye. In particular exemplary embodiments, the opening in the eye is a punctum of the eye for a mammalian body that is fluidly coupled to a lacrimal canaliculus, and the treatment medium delivery device is configured and arranged so it remains secured within the punctum and a portion of the lacrimal canaliculus during normal eye function. 
     The first body portion  610  is configurable in any number of ways, for example as a solid member, a member having a lumen or passage defined therein, a member having a passage passing through a portion of the first body portion, an open compartment located within the first body portion, and a body structure that corresponds to the structure of a stent. A stent provides a scaffold like structure that can be arranged to form a generally cylindrical shape or a shape that conforms to the opening and passage into which the stent is being inserted. The first body portion  610  also is constructed of any of a number of biocompatible materials as is known to those skilled in the art, including metals such as stainless steel and nitinol (nickel-titanium) and plastics that have strength and material characteristics suitable for the intended use. Such materials of the first body portion  610  also preferably are characterized as being non-toxic and non-sensitizing. 
     In more particular embodiments, the first body portion includes an end  612  that is configured to facilitate insertion of the first body portion  610  into the opening as well as to minimize significant trauma and/or injury to the tissue of the opening as the first body portion is being inserted therein, hi specific exemplary embodiments, the first body portion end  612  is arcuate and/or generally hemispherical. The first body portion end  612  can be configured so it presents an end that is appropriate for the intended function and use. For example, the end  612  is configurable so as to have a piercing capability if the function and use of the first end portion  610  would involve piercing of tissue or a membrane as the first portion end is being inserted into the body opening. 
     In an embodiment of the present invention, the second body portion  620  comprises a member, device (e.g., an eluting device, a sustained released device, an encapsulation device) or coating that is applied, secured, attached or bonded to the first body portion second end  614  using any of a number of techniques known to those skilled in the art such as adhesives. Such a second body portion  620  is constituted so as to carry one or more treatment mediums, and provide a delivery vehicle or structure, such as a matrix or medium, that is constituted so it releasably retains the one or more treatment mediums therein so the medium can be released there from under predetermined conditions. Such releasably retaining includes but is to limited to encapsulation of the treatment medium(s) within the structure comprising the delivery vehicle or structure. It also is contemplated that the second body portion  620  can comprise a medium or material, for example a polymer, that is formed, cured or otherwise appropriately processed such that it is bonded to the first body portion second end  614 , as a result of such forming, curing, polymerizing or processing. Additional description of the second body portion are described in WO 2006/014434. 
       FIG. 7  shows a retention element that comprises an elongate member for complete insertion into the canaliculus of the eye and a structure to release therapeutic agents that encompasses a coating on the retention element, according to an embodiment of the present invention. Structures suitable for incorporation with the present invention are described in U.S. Pat. No. 5,053,030, entitled “Intracanalicular implant for horizontal canalicular blockade treatment of the eye”, issued in the name of Herrick on Oct. 1, 1991, the full disclosure of which is incorporated herein by reference. The of therapeutic agent can include a medication, for example a treatment medium such as atropine to treat myopia of the eye. 
       FIG. 7  shows an implant for complete insertion into the canaliculus of the human eye with medication, according to an embodiment of the present invention. An implant Imp is constructed of two parts, with the second part M having a preselected configuration to be mounted to the nose N of the implant Imp and for loading it with medication. The illustrated configuration for the part M has one end defined to be complementary to the nose end of the part Imp to be carried thereby and a blunt nose for the opposite end. These medications can be loaded onto the intracanalicular implant Imp for timed release dosages to the eye. This release would work as a result of the reflex action of the eye and could be used, for example, to distribute atropine to the muscle of the eye. 
       FIGS. 8A and 8B  show retention elements that encompass punctual plugs and structures to release therapeutic agents that encompass the head portion of the punctual plug, according to an embodiment of the present invention. Structures suitable for incorporation with the present invention are described in U.S. Pat. No. 3,949,750, entitled “Punctum plug and method for treating keratoconjunctivitis sicca and other ophthalmic aliments using same”, issued in the name of Freeman on Apr. 13, 1976, the full disclosure of which is incorporated herein by reference. The head portion can include any of the therapeutic agents described herein to treat optical defects of the eye, for example atropine to treat myopia of the eye. 
     In the treatment of ophthalmic ailments where it is desired to prevent or decrease the drainage of lacrimal fluid and/or medication from the eye, the punctal aperture in either or both of the upper and lower lids are to be blocked by a removable plug member  820 , two respective embodiments of which are shown in  FIGS. 8A and 8B . Referring initially to the embodiment of  FIG. 8A , the punctum plug  820  has a projecting tip or barb portion  822 , a middle neck or waist portion  824  of somewhat smaller diameter than the tip, and a smooth disc-like head portion  826  of relatively larger diameter. The plug embodiment  820 ′ of  FIG. 8B  is of generally similar dimensions to the first-described embodiment with a somewhat blunted tip or barb portion  822 ′, a cylindrical middle portion  824 ′ of substantially the same dimension, and a dome-shaped head portion  826 ′ of somewhat smaller diameter than its counterpart in the embodiment of  FIG. 8A . The head portion  826 ,  826 ′ of both embodiments may be provided, if desired as an alternative to grasping it with forceps, with a central bore opening  828 ,  828 ′ adapted to receive the projecting tip of an inserter tool to provide a releasable grip on the plug as it is manipulated for insertion, as hereinafter described. 
     In certain embodiments of the invention the plugs  820 ,  820 ′, particularly the head portion  828 ,  828 ′, may be of medication-impregnable porous material such as HEMA hydrophilic polymer, or may be otherwise adapted as with capillaries or the like, to store and slowly dispense ophthalmic drugs to the eye as they are leached out by the lacrimal fluids. 
     In an embodiment, therapeutic agents as described herein are incorporated into a punctual plug as described in U.S. App. Pub. No. 2005/0197614, the full disclosure of which is incorporated herein by reference. A gel can be used to form a punctual plug, and the gel can swell from a first diameter to a second diameter in which the second diameter is about 50% greater than the first diameter. The gel can be used to entrap active therapeutic agents, for example within a microporous structure in which the agent is uniformly dispersed, and the gel can slowly elute therapeutic agents into the patient. Various therapeutic agents are described in U.S. Provisional Application No. 60/550,132, entitled “Punctum Plugs, Materials, And Devices”, the full disclosure of which is incorporated herein by reference, and may be combined with the gels and devices described herein. 
       FIG. 9  shows a retention element that encompasses a punctual plug and a retention element that encompasses a hollow implant, and structures to release therapeutic agents that encompass coatings applied to the retention elements, according to an embodiment of the present invention. Structures suitable for incorporation with the present invention are described in U.S. Pat. App. Pub. No. 2005/0232972, entitled “Drug delivery via punctual plug”, published in the name of Odrich on Oct. 20, 2005, the full disclosure of which is incorporated herein by reference. 
       FIG. 9  shows a punctal plug generally designated  910 , having a stem  912  for insertion into the punctal aperture  920  of an eye  924 , and along the canaliculus  922  communicating with the aperture. Plug  910  has a large stopper structure  914  connected to the outer end of stem  912  for seating against the aperture  920  and sealing the canaliculus  922  against the flow of tears onto the surface of an eye  924 . The same or similar numerals are used to designate functionally similar parts, for example upper and lower canaliculi  922   a  and  922   b , each with implants  910   a  and  910   b , respectively. Implant  910   a  is a substantially cylindrical and solid collagen plug that has been inserted into the upper punctum or tear duct  920   a , to block the flow of tears while lower implant  910   b  is hollow like a straw for the passage of tears. Implant  910   b  includes a tapered shaft or stem  912   a  with a flared open end  912   b  immobilized at the lower punctum  920   b . A mushroom shaped inner stopper  914   a  is formed at the opposite end of shaft  912   a  for further setting the location of the implant in the tear duct. The implants shown can be used in any desired combination, for example implant  910   a  can be positioned in the lower canaliculus and implant  910   b  can be positioned in the upper canaliculus. Alternatively, each type of implant (e.g.  910   b ) can be positioned in both canaliculi. 
     The active agent, e.g. a medicine or medication is applied, e.g. in one or more bands of polymer material at the inner end of the stem, or on the outer end of the stopper, or over some or all of the surfaces of the implants of  FIG. 9 , or otherwise. Polymer that is absorbent to the agent is preferable so that sufficient agent is present and available for discharge into the surrounding tissues. A porous or absorbent material can alternatively be used to make up the entire plug or implant which can be saturated with the active agent. 
     Unlike the tear stopping punctal plug, the hollow implant provides a very different drug administering method, scheme and structure. The hollow implant  910   b  of  FIG. 9  is particularly useful in that the active agent can be applied to, or is otherwise available at the inner surface or interior of the implant, and is uniquely structured to pass tears and thus administer the active agent to the tear stream in a fashion that is controlled by the flow of tears which thus act as the carrier for the agent. 
       FIGS. 10A to 10C  show deployment of a sustained release implant, according to an embodiment of the present invention. As shown in  FIG. 10A , a deployment instrument  1010  is inserted into a canaliculus  1000  through a punctum  1000 A. A sustained release implant  1020  is loaded into a tip of deployment instrument  1010 . As shown in  FIG. 10B , an outer sheath of deployment instrument  1010  is withdrawn to expose a retention element  1030  of sustained release implant  1020 . As shown in  FIG. 10C , deployment instrument  1010  has been removed and sustained release implant  1020  is implanted in canaliculus  1000 . A drug core  1040  is attached retention element  1030  and retained in the canaliculus. An outer body sheath  1050  covers at least a portion of drug core  1040  and drug core  1040  releases a therapeutic agent into a liquid tear or tear film  1060  near punctum  1000 A of canaliculus  1000 . 
       FIG. 11  shows sustained release therapeutic agent implants and implant locations on or near an eye  1100 , according to embodiments of the present invention. The sustained release implant can comprises many of the structures used with Lacrisert®, scleral plugs, intrascleral discs, episcleral implants, injectable rods, macular implants, intrascleral discs, Vitrasert®, Retisert®, Ocusert® and/or Prosert® implants. Similar structures are shown in the publication by Yasukawa, et al., “Expert Opinion on Drug Delivery”, Volume 3, Number 2, 1 Mar. 2006, pp. 261-273(13), Published by Informa Healthcare. A sustained release implant  1110  may comprise many structures of Lacrisert™ implants for administration into the inferior cul-de-sac of the eye, which are available from Merck &amp; CO., Inc. of Whitehouse Station, N.J. A sustained release implant  1120  may comprise many structures of a scleral plug implant for administration into the sclera and/or vitreous humor of the eye. A scleral plug and/or tack is described in U.S. Pat. No. 5,466,233, the full disclosure of which is incorporated herein by reference. A sustained release implant  1130  may comprise many structures of a scleral disc implant for administration into the sclera. An intrascleral disc can be inserted into the sclera tissue layer. A sustained release implant  1140  may comprise many structures of an episcleral disc implant that can be placed near a surface of the sclera and provide a trans-scleral drug delivery system. A sustained release implant  1150  may comprise many structures of a injectable rod for injection into the aqueous humor, the sclera and or lacrimal ducts. A sustained release implant  1160  may comprise many structures of a macular implant for implantation near a macular tissue of the eye. A sustained release implant  1170  may comprise many structures of Vitrasert® and/or Retisert® implants. Vitrasert® and Retisert® implants are commercially available from Chiron Ophthalmics, a subsidiary Bausch and Lomb of Rochester, N.Y. Ocusert® implants are commercially available from Alza, a subsidiary of Johnson &amp; Johnson of New Brunswick, N.J. Prosert® implants are commercially available from Novartis of Basel, Switzerland. 
       FIG. 12A  shows a device  1200  for treating optical defects of the eye that comprises a sustained release implant that releases a therapeutic agent to treat the optical defect of the eye and additional sustained release implants to counteract side effects of the therapeutic agent. Device  1200  comprises a sustained release implant  1210  that releases a therapeutic agent as described above. Device  1200  comprises a sustained release implant  1220  that releases a counteractive agent that counteracts a first side effect of the therapeutic agent. As the therapeutic agent may have more than one side effect, device  1200  may comprises a sustained release implant  1230  that counteracts a second side effect of the therapeutic agent. The sustained release implants may be simultaneously located in many of the locations of or near the eye as described above. In a preferred embodiment, sustained release implant  1210  may release atropine. One side effect of atropine is pupil dilation that can be associated with photophobia. Sustained release implant  1220  may release a miotic drug as a counteractive agent to counteract the dilation of the pupil caused by the therapeutic agent. Another possible side effect of atropine is glaucoma, and sustained release implant  1230  may release an anti-glaucoma drug as a counteractive agent to avoid glaucoma. 
       FIG. 12B  shows a sustained release implant  1250  that releases a therapeutic agent to treat an optical defect of the eye and releases counteractive agents that counteract side effects of the therapeutic agent, according to embodiments of the present invention. Sustained release implant  1250  may comprise a sheath body  1260  and a drug core  1270 . Sustained release implant  1250  may be placed in many of the locations of or near the eye as described above. Drug core  1270  comprises a therapeutic agent  1280  to treat an optical defect of the eye. Drug core  1270  may comprise a counteractive agent  1282  to counteract a side effect of therapeutic agent  1280 . In a preferred embodiment, sustained release implant  1250  may release atropine. Therapeutic agent  1282  may comprise a miotic drug as a counteractive agent to counteract the dilation of the pupil caused by the therapeutic agent. Another possible side effect of atropine is glaucoma, and therapeutic agent  1284  may release an anti-glaucoma drug as a counteractive agent to avoid glaucoma. The therapeutic agent, the miotic drug and the anti-glaucoma drug may be released together from sustained release implant  1250 . 
     Although the invention has been described by way of the specific embodiments described above, one will recognize various modifications and alterations that can be readily made and that are within the scope and spirit of the invention. Therefore, the present invention is limited only by the following claims and the full scope of their equivalents.