Patent Publication Number: US-2018028361-A1

Title: Uveoscleral drug delivery implant and methods for implanting the same

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation of U.S. patent application Ser. No. 13/201,423, filed Mar. 2, 2012, which is the U.S. National Phase application under 35 U.S.C. §371 of International Application No. PCT/US2010/024128, filed on Feb. 12, 2010, which claims the benefit of U.S. Provisional Application No. 61/152,651, filed on Feb. 13, 2009, each of which is incorporated in its entirety by reference herein. 
    
    
     BACKGROUND OF THE INVENTION 
     Field of the Invention 
     This disclosure relates to the delivery of a therapeutic agent to ocular tissue via an implant. The disclosure also relates to reducing intraocular pressure within the eye and to a treatment of glaucoma and/or other ocular disorders wherein aqueous humor is permitted to flow out of an anterior chamber of the eye through a surgically implanted pathway. 
     Description of the Related Art 
     A human eye is a specialized sensory organ capable of light reception and is able to receive visual images. Aqueous humor is a transparent liquid that fills at least the region between the cornea, at the front of the eye, and the lens. A trabecular meshwork, located in an anterior chamber angle, which is formed between the iris and the cornea, normally serves as a drainage channel for aqueous humor from the anterior chamber so as to maintain a balanced pressure within the anterior chamber of the eye by allowing aqueous humor to flow from the anterior chamber. 
     About two percent of people in the United States have glaucoma. Glaucoma is a group of eye diseases encompassing a broad spectrum of clinical presentations, etiologies, and treatment modalities. Glaucoma causes pathological changes in the optic nerve, visible on the optic disk, and it causes corresponding visual field loss, resulting in blindness if untreated. Lowering intraocular pressure is the major treatment goal in all glaucomas. 
     In glaucomas associated with an elevation in eye pressure (intraocular hypertension), the source of resistance to outflow is mainly in the trabecular meshwork. The tissue of the trabecular meshwork normally allows the aqueous humor (hereinafter referred to as “aqueous”) to enter Schlemm&#39;s canal, which then empties into aqueous collector channels in the posterior wall of Schlemm&#39;s canal and then into aqueous veins, which form the episcleral venous system. Aqueous is continuously secreted by a ciliary body around the lens, so there is a constant flow of aqueous from the ciliary body to the anterior chamber of the eye. Pressure within the eye is determined by a balance between the production of aqueous and its exit through the trabecular meshwork (major route) and uveoscleral outflow (minor route). The trabecular meshwork is located between the outer rim of the iris and the back of the cornea, in the anterior chamber angle. The portion of the trabecular meshwork adjacent to Schlemm&#39;s canal (the juxtacanilicular meshwork) causes most of the resistance to aqueous outflow. 
     While a majority of the aqueous leaves the eye through the trabecular meshwork and Schlemm&#39;s canal, it is believed that about  10  to about  20  percent of the aqueous in humans leaves through the uveoscleral pathway. The degree with which uveoscleral outflow contributes to the total outflow of the eye appears to be species dependent. As used herein, the term “uveoscleral outflow pathway” is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to the space or passageway whereby aqueous exits the eye by passing through the ciliary muscle bundles located angle of the anterior chamber and into the tissue planes between the choroid and the sclera, which extend posteriorly to the optic nerve. From these tissue planes, it is believed that the aqueous travels through the surrounding scleral tissue and drains via the scleral and conjunctival vessels, or is absorbed by the uveal blood vessels. It is unclear from studies whether the degree of physiologic uveoscleral outflow is pressure-dependent or pressure-independent. As used herein, the term “supraciliary space” is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to the portion of the uveoscleral pathway through the ciliary muscle and between the ciliary body and the sclera, and the term “suprachoroidal space” is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to the portion of the uveoscleral pathway between the choroid and sclera. Although it is not completely understood, some studies have suggested that there may be a “compact zone” of connective tissue associated with the junction between the retina and ciliary body, known as the ora serrata. This “compact zone” may act as a site of resistance along the uveoscleral outflow pathway. The ora serrata can vary in length from about 5.75 mm to 7.5 mm nasally to about 6.5 mm to about 8.5 mm temporally. Other studies suggest that the ciliary muscle bundles are the primary site of resistance. 
     Certain therapeutic agents have been shown to reduce intraocular pressure by increasing uveoscleral outflow, but the mechanism by which uveoscleral outflow is increased is unclear. Some studies have suggested that relaxation of the ciliary muscle may reduce resistance through the ciliary muscle bundles to increase flow. Other studies suggest that dilation of the post-capillary venules or constriction of the pre-capillary arterioles may reduce downstream fluid pressure and increase uveoscleral outflow. 
     Glaucoma is broadly classified into two categories: closed-angle glaucoma, also known as angle closure glaucoma, and open-angle glaucoma. Closed-angle glaucoma is caused by closure of the anterior chamber angle by contact between the iris and the inner surface of the trabecular meshwork. Closure of this anatomical angle prevents normal drainage of aqueous from the anterior chamber of the eye. Open-angle glaucoma is any glaucoma in which the exit of aqueous through the trabecular meshwork is diminished while the angle of the anterior chamber remains open. For most cases of open-angle glaucoma, the exact cause of diminished filtration is unknown. Primary open-angle glaucoma is the most common of the glaucomas, and is often asymptomatic in the early to moderately advanced stages of glaucoma. Patients may suffer substantial, irreversible vision loss prior to diagnosis and treatment. However, there are secondary open-angle glaucomas that may include edema or swelling of the trabecular spaces (e.g., from corticosteroid use), abnormal pigment dispersion, or diseases such as hyperthyroidism that produce vascular congestion. 
     Current therapies for glaucoma are directed toward decreasing intraocular pressure. Currently recognized categories of drug therapy for glaucoma include but are not limited to: (1) Miotics (e.g., pilocarpine, carbachol, and acetylcholinesterase inhibitors), (2) Sympathomimetics (e.g., epinephrine and dipivalylepinephxine), (3) Beta-blockers (e.g., betaxolol, levobunolol and timolol), (4) Carbonic anhydrase inhibitors (e.g., acetazolamide, methazolamide and ethoxzolamide), and (5) Prostaglandins (e.g., metabolite derivatives of arachidonic acid). Medical therapy includes topical ophthalmic drops or oral medications that reduce the production of aqueous or increase the outflow of aqueous. However, drug therapies for glaucoma are sometimes associated with significant side effects. The most frequent and perhaps most serious drawback to drug therapy, especially the elderly, is patient compliance. Patients often forget to take their medication at the appropriate times or else administer eye drops improperly, resulting in under- or overdosing. Patient compliance is particularly problematic with therapeutic agents requiring dosing frequencies of three times a day or more, such as pilocarpine. Because the effects of glaucoma are irreversible, when patients dose improperly, allowing ocular concentrations to drop below appropriate therapeutic levels, further permanent damage to vision occurs. Furthermore, current drug therapies are targeted to be deposited directly into the ciliary body where the aqueous is produced. And current therapies do not provide for a continuous slow-release of the drug. When drug therapy fails, surgical therapy is pursued. 
     Surgical therapy for open-angle glaucoma consists of laser trabeculoplasty, trabeculectomy, and implantation of aqueous shunts after failure of trabeculectomy or if trabeculectomy is unlikely to succeed. Trabeculectomy is a major surgery that is widely used and is augmented with topically applied anticancer drugs, such as 5-flurouracil or mitomycin-C to decrease scarring and increase the likelihood of surgical success. 
     Approximately 100,000 trabeculectomies are performed on Medicare-age patients per year in the United States. This number would likely increase if ocular morbidity associated with trabeculectomy could be decreased. The current morbidity associated with trabeculectomy consists of failure (10-15%); infection (a life long risk of 2-5%); choroidal hemorrhage, a severe internal hemorrhage from low intraocular pressure, resulting in visual loss (1%); cataract formation; and hypotony maculopathy (potentially reversible visual loss from low intraocular pressure). For these reasons, surgeons have tried for decades to develop a workable surgery for reducing intraocular pressure. 
     The surgical techniques that have been tried and practiced are goniotomy/trabeculotomy and other mechanical disruptions of the trabecular meshwork, such as trabeculopuncture, goniophotoablation, laser trabecular ablation, and goniocurretage. These are all major operations and are briefly described below. 
     Goniotomy and trabeculotomy are simple and directed techniques of microsurgical dissection with mechanical disruption of the trabecular meshwork. These initially had early favorable responses in the treatment of open-angle glaucoma. However, long-term review of surgical results showed only limited success in adults. In retrospect, these procedures probably failed due to cellular repair and fibrosis mechanisms and a process of “filling in.” Filling in is a detrimental effect of collapsing and closing in of the created opening in the trabecular meshwork. Once the created openings close, the pressure builds back up and the surgery fails. 
     Q-switched Neodynium (Nd) YAG lasers also have been investigated as an optically invasive trabeculopuncture technique for creating full-thickness holes in trabecular meshwork. However, the relatively small hole created by this trabeculopuncture technique exhibits a filling-in effect and fails. 
     Goniophotoablation is disclosed by Berlin in U.S. Pat. No. 4,846,172 and involves the use of an excimer laser to treat glaucoma by ablating the trabecular meshwork. This method did not succeed in a clinical trial. Hill et al. used an Erbium YAG laser to create full-thickness holes through trabecular meshwork (Hill et al., Lasers in Surgery and Medicine 11:341346, 1991). This laser trabecular ablation technique was investigated in a primate model and a limited human clinical trial at the University of California, Irvine. Although ocular morbidity was zero in both trials, success rates did not warrant further human trials. Failure was again from filling in of surgically created defects in the trabecular meshwork by repair mechanisms. Neither of these is a viable surgical technique for the treatment of glaucoma. 
     Goniocurretage is an “ab interno” (from the inside), mechanically disruptive technique that uses an instrument similar to a cyclodialysis spatula with a microcurrette at the tip. Initial results were similar to trabeculotomy: it failed due to repair mechanisms and a process of filling in. 
     Although trabeculectomy is the most commonly performed filtering surgery, viscocanalostomy (VC) and nonpenetrating trabeculectomy (NPT) are two new variations of filtering surgery. These are “ab externo” (from the outside), major ocular procedures in which Schlemm&#39;s canal is surgically exposed by making a large and very deep scleral flap. In the VC procedure, Schlemm&#39;s canal is cannulated and viscoelastic substance injected (which dilates Schlemm&#39;s canal and the aqueous collector channels). In the NPT procedure, the inner wall of Schlemm&#39;s canal is stripped off after surgically exposing the canal. 
     Trabeculectomy, VC, and NPT involve the formation of an opening or hole under the conjunctiva and scleral flap into the anterior chamber, such that aqueous is drained onto the surface of the eye or into the tissues located within the lateral wall of the eye. These surgical operations are major procedures with significant ocular morbidity. When trabeculectomy, VC, and NPT are thought to have a low chance for success, a number of implantable drainage devices have been used to ensure that the desired filtration and outflow of aqueous through the surgical opening will continue. The risk of placing a glaucoma drainage device also includes hemorrhage, infection, and diplopia (double vision). 
     All of the above embodiments and variations thereof have numerous disadvantages and moderate success rates. They involve substantial trauma to the eye and require great surgical skill in creating a hole through the full thickness of the sclera into the subconjunctival space. The procedures are generally performed in an operating room and involve a prolonged recovery time for vision. The complications of existing filtration surgery have prompted ophthalmic surgeons to find other approaches to lowering intraocular pressure or treating tissue of trabecular meshwork. 
     Because the trabecular meshwork and juxtacanilicular tissue together provide the majority of resistance to the outflow of aqueous, they are logical targets for surgical removal in the treatment of open-angle glaucoma. In addition, minimal amounts of tissue need be altered and existing physiologic outflow pathways can be utilized. Some procedures bypass the trabecular meshwork and juxtacanilicular tissue to drain fluid to physiologic outflow channels. However, in severe cases, it has been found that these procedures do not sufficiently reduce intraocular pressure. 
     As reported in Arch. Ophthalm. (2000) 118:412, glaucoma remains a leading cause of blindness, and filtration surgery remains an effective, important option in controlling glaucoma. However, modifying existing filtering surgery techniques in any profound way to increase their effectiveness appears to have reached a dead end. 
     Examples of implantable shunts and surgical methods for maintaining an opening for the release of aqueous from the anterior chamber of the eye to the sclera or space beneath the conjunctiva have been disclosed in, for example, Hsia et al., U.S. Pat. No. 6,059,772 and Baerveldt, U.S. Pat. No. 6,050,970. 
     Examples of implantable shunts or devices for maintaining an opening for the release of aqueous humor from the anterior chamber of the eye to the sclera or space underneath conjunctiva have been disclosed in U.S. Pat. No. 6,007,511 (Prywes), U.S. Pat. No. 6,007,510 (Nigam), U.S. Pat. No. 5,893,837 (Eagles et al.), U.S. Pat. No. 5,882,327 (Jacob), U.S. Pat. No. 5,879,319 (Pynson et al.), U.S. Pat. No. 5,807,302 (Wandel), U.S. Pat. No. 5,752,928 (de Roulhac et al.), U.S. Pat. No. 5,743,868 (Brown et al.), U.S. Pat. No. 5,704,907 (Nordquist et al.), U.S. Pat. No. 5,626,559 (Solomon), U.S. Pat. No. 5,626,558 (Suson), U.S. Pat. No. 5,601,094 (Reiss), U.S. Pat. No. 35,390 (Smith), U.S. Pat. No. 5,558,630 (Fisher), U.S. Pat. No. 5,558,629 (Baerveldt et al.), U.S. Pat. No. 5,520,631 (Nordquist et al.), U.S. Pat. No. 5,476,445 (Baerveldt et al.), U.S. Pat. No. 5,454,796 (Krupin), U.S. Pat. No. 5,433,701 (Rubinstein), U.S. Pat. No. 5,397,300 (Baerveldt et al.), U.S. Pat. No. 5,372,577 (Ungerleider), U.S. Pat. No. 5,370,607 (Memmen), U.S. Pat. No. 5,338,291 (Speckman et al.), U.S. Pat. No. 5,300,020 (L&#39;Esperance, Jr.), U.S. Pat. No. 5,178,604 (Baerveldt et al.), U.S. Pat. No. 5,171,213 (Price, Jr.), U.S. Pat. No. 5,041,081 (Odrich), U.S. Pat. No. 4,968,296 (Ritch et al.), U.S. Pat. No. 4,936,825 (Ungerleider), U.S. Pat. No. 4,886,488 (White), U.S. Pat. No. 4,750,901 (Molteno), U.S. Pat. No. 4,634,418 (Binder), U.S. Pat. No. 4,604,087 (Joseph), U.S. Pat. No. 4,554,918 (White), U.S. Pat. No. 4,521,210 (Wong), U.S. Pat. No. 4,428,746 (Mendez), U.S. Pat. No. 4,402,681 (Haas et al.), U.S. Pat. No. 4,175,563 (Arenberg et al.), and U.S. Pat. No. 4,037,604 (Newkirk). 
     All of the above embodiments and variations thereof have numerous disadvantages and moderate success rates. They involve substantial trauma to the eye and require great surgical skill in creating a hole through the full thickness of the sclera into the subconjunctival space. The procedures are generally performed in an operating room and involve a prolonged recovery time for vision. The complications of existing filtration surgery have prompted ophthalmic surgeons to find other approaches to lowering intraocular pressure. 
     SUMMARY OF THE INVENTION 
     Disclosed herein are systems for treating an ocular disorder in a patient. In one embodiment, the system comprises a drug delivery implant comprising one or more drug delivery portion which, following implantation at an implantation site in the eye, delivers one or more therapeutic agent to one or more of the anterior chamber and the uveoscleral outflow pathway of an eye, and a delivery instrument releasably coupleable to the drug delivery implant for implanting the drug delivery implant. In a preferred embodiment, the instrument is configured to deliver the implant through an insertion site in the sclera to a location in the suprachoroidal space proximate the anterior chamber, and comprises a plurality of members longitudinally moveable relative to each other. 
     In another embodiment, there is provided a system for treating glaucoma that comprises a plurality of implants configured for implantation into eye tissue, one or more of the implants comprising one or more drug delivery portion which, following implantation at an implantation site in the eye, delivers one or more therapeutic agent to one or more of the anterior chamber and the suprachoroidal space of the eye, and an instrument having a chamber in which the implants are loaded for serial delivery into eye tissue, wherein at least a first implant of the plurality of implants is configured to extend generally alongside a second implant of said plurality of implants. 
     In another embodiment, there is provided an intraocular implant that comprises a generally elongated body configured for implantation in eye tissue, one or more recess formed in the body and extending from an end of the body generally along an axis, and a therapeutic agent disposed in the recess in a sufficient quantity to treat the eye over a desired period of time and configured to be released to the eye at a desired rate over said period of time. The implant may comprise a lumen extending along the length of the implant about a second axis generally parallel to the axis, the lumen configured to allow flow therethrough. 
     In another embodiment, there is provided an implant for treating glaucoma that comprises a body configured for implantation in an eye between an anterior chamber and suprachoroidal space of the eye, the body including a therapeutic agent, said body having a lumen extending between an inlet portion and an outlet portion of the body, said inlet portion configured to transport aqueous fluid from the anterior chamber of the eye to the outlet portion, where the outlet portion is disposed in the suprachoroidal space of the eye, said outlet portion having an outflow opening. 
     Certain embodiments may additionally include one or more of the following features or characteristics : (i) the implant is configured to deliver one or more therapeutic agents to the suprachoroidal space of the uveoscleral outflow pathway; (ii) the instrument and/or device has a sufficiently small cross section such that the insertion site self seals without suturing upon withdrawal of the instrument from the eye; (iii) the implant comprises a lumen extending configured to allow fluid communication between the anterior chamber of the eye and the uveoscleral outflow pathway following implantation of the implant; (iv) at least one of the one or more drug delivery portion comprises at least one of the one or more therapeutic agent compounded with a biodegradable PLGA copolymer, wherein the lactic acid to glycolic acid ratio and/or average molecular weight of the PLGA copolymer is selected to achieve a desired delivery rate of the therapeutic agent over time; (v) a therapeutic agent in fluid communication with the lumen such that the aqueous fluid contacts the therapeutic agent as it flows through the lumen; (vi) a therapeutic agent disposed on an outer surface of the elongated body, where the therapeutic agent is configured to contact ocular tissue following implantation of the drug delivery implant; and (vii) a therapeutic agent compounded with a biodegradable polymer adapted to provide a desired rate of release.. 
     In another embodiment there is provided a method for reducing intraocular pressure in an eye of a mammal, comprising introducing an ocular implant through an incision in ocular tissue, the ocular implant comprising a therapeutic agent and having proximal and distal ends; and advancing the implant to an implantation site in a uveoscleral outflow pathway of the eye such that one of the ends of the implant is in communication with the anterior chamber of the eye and the other of the ends of the implant is in communication with the suprachoroidal space of the eye. Further embodiments may include (i) introducing the implant comprises introducing the implant through an incision in the sclera of the eye made posteriorly of the limbus of the eye, the ocular implant advanced anteriorly into said position in the uveoscleral path, and/or (ii) introducing the implant comprises introducing the implant across the anterior chamber of the eye through an incision at or near a limbus of the eye opposite from the implantation site, advancing the implant across the anterior chamber and posteriorly along the uveoscleral outflow pathway into said implantation site such that the distal end of the implant is located in the suprachoroidal space and the proximal end of the implant is located in the anterior chamber. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       These and other features, aspects, and advantages of the present disclosure will now be described with reference to the drawings of embodiments, which embodiments are intended to illustrate and not to limit the disclosure. 
         FIG. 1  illustrates a schematic cross-sectional view of an eye. 
         FIG. 2A  is a longitudinal cross-section of one embodiment of a drug delivery implant. 
         FIG. 2B  is a transverse cross-section of the drug delivery implant of FIG. 
         2 A. 
         FIG. 3  is a longitudinal cross-section of another embodiment of a drug delivery implant. 
         FIG. 4A  is a longitudinal cross-section of another embodiment of a drug delivery implant. 
         FIG. 4B  is a transverse cross-section of the drug delivery implant of  FIG. 4A . 
         FIG. 5  is a longitudinal cross-section of another embodiment of a drug delivery implant. 
         FIG. 6  is a longitudinal cross-section of another embodiment of a drug delivery implant. 
         FIG. 7  is a longitudinal cross-section of another embodiment of a drug delivery implant. 
         FIG. 8A  is a longitudinal cross-section of another embodiment of a drug delivery implant. 
         FIG. 8B  is a transverse cross-section of the drug delivery implant of  FIG. 8A . 
         FIG. 9A  is a longitudinal cross-section of another embodiment of a drug delivery implant. 
         FIG. 9B  is a transverse cross-section of the drug delivery implant of  FIG. 9A . 
         FIG. 10  is a longitudinal cross-section of another embodiment of a drug delivery implant. 
         FIG. 11A  is a partial top view of an eye showing one embodiment of a method for implantation of a drug delivery implant into the eye. 
         FIG. 11B  is an enlarged cross-sectional detailed view of  FIG. 11A . 
         FIG. 12A  is a partial top view of an eye into which a drug delivery implant has been implanted. 
         FIG. 12B  is an enlarged cross-sectional detailed view of the implant in  FIG. 12A . 
         FIG. 13A  illustrates a schematic cross-sectional view of an eye with a delivery device containing an implant being advanced across the anterior chamber. 
         FIG. 13B  illustrates a schematic cross-sectional view of an eye with a delivery device being advanced adjacent the anterior chamber angle. 
         FIG. 13C  illustrates a schematic cross-section view of an eye with a delivery device implanting an implant that extends between the anterior chamber and the uveoscleral outflow pathway. 
         FIG. 14  illustrates a schematic cross-sectional view of an eye with another delivery device being advanced across the anterior chamber for use in delivering an implant into ocular tissue. 
         FIG. 15  illustrates a schematic cross-sectional view of an eye with another delivery device being advanced across the anterior chamber for use in delivering an implant into ocular tissue. 
     
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     An ophthalmic implant system is provided that comprises a drug delivery implant, which can include a shunt, and a delivery instrument for implanting the drug delivery implant. While this and other systems and associated methods are described herein in connection with glaucoma treatment, the disclosed systems and methods can be used to treat other types of ocular disorders in addition to glaucoma. 
       FIG. 1  illustrates the anatomy of an eye, which includes the sclera  11 , which joins the cornea  12  at the limbus  21 , the iris  13  and the anterior chamber  20  between the iris  13  and the cornea  12 . The eye also includes the lens  26  disposed behind the iris  13 , the ciliary body  16  and Schlemm&#39;s canal  22 . The eye also includes the uveoscleral outflow pathway  24   a , which defines the suprachoroidal space  24  between the choroids  28  and the sclera  11 . 
     In embodiments that include the shunt, the shunt, following implantation at an implantation site, can drain fluid from the anterior chamber into a physiologic outflow space. In some embodiments, the shunt can be configured to provide a fluid flow path for draining aqueous humor from the anterior chamber of an eye to the uveoscleral outflow pathway to reduce intraocular pressure. In some embodiments, an instrument is provided for delivering and/or implanting the drainage shunt ab interno in an eye to divert aqueous humor from the anterior chamber to the uveoscleral outflow pathway. In some embodiments, a method is provided for implanting a drainage shunt ab interno in an eye to divert aqueous humor from the anterior chamber to the uveoscleral outflow pathway. In some embodiments, the aqueous humor is diverted to the supraciliary space or the suprachoroidal space of the uveoscleral outflow pathway. 
     The term “shunt” as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to an implant defining one or more fluid passages. The fluid passage(s) in some embodiments remains patent and, in other embodiments, the passage(s) is fully or partially occluded under at least some circumstances (e.g., at lower intraocular pressure levels). The shunts may feature a variety of characteristics, described in more detail below, which facilitate the regulation of intraocular pressure. The mechanical aspects and material composition of the shunt can be important for controlling the amount and direction of fluid flow. Therefore, various examples of shunt dimensions, features, tip configurations, material flexibility, coatings, and valve design, in accordance with some embodiments of the present disclosure, are discussed in detail below. 
     The delivery instruments, described in more detail below, may be used to facilitate delivery and/or implantation of the drug delivery implant to the desired location of the eye. The delivery instrument preferably is used to place the implant into a desired position by application of a continual implantation force, by tapping the implant into place using a distal portion of the delivery instrument, or by a combination of these methods. The design of the delivery instruments may take into account, for example, the angle of implantation and the location of the implant relative to an incision. For example, in some embodiments, the delivery instrument may have a fixed geometry, be shape-set, or actuated. In some embodiments, the delivery instrument may have adjunctive or ancillary functions. In some embodiments, the delivery instrument may additionally be used to, for example, inject dye and/or viscoelastic fluid, to dissect, or be used as a guidewire. 
     In one embodiment, the implant can be advanced through the ciliary attachment tissue, which lies to the posterior of the scleral spur, during implantation. This tissue typically is fibrous or porous, which is relatively easy to pierce or cut with a surgical device, and lies inward of the scleral spur. The implant can be advanced through this tissue and abut against the sclera once the implant extends into the uveoscleral outflow pathway. The implant can then slide within the uveoscleral outflow pathway along the interior wall of the sclera. As the implant is advanced into the uveoscleral outflow pathway and against the sclera, the implant will likely be oriented at an angle with respect to the interior wall of the sclera. The implant is advanced until it reaches the desired implantation site within the uveoscleral outflow pathway. In some embodiments, an implant that includes a shunt is advanced into the ciliary body or ciliary muscle bundles to achieve drainage into the supraciliary space. In other embodiments, the implant with the shunt is advanced through the ciliary body or ciliary muscle bundles to achieve fluid communication between the anterior chamber and the suprachoroidal space. In still other embodiments, the implant with the shunt is advanced into the compact zone or through the compact to drain aqueous humor into the more distal portions of the suprachoroidal space. 
     Shunts 
     At least some of the disclosed embodiments include shunts that provide a fluid flow path for conducting aqueous humor from the anterior chamber of an eye to the uveoscleral outflow pathway to reduce intraocular pressure, preferably below episcleral venous pressure without hypotony. The shunts can have an inflow portion and an outflow portion. The outflow portion of the shunt preferably is disposed at or near a distal end of the shunt. When the shunt is implanted, the inflow portion may be sized and configured to reside in the anterior chamber of the eye and the outflow portion may be sized and configured to reside in the uveoscleral outflow pathway. In some embodiments, the outflow portion may be sized and configured to reside in the supraciliary region of the uveoscleral outflow pathway or in the suprachoroidal space. 
     One or more lumens can extend through the shunt to form at least a portion of the flow path. Preferably, there is at least one lumen that operates to conduct the fluid through the shunt. Each lumen preferably extends from an inflow end to an outflow end along a lumen axis. In some embodiments the lumen extends substantially through the longitudinal center of the shunt. In other embodiments, the lumen can be offset from the longitudinal center of the shunt. In still other embodiments, the flow path can be defined by grooves, channel or reliefs formed on an outer surface of the shunt body. 
     One or more openings can extend through the wall of the shunt. In some embodiments, the openings can extend through a middle portion of the shunt. In other embodiments the openings can extend through other portions of the shunt. The openings can be one or more of a variety of functions. One such function is that when the shunt is inserted into the suprachoroidal or supraciliary space, the openings provide a plurality of routes through which the aqueous humor can drain. For example, once the shunt is inserted into the eye, if the shunt only has one outflow channel (e.g., one end of a lumen), that outflow channel can be plugged, for example, by the shunt&#39;s abutment against the interior surface of the sclera or the outer surface of the choroid. Additionally, the outflow channel can be clogged with tissue that is accumulated or cored during the advancement of the shunt through the fibrous or porous tissue. A plurality of openings can provide a plurality of routes through which the fluid may flow to maintain patency and operability of the drainage shunt. In embodiments where the shunt has a porous body, the openings can define surface discontinuities to assist in anchoring the shunt once implanted. 
     The shunt in some embodiments can include a distal portion that is sufficiently sharp to pierce eye tissue near the scleral spur of the eye, and that is disposed closer to the outlet portion than to the inlet portion. In some embodiments, the distal portion is located at the distal end of the implant. In another embodiment, the distal portion can be sufficiently blunt so as not to substantially penetrate scleral tissue of the eye. In some embodiments, the shunts have a generally sharpened forward end and are self-trephinating, i.e., self-penetrating, so as to pass through tissue without pre-forming an incision, hole or aperture. The sharpened forward end can be, for example, conical or tapered. The tip can be sufficiently sharp to pierce eye tissue near the scleral spur of the eye. The tip also can be sufficiently blunt so as not to substantially penetrate scleral tissue of the eye. The taper angle of the sharpened end can be, for example, about 30°±15° in some embodiments. The radius of the tip can be about 70 to about 200 microns. In other embodiments, where an outlet opening is formed at the distal end of the shunt, the distal portion can gradually increase in cross-sectional size in the proximal direction, preferably at a generally constant taper or radius or in a parabolic manner. 
     In some embodiments, the body of the shunt can include at least one surface irregularity. The surface irregularity can comprise, for example, a ridge, groove, relief, hole, or annular groove. The surface discontinuities or irregularities can also be formed by barbs or other projections, which extend from the outer surface of the shunt, to inhibit migration of the shunt from its implanted position. In some embodiments, the projections may comprise external ribbing to resist displacement of the shunt. The surface irregularity in some embodiments can interact with the tissue of the interior wall of the sclera and/or with the tissue of the ciliary attachment tissue. In some embodiments, the shunts are anchored by mechanical interlock between tissue and an irregular surface and/or by friction fit. In other embodiments, the shunt includes cylindrical recessed portions (e.g., annular groves) along an elongate body to provide enhanced gripping features during implantation and anchoring following implantation within the eye tissue. 
     The shunt may also incorporate fixation features, such as flexible radial (i.e., outwardly extending) extensions. The extensions may be separate pieces attached to the shunt, or may be formed by slitting the shunt wall, and thermally forming or mechanically deforming the extensions radially outward. If the extensions are separate pieces, they may be comprised of flexible material such as nitinol or polyimide. The extensions may be located at the proximal or distal ends of the shunt, or both, to prevent extrusion of the shunt from its intended location. The flexibility of the fixation features will facilitate entry through the corneal incision, and also through the ciliary muscle attachment tissue. 
     In some embodiments, the body of the shunt has an outlet opening on a side surface to allow fluid flow. In some embodiments, the body of the shunt has a plurality of outlet openings on a side surface to allow fluid flow. In other embodiments, there is a plurality of outlet openings at one end of the shunt, such as the distal end. The openings can facilitate fluid flow through the shunt. 
     The shunt can in some embodiments have a cap, or tip, at one end. The cap can include a tissue-piercing end and one or more outlet openings. Each of the one or more outlet openings can communicate with at least one of the one or more lumens. In some embodiments the cap can have a conically shaped tip with a plurality of outlet openings disposed proximal of the tip&#39;s distal end. In other embodiments, the cap can have a tapered angle tip. The tip can be sufficiently sharp to pierce eye tissue near the scleral spur of the eye. The tip also can be sufficiently blunt so as not to substantially penetrate scleral tissue of the eye. In some embodiments, the conically shaped tip facilitates delivery of the shunt to the desired location. In some embodiments, the cap has an outlet opening on a side surface to allow fluid flow. In some embodiments, the cap has a plurality of outlet openings on a side surface to allow fluid flow. In other embodiments, there is a plurality of outlet openings on the conical surface of the cap. The openings on the cap can facilitate fluid flow through the shunt. The opening may provide an alternate route for fluid flow which is beneficial in case the primary outflow portion of the shunt becomes blocked. 
     In some embodiments, multiple shunts are configured to be delivered during a single procedure. In some embodiments when multiple shunts are delivered, the shunts can be arranged tandemly. In one embodiment, the shunt can include a tip protector at one end. The tip protector can comprise a recess shaped to receive and protect, for example, the tip of an adjacent shunt. In some embodiments, the tip of the adjacent shunt has a conical shape. The recess may be shaped to contact the sides of the conical tip while protecting the more tapered tip, or end, from impact. The tip protector is particularly useful for delivery of multiple shunts. 
     The shunts may be of varied lengths to optimize flows. In some preferred embodiments, the shunt has sufficient length such that the outflow portion resides in the suprachoroidal space and the inflow portion is exposed to the anterior chamber. In other preferred embodiments, the length of the shunt is a length such that the outflow portion resides in the supraciliary space of the uveoscleral outflow pathway. In some embodiments, the length of the shunt is a length such that the outflow portion resides in the membranous region of the uveoscleral outflow pathway adjacent to the retina, while in other embodiments, the shunt has a length that extends distally past the membranous region. In some embodiments, the length of the shunt from the portion residing in the anterior chamber to the portion residing in the uveoscleral outflow pathway may be about 0.5 mm to about 5 mm. In preferred embodiments, the length of the shunt may be about 1.5 mm to about 5 mm. In more preferred embodiments, the length of the shunt may be about 2.0 mm. In some embodiments, the length of the shunt is about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0 mm. 
     In some embodiments, the shunt can have an outer diameter that will permit the shunt to fit within a 23-gauge needle during implantation. The shunt can also have a diameter that is designed to be inserted with larger needles. For example, the shunt can also be delivered with 18-, 19- or 20-gauge needles. In other embodiments, smaller gauge applicators, such as a 23-gauge (or smaller) applicator, may be used. The shunt can have a substantially constant cross-sectional shape through most of the length of the shunt, or the shunt can have portions of reduced or enlarged cross-sectional size (e.g., diameter), or cylindrical channels, e.g., annular grooves, disposed on the outer surface between the proximal end and the distal end. The distal end of the shunt can have a tapered portion, or a portion having a continually decreasing radial dimension with respect to the lumen axis along the length of the axis. The tapered portion preferably in some embodiments terminates with a smaller radial dimension at the outflow end. During implantation, the tapered portion can operate to form, dilate, and/or increase the size of, an incision or puncture created in the tissue. The tapered portion may have a diameter of about 23 gauge to about 30 gauge, and preferably about 25 gauge. However, other dimensions are possible. 
     The diameter of one or more drainage lumens within the shunt may be varied to alter flow characteristics. The cross-sectional size of a shunt may be, for example, 0.1 mm to about 1.0 mm, or preferably about 0.3 mm to about  0 . 4  mm. A small cross-sectional size can be used to restrict flow. The cross-sectional shape of the shunt or a shunt may be any of a variety of cross-sectional shapes suitable for allowing fluid flow. For example, the cross-sectional shape of the shunt or shunt may be circular, oval, square, trapezoidal, rectangular, or any combination thereof. 
     In some embodiments, the shunt is configured to expand, either radially or axially, or both radially and axially. In some embodiments, the shunt may be self-expanding. In other embodiments, the shunt may be expanded by, for example, using a balloon device. 
     In some embodiments, the structure of the shunt may be flexible. At least a portion of the structure of the shunt may be flexible, or the whole structure may be flexible. In some embodiments, the structure of the shunt is accordion- or balloon-like. This pleated like structure provides flexibility. In other embodiments, at least a portion of the shunt is curved. In some embodiments, at least a portion of the shunt is straight. In some embodiments, the shunt has both curved and straight portions, and in some embodiments, the shunt is generally rigid (i.e., maintains its preformed shape when implanted). 
     The shunt is preferably made of one or more biocompatible materials. Suitable biocompatible materials include, for example, polypropylene, polyimide, glass, nitinol, polyvinyl alcohol, polyvinyl pyrolidone, collagen, chemically-treated collagen, polyethersulfone (PES), poly(styrene-isobutyl-styrene), Pebax, acrylic, polyolefin, polysilicon, polypropylene, hydroxyapetite, titanium, gold, silver, platinum, other metals, ceramics, plastics and a mixture thereof. The shunts can be manufactured by conventional sintering, micro machining, laser machining, and/or electrical discharge machining. However, other suitable manufacturing methods can be used 
     In some embodiments, the shunt is made of a flexible material. In other embodiments, the shunt is made of a rigid material. In some embodiments, a portion of the shunt is made from flexible material while another portion of the shunt is made from rigid material. The body can have an outer surface of which at least a portion is porous. Some embodiments include porosity that can be varied by masking a portion of the exterior with a band. Where the shunts include a porous body, the cross-section and porosity can be calibrated (down to 0.5 micrometers) to control the flow rates of aqueous humor through the shunt. 
     In some embodiments, at least a portion of the shunt (e.g., an internal spine or an anchor) is made of a material capable of shape memory. A material capable of shape memory may be compressed and, upon release, may expand axially or radially, or both axially and radially, to assume a particular shape. In some embodiments, at least a portion of the shunt has a preformed shape. In other embodiments, at least a portion of the shunt is made of a superelastic material. In some embodiments, at least a portion of the shunt is made up nitinol. In other embodiments, at least a portion of the shunt is made of a deformable material. 
     In some embodiments, the body of the shunt can comprise material that includes a therapeutic agent, and/or can house, anchor, or support a therapeutic agent, or can include a coating. The coating can include a therapeutic agent. The coatings can be, for example, a drug eluting coating, an antithrombogenic coating, and a lubricious coating. The therapeutic agent can be selected from the group consisting of: heparin, TGF-beta, an intraocular pressure-lowering drug, and an anti-proliferative agent. Materials that may be used for a drug-eluting coating include parylene C, poly (butyl methacrylate), poly (methyl methacrylate), polyethylene-co-vinyl acetate, and other materials known in the art. 
     In some embodiments, the shunt can further comprise a biodegradable material in or on the shunt. Such biodegradable copolymers may be situated within a lumen of the shunt, on the tip of the shunt, or on the cap of the shunt. In some embodiments, at least a portion of the shunt itself may comprise a biodegradable material. Still other embodiments may comprise a shunt made entirely of a biodegradable material, such that the entire shunt is degraded over time. The biodegradable material can be any suitable material including, but not limited to, poly(lactic acid), polyethylene-vinyl acetate, poly(lactic-co-glycolic acid), poly(D,L-lactide), poly(D,L-lactide-co-trimethylene carbonate), collagen, heparinized collagen, poly(caprolactone), poly(glycolic acid), and/or other polymer or copolymer. All or a portion of the shunt may be coated with a therapeutic agent, e.g. with heparin, preferably in the flow path, to reduce blood thrombosis or tissue restenosis. The biodegradable material may also include a therapeutic agent, such as a drug, mixed or compounded therein such that the therapeutic agent is released as the biodegradable material degrades or erodes following implantation. 
     The biodegradable material used in the shunt or any other device disclosed herein includes any suitable material that degrades or erodes over time when placed in the human or animal body. Accordingly, as the term is used herein, biodegradable material includes bioerodible materials. Biodegradable materials may be advantageously used to deliver one or more drugs or therapeutic agents. Therefore, it will be understood that embodiments incorporating a therapeutic agent as described herein can include having the therapeutic agent compounded with a biodegradable material or other agent modifying the release characteristics of the therapeutic agent. 
     One or more therapeutic agents may be compounded with one or more types of biodegradable polymers (including copolymers), providing release of the therapeutic agent(s) as the polymer degrades or erodes in vivo. Depending on the ocular disorder to be treated and the placement of the device in the eye, it may be advantageous to place a biodegradable polymer incorporating a therapeutic agent at different locations in or on the device, such that the therapeutic agent(s) may be released at a target site or region of the eye. Devices comprising biodegradable polymer with a therapeutic agent may also be coated (fully or partially) with one or more coatings comprising one or more drugs or other therapeutic agent(s). 
     Preferred biodegradable materials include copolymers of lactic acid and glycolic acid, also known as poly (lactic-co-glycolic acid) or PLGA. It will be understood by one skilled in the art that although some disclosure herein specifically describes use of PLGA, other suitable biodegradable materials may be substituted for PLGA or used in combination with PLGA in such embodiments. It may be desirable, in some embodiments, to provide for a particular rate of release of therapeutic agent from a PLGA copolymer. As the release rate of a therapeutic agent from a PLGA copolymer correlates with the degradation rate of that copolymer, control of the degradation rate provides a means for control of the delivery rate of a therapeutic agent. Variation of the average molecular weight of the polymer or copolymer chains which make up the PLGA copolymer can be used to control the degradation rate of the copolymer, thereby achieving a desired duration or other release profile of therapeutic agent delivery to the eye. In certain other embodiments employing PLGA copolymers, rate of biodegradation of the PLGA copolymer may be controlled by varying the ratio of lactic acid to glycolic acid units in a copolymer. Still other embodiments may utilize combinations of varying the average molecular weights of the constituents of the copolymer and varying the ratio of lactic acid to glycolic acid in the copolymer to achieve a desired biodegradation rate. In addition, as described in more detail below, the incorporation of a copolymer in or on a device in a particular location may affect the biodegradation rate of the copolymer, thus providing another means of controlling the release rate of the therapeutic agent. 
     In some ocular disorders, therapy may require a defined kinetic profile of administration of therapeutic agents to the eye. In certain embodiments, devices made from PLGA copolymers or which incorporate PLGA copolymers, wherein the copolymer is compounded with a therapeutic agent, may provide particular kinetic profiles of release of such therapeutic agent. By tailoring the ratio of lactic to glycolic acid in a copolymer and/or average molecular weight of polymers or copolymers having the therapeutic agent therein, sustained release of a therapeutic agent, or other desirable release profile, may be achieved. In certain embodiments, zero-order release of a therapeutic agent may be achieved by tailoring the ratio of lactic to glycolic acid and/or average molecular weights in the copolymer composition so that that the biodegradation of the PLGA copolymer is the principal factor controlling therapeutic agent release from the copolymer. In certain embodiments, pseudo zero-order release (or other desired release profile) may be achieved by using multiple PLGA copolymer formulations in or on one or more devices, each copolymer formulation achieving a different therapeutic agent release profile such that the additive effect over time replicates true zero-order kinetics. For example, a series of devices or a single device having multiple regions incorporating PLGA with one or more therapeutic agents may be delivered to the eye, wherein the devices or regions incorporate at least two different PLGA copolymer formulations. As each copolymer biodegrades or erodes at its individual and desired rate, the sum total of therapeutic agent released to the eye over time is in effect released with zero-order kinetics. 
     Non-continuous or pulsatile release may also be desirable. This may be achieved, for example, by incorporating multiple PLGA formulations with varying biodegradation rates into a single device or a series of devices so that, with clearance of a therapeutic agent from the eye and/or varying rates of release of therapeutic agent from the copolymers results in a concentration of a therapeutic agent that is not constant over time. 
     The flow path through the shunt can be configured to be regulated to a flow rate that will reduce the likelihood of hypotony in the eye. In some embodiments, the intraocular pressure is maintained at about 8 mm Hg. In other embodiments, the intraocular pressure is maintained at pressures less than about 8 mmHg, for example the intraocular pressure may be maintained between about 6 mm Hg and about 8 mm Hg. In other embodiments, the intraocular pressure is maintained at pressures greater than about 8 mm Hg. For example, the pressures may be maintained between about 8 mmHg and about  1 8 mm Hg, and more preferably between 8 mm Hg and 16 mm Hg, and most preferably not greater than 12 mm Hg. In some embodiments, the flow rate can be limited to about 2.5 μL/min or less. In some embodiments the flow rate can be limited to between about 1.9 μL/min and about 3.1 μL/min. 
     For example, the Hagen-Poiseuille equation suggests that a 4 mm long stent at a flow rate of 2.5 μL/min should have an inner diameter of 52  82  m to create a pressure gradient of 5 mm Hg above the pressure in the suprachoroidal space. 
     The shunt may or may not include a mechanism for regulating fluid flow through the shunt. Mechanisms for regulating fluid flow can include flow restrictors, pressure regulators, or both. Alternatively, in some embodiments the shunt has neither a flow restrictor nor a pressure regulator. Regulating flow of aqueous humor can comprise varying between at least first and second operational states in which aqueous humor flow is more restricted in a first state and less restricted in a second state. Increasing the restriction to flow when changing from the second state to the first state can involve moving a valve toward a valve seat in a direction generally parallel or generally normal to a line connecting the proximal and distal ends of the shunt. 
     As noted above, the outflow portion of the shunt, in some embodiments is sized and configured to reside in the supraciliary region of the uveoscleral outflow pathway. In such embodiments, there is a lesser need for a mechanism for regulating fluid flow through the shunt. 
     The mechanism for flow restriction may be, for example, a valve, a long lumen length, small lumen cross section, or any combination thereof. In some embodiments, the flow of fluid is restricted by the size of a lumen within the shunt, which produces a capillary effect that limits the fluid flow for given pressures. The capillary effect of the lumen allows the shunt to restrict flow and provides a valveless regulation of fluid flow. 
     In one embodiment, the flow path length may be increased without increasing the overall length of the shunt by creating a lumen with a spiral flow path. A lumen within the shunt is configured to accommodate placement therein of a spiral flow channel core that is configured to provide preferred flow restriction. In effect, the spiral flow channel provides an extended path for the flow of fluid between the inlet(s) and outlet(s) of the shunt that is greater than a straight lumen extending between the ends of the shunt. The extended path provides a greater potential resistance of fluid flow through the shunt without increasing the length of the shunt. The core could have a single spiral flow channel, or a plurality of spiral flow channels for providing a plurality of flow paths through which fluid may flow through the shunt. For example, the core can have two or more spiral flow channels, which can intersect. 
     In some embodiments, the mechanism for flow regulation can include a pressure regulating valve. In one embodiment, the valve can open when fluid pressure within the anterior chamber exceeds a predetermined level (e.g., a preset pressure). Intraocular pressure may be used to apply a force to move a valve surface within the shunt in a direction transverse to a longitudinal axis of the shunt such that aqueous humor flows from the anterior chamber to the uveoscleral outflow pathway at intraocular pressures greater than a threshold pressure. 
     In some embodiments, the shunt may have any number of valves to restrict flow and/or regulate pressure. The valve can be located between the anterior chamber and one or more effluent openings such that movement of the valve regulates flow from the anterior chamber to the one or more effluent openings. A variety of valves are useful with the shunt for restricting flow. In some embodiments, the valve is a unidirectional valve and/or is a pressure relief valve. The pressure relief valve can comprise a ball, a ball seat and a biasing member urging the ball towards the ball seat. In some embodiments, the valve is a reed-type valve. In a reed valve, for example, one end of the valve may be fixed to a portion of the shunt. The body of the reed valve can be deflected in order to allow flow through the valve. Pressure from fluid in the anterior chamber can deflect the body of the reed valve, thereby causing the valve to open. 
     In some embodiments, the shunt can include a pressure regulation valve having a deflectable plate or diaphragm with a surface area exposed to fluid within the anterior chamber, the surface area being substantially greater than the total cross-sectional flow area of the one or more influent openings of the shunt. Such a valve can be disposed between an anterior chamber of the shunt and the one or more effluent openings such that movement of the deflectable plate regulates flow from the anterior chamber to the one or more effluent openings. The plate can extend in a direction generally parallel to the inlet flow path and to the outlet flow path. 
     When the intraocular pressure exceeds a predetermined pressure, the check pressure relief valve can open and permit fluid to flow between the anterior chamber and the uveoscleral outflow pathway. When the intraocular pressure decreases to a second, lower pressure, the valve can close to limit or inhibit fluid from flowing to the suprachoroidal space. In one embodiment, the valve can remain closed until the intraocular pressure again reaches the predetermined pressure, at which time the valve can reopen to permit or enhance drainage of fluid to the uveoscleral outflow pathway. Accordingly, the shunt can provide drainage of the anterior chamber through the shunt based on the intraocular pressure levels and reduce the likelihood for over-draining the anterior chamber and causing hypotony. 
     Delivery Instruments 
     Another aspect of the systems and methods described herein relates to delivery instruments for implanting the drug delivery implant, which may include a shunt for draining fluid from the anterior chamber into a physiologic outflow space. In some embodiments, the drug delivery implant is inserted from a site transocularly situated from the implantation site. The delivery instrument can be sufficiently long to advance the implant transocularly from the insertion site across the anterior chamber to the implantation site. At least a portion of the instrument can be flexible. Alternatively, in other embodiments the instrument can be rigid. The instrument can include a plurality of members longitudinally moveable relative to each other. In some embodiments, at least a portion of the delivery instrument is curved or angled. In some embodiments, a portion of the delivery instrument is rigid and another portion of the instrument is flexible. 
     In some embodiments, the delivery instrument has curved distal portion. The curvature of the distal portion of the delivery instrument can have as a radius of between about 10 mm and about 30 mm, and preferably about 20 mm. 
     In some embodiments, the delivery instrument can have an angled distal segment. For example, the angle of the distal segment can be between about 90° and about 170° relative to an axis of the proximal segment of the delivery instrument, and preferably about 145°. In one embodiment, the angle can incorporate a small radius of curvature at the “elbow” between the proximal and distal segments so as to define a smooth transition from the proximal segment of the delivery instrument to the distal segment. In one embodiment, the length of the distal segment may be between approximately 0.5 to 7 mm, and preferably about 2 to 3 mm. However, the distal segment of the delivery instrument can have other suitable lengths. 
     In some embodiments, the instrument can have a sharpened forward end and be self-trephinating, i.e., self-penetrating, so as to pass through tissue without pre-forming an incision, hole or aperture. Alternatively, a trocar, scalpel, or similar instrument can be used to pre-form an incision in the eye tissue before passing the implant into such tissue. 
     For delivery of some embodiments of the drug delivery implant, the instrument can have a sufficiently small cross section such that the insertion site self seals without suturing upon withdrawal of the instrument from the eye. In one embodiment, an outer diameter of the delivery instrument is preferably no greater than about 18 gauge and not smaller than about 27 gauge. However, the delivery instrument can have other suitable outer diameter dimensions. 
     For delivery of some embodiments of the drug delivery implant, the incision in the corneal tissue is preferable made with a hollow needle through which the implant can be passed. The needle can have a small diameter size (e.g., 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 gauge) so that the incision is self sealing and the implantation occurs in a closed chamber with or without viscoelastic. A self-sealing incision also can be formed using a conventional “tunneling” procedure in which a spatula-shaped scalpel is used to create a generally inverted V-shaped incision through the cornea. In a preferred mode, the instrument used to form the incision through the cornea remains in place (that is, extends through the corneal incision) during the procedure and is not removed until after implantation. Such incision-forming instrument either can be used to carry the implant or can cooperate with a delivery instrument to allow implantation through the same incision without withdrawing the incision-forming instrument. Of course, in other embodiments, various surgical instruments can be passed through one or more corneal incisions multiple times. 
     Once into the anterior chamber, a delivery instrument can be advanced from the insertion site transocularly into the anterior chamber angle and positioned at a location near the scleral spur. Using the scleral spur as a reference point, the delivery instrument can be advanced further in a generally posterior direction to drive the implant into the uveoscleral pathway. The placement and implantation of the implant can be performed using a gonioscope or other conventional imaging equipment. The delivery instrument preferably is used to force the implant into a desired position by application of a continual implantation force, by tapping the implant into place using a distal portion of the delivery instrument, or by a combination of these methods. Once the implant is in the desired position, it may be further seated by tapping using a distal portion of the delivery instrument. 
     In one embodiment, the delivery instrument can include an open distal end with a lumen extending therethrough. Positioned within the lumen is preferably a pusher tube that is axially movable within the lumen. The pusher tube can be any device suitable for pushing or manipulating the implant in relation to the delivery instrument, such as, for example, but without limitation a screw, a rod, a stored energy device such as a spring. A wall of the delivery instrument can extend beyond pusher tube to accommodate placement within the lumen of a drug delivery implant. The implant can be secured in position. For example, the implant can be secured by viscoelastic or mechanical interlock with the pusher tube or wall. When the implant is brought into position adjacent the uveoscleral pathway in the anterior chamber angle, the pusher tube is advanced axially toward the open distal end of the delivery instrument. As the pusher tube is advanced, the implant is also advanced. When the implant is advanced into the uveoscleral pathway and such that it is no longer in the lumen of the delivery instrument, the delivery instrument can be retracted, leaving the drug delivery implant in the uveoscleral pathway. 
     Some embodiments can include a spring-loaded or stored-energy pusher system. The spring-loaded pusher preferably includes a button operably connected to a hinged rod device. The rod of the hinged rod device engages a depression in the surface of the pusher, keeping the spring of the pusher in a compressed conformation. When the user pushes the button, the rod is disengaged from the depression, thereby allowing the spring to decompress, thereby advancing the pusher forward. 
     In some embodiments, an over-the wire system can be used to deliver the drug delivery implant. The implant can be delivered over a wire. Preferably, the wire is self-trephinating. In one embodiment, the wire can function as a trocar. The wire can be superelastic, flexible, or relatively inflexible with respect to the implant. The wire can be pre-formed to have a certain shape. The wire can be curved. The wire can have shape memory, or be elastic. In some embodiments, the wire is a pull wire. The wire can be a steerable catheter. 
     In some embodiments, the wire is positioned within a lumen in the drug delivery implant, such as a lumen of a shunt of the implant. The wire can be axially movable within the lumen. The lumen may or may not include valves or other flow regulatory devices. 
     In some embodiments, the delivery instrument is a trocar. The trocar may be angled or curved. The trocar can be rigid, semi-rigid or flexible. In embodiments where the trocar can be stiff, the implant can be, but need not be relatively flexible. The diameter of the trocar can be about 0.001 inches to about 0.01 inches. In some embodiments, the diameter of the trocar is 0.001, 0.002, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, or 0.01 inches. 
     In some embodiments, delivery of the drug delivery implant is achieved by applying a driving force at or near the distal end of the implant. The driving force can be a pulling or a pushing applied generally to the end of the implant. 
     The instrument can include a seal to prevent aqueous humor from passing through the delivery instrument and/or between the members of the instrument when the instrument is in the eye. The seal can also aid in preventing backflow of aqueous humor through the instrument and out the eye. Suitable seals for inhibiting leakage include, for example, an o-ring, a coating, a hydrophilic agent, a hydrophobic agent, and combinations thereof. The coating can be, for example, a silicone coat such as MDX™ silicone fluid. In some embodiments, the instrument is coated with the coating and a hydrophilic or hydrophobic agent. In some embodiments, one region of the instrument is coated with the coating plus the hydrophilic agent, and another region of the instrument is coated with the coating plus the hydrophobic agent. The delivery instrument can additionally comprise a seal between various members comprising the instrument. The seal can comprise a hydrophobic or hydrophilic coating between slip-fit surfaces of the members of the instrument. The seal can be disposed proximate of the drug delivery implant when carried by the delivery instrument. Preferably, the seal is present on at least a section of each of two devices that are machined to fit closely with one another. 
     In some embodiments, the delivery instrument can include a distal end having a beveled shape. The delivery instrument can include a distal end having a spatula shape. The beveled or spatula shape can have a sharpened edge. The beveled or spatula shape can include a recess to contain the drug delivery implant. The recess can include a pusher or other suitable means to push out or eject the implant. 
     The delivery instrument further can be configured to deliver multiple drug delivery implants. In some embodiments, when multiple drug delivery implants are delivered, the implants can be arranged in tandem, as described in greater detail below. 
     Therapeutic Agents 
     The therapeutic agents utilized with the drug delivery implant, may include one or more drugs provided below, either alone or in combination. The drugs utilized may also be the equivalent of, derivatives of, or analogs of one or more of the drugs provided below. The drugs may include but are not limited to pharmaceutical agents including anti-glaucoma medications, ocular agents, antimicrobial agents (e.g., antibiotic, antiviral, antiparasitic, antifungal agents), anti-inflammatory agents (including steroids or non-steroidal anti-inflammatory), biological agents including hormones, enzymes or enzyme-related components, antibodies or antibody-related components, oligonucleotides (including DNA, RNA, short-interfering RNA, antisense oligonucletides, and the like), DNA/RNA vectors, viruses (either wild type or genetically modified) or viral vectors, peptides, proteins, enzymes, extracellular matrix components, and live cells configured to produce one or more biological components. The use of any particular drug is not limited to its primary effect or regulatory body-approved treatment indication or manner of use. Drugs also include compounds or other materials that reduce or treat one or more side effects of another drug or therapeutic agent. As many drugs have more than a single mode of action, the listing of any particular drug within any one therapeutic class below is only representative of one possible use of the drug and is not intended to limit the scope of its use with the ophthalmic implant system. 
     Examples of drugs may include various anti-secretory agents; antimitotics and other anti-proliferative agents, including among others, anti-angiogenesis agents such as angiostatin, anecortave acetate, thrombospondin, VEGF receptor tyrosine kinase inhibitors and anti-vascular endothelial growth factor (anti-VEGF) drugs such as ranibizumab (LUCENTIS®) and bevacizumab (AVASTIN®), pegaptanib (MACUGEN®), sunitinib and sorafenib and any of a variety of known small-molecule and transcription inhibitors having anti-angiogenesis effect; classes of known ophthalmic drugs, including: glaucoma agents, such as adrenergic antagonists, including for example, beta-blocker agents such as atenolol propranolol, metipranolol, betaxolol, carteolol, levobetaxolol, levobunolol and timolol; adrenergic agonists or sympathomimetic agents such as epinephrine, dipivefrin, clonidine, aparclonidine, and brimonidine; parasympathomimetics or cholingeric agonists such as pilocarpine, carbachol, phospholine iodine, and physostigmine, salicylate, acetylcholine chloride, eserine, diisopropyl fluorophosphate, demecarium bromide); muscarinics; carbonic anhydrase inhibitor agents, including topical and/or systemic agents, for example acetozolamide, brinzolamide, dorzolamide and methazolamide, ethoxzolamide, diamox, and dichlorphenamide; mydriatic-cycloplegic agents such as atropine, cyclopentolate, succinylcholine, homatropine, phenylephrine, scopolamine and tropicamide; prostaglandins such as prostaglandin F 2  alpha, antiprostaglandins, prostaglandin precursors, or prostaglandin analog agents such as bimatoprost, latanoprost, travoprost and unoprostone. 
     Other examples of drugs may also include anti-inflammatory agents including for example glucocorticoids and corticosteroids such as betamethasone, cortisone, dexamethasone, dexamethasone 21-phosphate, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, prednisolone, fluroometholone, loteprednol, medrysone, fluocinolone acetonide, triamcinolone acetonide, triamcinolone, triamcinolone acetonide, beclomethasone, budesonide, flunisolide, fluorometholone, fluticasone, hydrocortisone, hydrocortisone acetate, loteprednol, rimexolone and non-steroidal anti-inflammatory agents including, for example, diclofenac, flurbiprofen, ibuprofen, bromfenac, nepafenac, and ketorolac, salicylate, indomethacin, ibuprofen, naxopren, piroxicam and nabumetone; anti-infective or antimicrobial agents such as antibiotics including, for example, tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, rifampicin, ciprofloxacin, tobramycin, gentamycin, erythromycin, penicillin, sulfonamides, sulfadiazine, sulfacetamide, sulfamethizole, sulfisoxazole, nitrofurazone, sodium propionate, aminoglycosides such as gentamicin and tobramycin; fluoroquinolones such as ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin; bacitracin, erythromycin, fusidic acid, neomycin, polymyxin B, gramicidin, trimethoprim and sulfacetamide; antifungals such as amphotericin B and miconazole; antivirals such as idoxuridine trifluorothymidine, acyclovir, gancyclovir, interferon; antimicotics; immune-modulating agents such as antiallergenics, including, for example, sodium chromoglycate, antazoline, methapyriline, chlorpheniramine, cetrizine, pyrilamine, prophenpyridamine anti-histamine agents such as azelastine, emedastine and levocabastine; immunological drugs (such as vaccines and immune stimulants); MAST cell stabilizer agents such as cromolyn sodium, ketotifen, lodoxamide, nedocrimil, olopatadine and pemirolastciliary body ablative agents, such as gentimicin and cidofovir; and other ophthalmic agents such as verteporfin, proparacaine, tetracaine, cyclosporine and pilocarpine; inhibitors of cell-surface glycoprotein receptors; decongestants such as phenylephrine, naphazoline, tetrahydrazoline; lipids or hypotensive lipids; dopaminergic agonists and/or antagonists such as quinpirole, fenoldopam, and ibopamine; vasospasm inhibitors; vasodilators; antihypertensive agents; angiotensin converting enzyme (ACE) inhibitors; angiotensin-1 receptor antagonists such as olmesartan; microtubule inhibitors; molecular motor (dynein and/or kinesin) inhibitors; actin cytoskeleton regulatory agents such as cyctchalasin, latrunculin, swinholide A, ethacrynic acid, H-7, and Rho-kinase (ROCK) inhibitors; remodeling inhibitors; modulators of the extracellular matrix such as tert-butylhydro-quinolone and AL-3037A; adenosine receptor agonists and/or antagonists such as N-6-cylclophexyladenosine and (R)-phenylisopropyladenosine; serotonin agonists; hormonal agents such as estrogens, estradiol, progestational hormones, progesterone, insulin, calcitonin, parathyroid hormone, peptide and vasopressin hypothalamus releasing factor; growth factor antagonists or growth factors, including, for example, epidermal growth factor, fibroblast growth factor, platelet derived growth factor, transforming growth factor beta, somatotrapin, fibronectin, connective tissue growth factor, bone morphogenic proteins (BMPs); cytokines such as interleukins, CD44, cochlin, and serum amyloids, such as serum amyloid A. 
     Other therapeutic agents may include neuroprotective agents such as lubezole, nimodipine and related compounds, and including blood flow enhancers, sodium channels blockers, glutamate inhibitors such as memantine, neurotrophic factors, nitric oxide synthase inhibitors; free radical scavengers or anti-oxidants; chelating compounds; apoptosis-related protease inhibitors; compounds that reduce new protein synthesis; radiotherapeutic agents; photodynamic therapy agents; gene therapy agents; genetic modulators; and dry eye medications such as cyclosporine A, delmulcents, and sodium hyaluronate. 
     Other therapeutic agents that may be used include: other beta-blocker agents such as acebutolol, atenolol, bisoprolol, carvedilol, asmolol, labetalol, nadolol, penbutolol, and pindolol; other corticosteroidal and non-steroidal anti-inflammatory agents such aspirin, betamethasone, cortisone, diflunisal, etodolac, fenoprofen, fludrocortisone, flurbiprofen, hydrocortisone, ibuprofen, indomethacine, ketoprofen, meclofenamate, mefenamic acid, meloxicam, methylprednisolone, nabumetone, naproxen, oxaprozin, prednisolone, prioxicam, salsalate, sulindac and tolmetin; COX-2 inhibitors like celecoxib, rofecoxib and. Valdecoxib; other immune-modulating agents such as aldesleukin, adalimumab (HUMIRA®), azathioprine, basiliximab, daclizumab, etanercept (ENBREL®), hydroxychloroquine, infliximab (REMICADE®), leflunomide, methotrexate, mycophenolate mofetil, and sulfasalazine; other anti-histamine agents such as loratadine, desloratadine, cetirizine, diphenhydramine, chlorpheniramine, dexchlorpheniramine, clemastine, cyproheptadine, fexofenadine, hydroxyzine and promethazine; other anti-infective agents such as aminoglycosides such as amikacin and streptomycin; anti-fungal agents such as amphotericin B, caspofungin, clotrimazole, fluconazole, itraconazole, ketoconazole, voriconazole, terbinafine and nystatin; anti-malarial agents such as chloroquine, atovaquone, mefloquine, primaquine, quinidine and quinine; anti-mycobacterium agents such as ethambutol, isoniazid, pyrazinamide, rifampin and rifabutin; anti-parasitic agents such as albendazole, mebendazole, thiobendazole, metronidazole, pyrantel, atovaquone, iodoquinaol, ivermectin, paromycin, praziquantel, and trimatrexate; other anti-viral agents, including anti-CMV or anti-herpetic agents such as acyclovir, cidofovir, famciclovir, gangciclovir, valacyclovir, valganciclovir, vidarabine, trifluridine and foscarnet; protease inhibitors such as ritonavir, saquinavir, lopinavir, indinavir, atazanavir, amprenavir and nelfinavir; nucleotide/nucleoside/non-nucleoside reverse transcriptase inhibitors such as abacavir, ddl, 3TC, d4T, ddC, tenofovir and emtricitabine, delavirdine, efavirenz and nevirapine; other anti-viral agents such as interferons, ribavirin and trifluridiene; other anti-bacterial agents, including cabapenems like ertapenem, imipenem and meropenem; cephalosporins such as cefadroxil, cefazolin, cefdinir, cefditoren, cephalexin, cefaclor, cefepime, cefoperazone, cefotaxime, cefotetan, cefoxitin, cefpodoxime, cefprozil, ceftaxidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime and loracarbef; other macrolides and ketolides such as azithromycin, clarithromycin, dirithromycin and telithromycin; penicillins (with and without clavulanate) including amoxicillin, ampicillin, pivampicillin, dicloxacillin, nafcillin, oxacillin, piperacillin, and ticarcillin; tetracyclines such as doxycycline, minocycline and tetracycline; other anti-bacterials such as aztreonam, chloramphenicol, clindamycin, linezolid, nitrofurantoin and vancomycin; alpha blocker agents such as doxazosin, prazosin and terazosin; calcium-channel blockers such as amlodipine, bepridil, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine and verapamil; other anti-hypertensive agents such as clonidine, diazoxide, fenoldopan, hydralazine, minoxidil, nitroprus side, phenoxybenzamine, epoprostenol, tolazoline, treprostinil and nitrate-based agents; anti-coagulant agents, including heparins and heparinoids such as heparin, dalteparin, enoxaparin, tinzaparin and fondaparinux; other anti-coagulant agents such as hirudin, aprotinin, argatroban, bivalirudin, desirudin, lepirudin, warfarin and ximelagatran; anti-platelet agents such as abciximab, clopidogrel, dipyridamole, optifibatide, ticlopidine and tirofiban; prostaglandin PDE-5 inhibitors and other prostaglandin agents such as alprostadil, carboprost, sildenafil, tadalafil and vardenafil; thrombin inhibitors; antithrombogenic agents; anti-platelet aggregating agents; thrombolytic agents and/or fibrinolytic agents such as alteplase, anistreplase, reteplase, streptokinase, tenecteplase and urokinase; anti-proliferative agents such as sirolimus, tacrolimus, everolimus, zotarolimus, paclitaxel and mycophenolic acid; hormonal-related agents including levothyroxine, fluoxymestrone, methyltestosterone, nandrolone, oxandrolone, testosterone, estradiol, estrone, estropipate, clomiphene, gonadotropins, hydroxyprogesterone, levonorgestrel, medroxyprogesterone, megestrol, mifepristone, norethindrone, oxytocin, progesterone, raloxifene and tamoxifen; anti-neoplastic agents, including alkylating agents such as carmustine lomustine, melphalan, cisplatin, fluorouracil 3 , and procarbazine antibiotic-like agents such as bleomycin, daunorubicin, doxorubicin, idarubicin, mitomycin and plicamycin; anti proliferative agents (such as 1,3-cis retinoic acid, 5-fluorouracil, taxol, rapamycin, mitomycin C and cisplatin); antimetabolite agents such as cytarabine, fludarabine, hydroxyurea, mercaptopurine and 5-fluorouracil (5-FU); immune modulating agents such as aldesleukin, imatinib, rituximab and tositumomab; mitotic inhibitors docetaxel, etoposide, vinblastine and vincristine; radioactive agents such as strontium- 89 ; and other anti-neoplastic agents such as irinotecan, topotecan and mitotane. 
     The therapeutic agents may be released or eluted from the drug delivery implant, bound to a surface of the implant, and/or disposed in the implant. The therapeutic agents may also be released from a separate drug eluting implant that is implantable in the same or a different location in the eye or orbital cavity. The separate drug eluting implant may be located in a physiologic outflow pathway or physiologic cavity of the eye or body, or may be implanted into an artificially formed site of the eye or body. A variety of controlled-release technologies may be used with the drug delivery implant, including non-degradable and biodegradable polymeric and non-polymeric release platforms that are known in the art and that which is described hereinabove including with respect to biodegradable polymers such as PLGA. 
     In one embodiment, an injection/infusion/implantation routes or sites include a suprachoroidal site and other sites along the uveoscleral pathway. 
     In some embodiments, combinations of agents having synergistic and/or complementary effects for a particular disease or set of related conditions or symptoms may be used. In one example, a disease-treating agent may be used in combination with a metabolism-altering agent affecting the cytochrome P450 system to affect the pharmacokinetics of the disease-treating agent. In another example, an anti-infective agent may be combined with an anti-inflammatory agent to treat inflammation resulting from the infection. 
     As is well known in the art, an implant device coated or loaded with a slow-release substance can have prolonged effects on local tissue surrounding the device. The slow-release delivery can be designed such that an effective amount of substance is released over a desired duration. “Substance,” as used herein, is defined as any therapeutic or bioactive drug or agents that can stop, mitigate, slow-down or reverse undesired disease processes. 
     In one embodiment, the drug delivery implant may be coated, loaded or made in whole or in part of a biodegradable (also including bioerodible) material admixed or compounded with a substance for substance slow-release into ocular tissues. Accordingly, in the embodiments described herein, it is to be understood that incorporation of a therapeutic agent(s) in or on a device includes having the therapeutic agent included alone, with one or more pharmaceutically acceptable excipients, and compounded or admixed with a biodegradable polymer or other material to deliver the therapeutic agent(s) at a desired rate over time. 
     In another embodiment, polymer films may function as substance containing release devices whereby the polymer films may be coupled or secured to the drug delivery implant. The polymer films may be designed to permit the controlled release of the substance at a chosen rate and for a selected duration, which may also be episodic or periodic. Such polymer films may be synthesized such that the substance is bound to the surface or resides within a pore in the film so that the substance is relatively protected from enzymatic attack. The polymer films may also be modified to alter their hydrophilicity, hydrophobicity and vulnerability to platelet adhesion and enzymatic attack. In one embodiment, the polymer film is made of biodegradable material. 
     Furthermore, the film may be coupled (locally or remotely) to a power source such that when substance delivery is desired, a brief pulse of current is provided to alter the potential on the film to cause the release of a particular amount of the substance for a chosen duration. Application of current causes release of a substance from the surface of the film or from an interior location in the film such as within a pore. The rate of substance delivery is altered depending on the degree of substance loading on the film, the voltage applied to the film, and by modifying the chemical synthesis of substance delivery polymer film. 
     The power-activated substance delivery polymer film may be designed to be activated by an electromagnetic field, such as, by way of example, NMR, MRI, or short range RF transmission (such as a Bluetooth® apparatus). In addition, ultrasound can be used to cause a release of a particular amount of substance for a chosen duration. This is particularly applicable to a substance coated implant or an implant made of a substrate containing the desired substance. 
     The drug delivery implant can be used for a direct release of pharmaceutical preparations into ocular tissues. As discussed above, the pharmaceuticals may be compounded within the drug delivery implant or form a coating on the implant. Any known drug therapy for glaucoma may be utilized, including but not limited to, the following: 
     U.S. Pat. No. 6,201,001, issued Mar. 13, 2001, the entire contents of which are incorporated herein by reference, discloses Imidazole antiproliferative agents useful for neovascular glaucoma. 
     U.S. Pat. No. 6,228,873, issued May 8, 2001, the entire contents of which are incorporated herein by reference, discloses a new class of compounds that inhibit function of sodium chloride transport in the thick ascending limb of the loop of Henle, wherein the preferred compounds useful are furosemide, piretanide, benzmetanide, bumetanide, torasernide and derivatives thereof. 
     U.S. Pat. No. 6,194,415, issued Feb. 27, 2001, the entire contents of which are incorporated herein by reference, discloses a method of using quinoxalines (2-imidazolin-2-ylamino) in treating neural injuries (e.g., glaucomatous nerve damage). 
     U.S. Pat. No. 6,060,463, issued May 9, 2000, and U.S. Pat. No. 5,869,468, issued Feb. 9, 1999, the entire contents of which are incorporated herein by reference, disclose treatment of conditions of abnormally increased intraocular pressure by administration of phosphonylmethoxyalkyl nucleotide analogs and related nucleotide analogs. 
     U.S. Pat. No. 5,925,342, issued Jul. 20, 1999, the entire contents of which are incorporated herein by reference, discloses a method for reducing intraocular pressure by administration of potassium channel blockers. 
     U.S. Pat. No. 5,814,620, issued Sep. 29, 1998, the entire contents of which are incorporated herein by reference, discloses a method of reducing neovascularization and of treating various disorders associated with neovascularization. These methods include administering to a tissue or subject a synthetic oligonucleotide. 
     U.S. Pat. No. 5,767,079, issued Jun. 16, 1998, the entire contents of which are incorporated herein by reference, discloses a method for treatment of ophthalmic disorders by applying an effective amount of Transforming Growth Factor-Beta (TGF-beta) to the affected region. 
     U.S. Pat. No. 5,663,205, issued Sep. 2, 1997, the entire contents of which are incorporated herein by reference, discloses a pharmaceutical composition for use in glaucoma treatment which contains an active ingredient 5-[1-hydroxy-2-[2-(2-methoxyphenoxyl)ethylamino]ethyl]-2-methylbenzenesulfonamide. This agent is free from side effects, and stable and has an excellent intraocular pressure reducing activity at its low concentrations, thus being useful as a pharmaceutical composition for use in glaucoma treatment. 
     U.S. Pat. No. 5,652,236, issued Jul. 29, 1997, the entire contents of which are incorporated herein by reference, discloses pharmaceutical compositions and a method for treating glaucoma and/or ocular hypertension in the mammalian eye by administering thereto a pharmaceutical composition which contains as the active ingredient one or more compounds having guanylate cyclase inhibition activity. Examples of guanylate cyclase inhibitors utilized in the pharmaceutical composition and method of treatment are methylene blue, butylated hydroxyanisole and N-methylhydroxylamine. 
     U.S. Pat. No. 5,547,993, issued Aug. 20, 1996, the entire contents of which are incorporated herein by reference, discloses that 2-(4methylaminobutoxy) diphenylmethane or a hydrate or pharmaceutically acceptable salt thereof have been found useful for treating glaucoma. 
     U.S. Pat. No. 5,502,052, issued Mar. 26, 1996, the entire contents of which are incorporated herein by reference, discloses use of a combination of apraclonidine and timolol to control intraocular pressure. The compositions contain a combination of an alpha-2 agonist (e.g., para-amino clonidine) and a beta blocker (e.g., betaxolol). 
     U.S. Pat. No. 6,184,250, issued Feb. 6, 2001, the entire contents of which are incorporated herein by reference, discloses use of cloprostenol and fluprostenol analogues to treat glaucoma and ocular hypertension. The method comprises topically administering to an affected eye a composition comprising a therapeutically effective amount of a combination of a first compound selected from the group consisting of beta-blockers, carbonic anhydrase inhibitors, adrenergic agonists, and cholinergic agonists, together with a second compound. 
     U.S. Pat. No. 6,159,458, issued Dec. 12, 2000, the entire contents of which are incorporated herein by reference, discloses an ophthalmic composition that provides sustained release of a water soluble medicament formed by comprising a cross-linked carboxy-containing polymer, a medicament, a sugar and water. 
     U.S. Pat. No. 6,110,912, issued Aug. 29, 2000, the entire contents of which are incorporated herein by reference, discloses methods for the treatment of glaucoma by administering an ophthalmic preparation comprising an effective amount of a non-corneotoxic serine-threonine kinase inhibitor, thereby enhancing aqueous outflow in the eye and treatment of the glaucoma. In some embodiments, the method of administration is topical, whereas it is intracameral in other embodiments. In still further embodiments, the method of administration is intracanalicular. 
     U.S. Pat. No. 6,177,427, issued Jan. 23, 2001, the entire contents of which are incorporated herein by reference, discloses compositions of non-steroidal glucocorticoid antagonists for treating glaucoma or ocular hypertension. 
     U.S. Pat. No. 5,952,378, issued Sep. 14, 1999, the entire contents of which are incorporated herein by reference, discloses the use of prostaglandins for enhancing the delivery of drugs through the uveoscleral route to the optic nerve head for treatment of glaucoma or other diseases of the optic nerve as well as surrounding tissue. The method for enhancing the delivery to the optic nerve head comprises contacting a therapeutically effective amount of a composition containing one or more prostaglandins and one or more drug substances with the eye at certain intervals. 
     Drug Delivery Implants 
     Embodiment Illustrated in  FIGS. 2A-2B   
       FIGS. 2A-2B  show one embodiment of a drug delivery implant  30 . The drug delivery implant  30  can have an elongated body  32  extending from a proximal end  32   a  to a distal end  32   b  that in one embodiment can be generally cylindrical with a circular cross-section. However, in other embodiments the elongated body  32  can have other cross-sectional shapes, such as a semi-sphere, a paraboloid, or a hyperboloid. 
     The drug delivery implant  30  preferably has an outer diameter that will permit the implant  30  to fit within a 21-gauge or 23-gauge needle or hollow instrument during implantation; however, larger or smaller gauge instruments can also be used. The implant  30  can also have a diameter that is designed to be delivered with larger needles. For example, the implant  30  can also be delivered with 18-, 19- or 20-gauge needles. The implant  30  can have a constant diameter through most of the length of the implant  30 , or the implant  30  can have portions of reduced diameter, e.g., annular grooves (not shown), between the proximal end  32   a  and the distal end  32   b . The annular grooves can produce an irregular outer surface on the body  32  that can operate to mechanically lock or anchor the implant  30  in place when implanted. Of course, such surface discontinuities or irregularities can also be formed by barbs or other projections, which extend from the outer surface of the implant  30 , to inhibit migration of the implant  30  from its implanted position, as described above. 
     In one embodiment, at least one of the proximal and distal ends,  32   a ,  32   b  can include a tapered portion. During implantation, the tapered end can operate to form, dilate, and/or increase the size of, an incision or puncture created in the tissue. For example, the distal end  32   b  can operate as a trocar to puncture or create an incision in the tissue. Following advancement of the distal end  32   b  of the implant  30 , the tapered portion can be advanced through the puncture or incision. The tapered portion can operate to stretch or expand the tissue around the puncture or incision to accommodate the increasing size of the tapered portion as it is advanced through the tissue. The interaction of the tissue and the edges of the implant  30  will provide an anchor for the implant  30  following implantation to inhibit migration of the drug delivery implant  30 . 
     The tapered portion can also facilitate proper location of the drug delivery implant  30  into the supraciliary or suprachoroidal spaces. For example, the implant  30  is preferably advanced through the tissue within the anterior chamber angle during implantation. This tissue typically is fibrous or porous, which is relatively easy to pierce or cut with a surgical device, such as the tip of the implant  30 . The implant  30  can be advanced through this tissue and abut against the sclera once the implant  30  extends into the uveoscleral outflow pathway. As the implant  30  abuts against the sclera, the tapered portion can preferably provide a generally rounded edge or surface that facilitates sliding of the implant  30  within the suprachoroidal space along the interior wall of the sclera  11 . For example, as the implant  30  is advanced into the uveoscleral outflow pathway and against the sclera  11 , the implant  30  will likely be oriented at an angle with respect to the interior wall of the sclera  11 . As the tip of the implant  30  engages the sclera  11 , the tip preferably has a radius that will permit the implant  30  to slide along the sclera  11  instead of piercing or substantially penetrating the sclera  11 . As the implant  30  slides along the sclera  11 , the tapered portion will provide an edge against which the implant  30  can abut against the sclera  11  and reduce the likelihood that the drug delivery implant  30  will pierce the sclera. 
     In one embodiment, once the implant  30  is implanted in position, the distal portion  32   b  can reside in the anterior chamber  20  and the proximal portion  32   a  can reside in the suprachoroidal space  24  of the uveoscleral outflow pathway  24   a.    
     The implant  30  preferably comprises any of the materials previously described above. The implant  30  can be fabricated through micro machining techniques or through procedures commonly used for fabricating optical fibers. For example, in some embodiments, the implant  30  is drawn with a recess extending therethrough. In the illustrated embodiment, the drug delivery implant  30  includes a first elongated recess  34  extending along an axis of the implant body  32  from the proximal end  32   a  of the implant  30 , and a second elongated recess  36  extending along the axis of the implant body  32  from the distal end of the implant  30 . In one embodiment a therapeutic agent  38 , as described herein, can be disposed in the recesses  34 ,  36  of the drug delivery implant  30 . 
     In one embodiment, the drug delivery implant  30  can be implanted in the uveoscleral outflow pathway  24   a  such that the proximal portion  32   a  is in the suprachoroidal space  24  and the distal portion  32   b  is near the anterior chamber  20 , so that the therapeutic agent  38  in the implant  30  can be delivered to both the suprachoroidal space  24  and the anterior chamber  20 . In one embodiment, the same therapeutic agent  38  can be disposed in the recesses  34 ,  36 . In another embodiment, the therapeutic agents  38  in the recesses  34 ,  36  can be different so as to provide different therapies to the anterior chamber  20  and the suprachoroidal space  24 . 
     Embodiment Illustrated in  FIG. 3   
       FIG. 3  shows another embodiment of a drug delivery implant  30 ′. The drug delivery implant  30 ′ is similar to the drug delivery implant  30  of  FIGS. 2A-2B , except as noted below. Thus, the reference numerals used to designate the various features of the drug delivery implant  30 ′ are identical to those used for identifying the corresponding features of the drug delivery implant  30 , except that a “′” has been added to the reference numerals. 
     The drug delivery implant  30 ′ includes a first elongated body  32   a  with a recess  34 ′ at a proximal end  33   a  thereof that can have a therapeutic agent  38   a  therein. The drug delivery implant  30 ′ also includes a second elongated body  32   b  with a recess  36 ′ at a distal end  33   b  thereof that can include a therapeutic agent  38   b  therein. In one embodiment, the therapeutic agents  38   a ,  38   b  are the same. In another embodiment, the therapeutic agents  38   a ,  38   b  are different. 
     Preferably, the first and second elongated bodies  32   a ,  32   b  have the same length and can couple to each other along their lengths so that the first and second elongated bodies  32   a ,  32   b  can define a unitary body. For example, the first and second elongated bodies  32   a ,  32   b  can define an interlocking mechanism on at least a portion of their respective outer surfaces (e.g., interlocking key and groove features) to allow for said coupling of the elongated bodies  32   a ,  32   b . In one embodiment, the elongated bodies  32   a ,  32   b  can be delivered sequentially to the implantation site and coupled together following implantation. In another embodiment, the elongated bodies  32   a ,  32   b  can be coupled prior to implantation and delivered to the implantation site as a unitary body. In one embodiment, the first and second elongated bodies  32   a ,  32   b  can be oriented so that the therapeutic agents  38   a ,  38   b  are directed in opposite directions (e.g., one toward the anterior chamber  20  and the second toward the suprachoroidal space  24 ). In another embodiment, the first and second elongated bodies  32   a ,  32   b  can be oriented so that the therapeutic agents  38   a ,  38   b  are directed in the same direction. 
     Embodiment Illustrated in  FIGS. 4A-4B   
       FIGS. 4A-4B  illustrate another embodiment of a drug delivery implant  40 . The drug delivery implant  40  is similar to the drug delivery implant  30  of  FIGS. 2A-2B , except as noted below. 
     The drug delivery implant  40  includes an elongated body  42  that can extend along an axis between a proximal end  42   a  and a distal end  42   b . The implant  40  can include a first recess  44  at the proximal end  42   a  thereof and a second recess  46  at the distal end  42   b  thereof, where each of the recesses  44 ,  46  can have a therapeutic agent  47  therein. In the illustrated embodiment, the recesses  44 ,  46  are aligned along a first axis X 1 . 
     The drug delivery implant  40  also defines a shunt with a lumen  48  that extends through the implant  40  along a second axis X 2  generally parallel to the first axis X 1 . Preferably, the lumen  48  is sized to allow flow of aqueous humor therethrough. In one embodiment, where the drug delivery implant  40  is implanted in the uveoscleral outflow pathway  24   a  so that the proximal end  42   a  is oriented toward the suprachoroidal space  24  and the distal end  42   b  is directed toward the anterior chamber  20 , the lumen  48  preferably enhances the drainage of aqueous humor from the anterior chamber  20  to the suprachoroidal space  24  via the implant  40 . 
     The flow of fluid is preferably restricted by the size of the lumen  48 , which produces a capillary effect that limits the fluid flow for given pressures. The capillary effect of the lumen  48  allows the shunt of the implant  40  to restrict flow and provides a valveless regulation of fluid flow. The flow of fluid through the implant  40  is preferably configured to be restricted to flow rated that will reduce the likelihood of hypotony in the eye. For example, in some embodiments, the flow rate can be limited to about 2.5 μL/min or less. In some embodiments the flow rate can be limited to between about 1.9 μL/min and about 3.1 μL/min. In other applications, a plurality of drug delivery implants  40  can be used in a single eye to conduct fluid from the anterior chamber to the uveoscleral outflow pathway. In such applications, the cumulative flow rate through the shunts of the implants  40  preferably is within the range of about 1.9 μL/min to about 3.1 μL/min, although the flow rate for each of the shunts of the implants  40  can be significantly less than about 2.5 μL/min. For example, if an application called for implantation of five shunts, then each implant  40  can be configured to have a flow rate of about 0.5 μL/min. 
     In the illustrated embodiment, the lumen  48  of the implant  40  is depicted as extending along the axis X 2  and offset from the longitudinal center of the implant  40 . In another embodiment, the lumen  48  can extend along the longitudinal center of the implant  40 . Additionally, the lumen  48  can vary in direction along its length. Also, though the illustrated embodiment shows the lumen  48  having a generally straight configuration between the proximal and distal ends  42   a ,  42   b  of the implant, in one embodiment the lumen  48  can have a non-linear (e.g., spiral) configuration. In the illustrated embodiment, the lumen  48  has a generally constant diameter from the proximal to the distal ends  42   a ,  42   b . In another embodiment, the diameter of the lumen  48  can vary (e.g., taper) along its length, or there can be a discontinuity in the diameter of the lumen  48  at a location along its length (e.g., to control the flow rate of aqueous humor therethrough). 
     The drug delivery implant  40  can be of any of the materials described herein. The implant  40  can be fabricated through conventional micro machining techniques or through procedures commonly used for fabricating optical fibers. Other materials can be used for the implant  40 , and other methods of manufacturing the implant  40  can also be used. For example, the implant  40  can be constructed of metals or plastics, and the implant  40  can be machined with a bore that is drilled as described above. 
     Embodiment Illustrated in  FIG. 5   
       FIGS. 5  illustrates another embodiment of a drug delivery implant  40 ′. The drug delivery implant  40 ′ is similar to the drug delivery implant  40  of  FIGS. 4A-4B , except as noted below. Thus, the reference numerals used to designate the various features of the drug delivery implant  40 ′ are identical to those used for identifying the corresponding features of the drug delivery implant  40 , except that a “′” has been added to the reference numerals. 
     In the illustrated embodiment, the drug delivery implant  40 ′ has a lumen  48 ′ that extends between a proximal end  43   a  and a distal end  43   b  of an elongated body  41   a  (e.g., shunt) that is separate from an elongated body  41   b  that includes the recesses  44 ′,  46 ′ and therapeutic agent  47 ′. The recesses  44 ′,  46 ′ extend along the central axis of the elongated body  41   b  and the lumen  48  extends along the central axis of the elongated body  41   a.    
     Preferably, the first and second elongated bodies  41   a ,  41   b  have the same length and can couple to each other along their lengths, prior to or following implantation, so that the first and second elongated bodies  41   a ,  41   b  can define a unitary body. For example, the first and second elongated bodies  41   a ,  41   b  can define an interlocking mechanism, as discussed above, on at least a portion of their respective outer surfaces (e.g., interlocking key and groove features) to allow for said coupling of the elongated bodies  41   a ,  41   b . In one embodiment, the elongated bodies  41   a ,  41   b  can be delivered sequentially to the implantation site and coupled together following implantation. In another embodiment, the elongated bodies  41   a ,  41   b  can be coupled prior to implantation and delivered to the implantation site as a unitary body. 
     Embodiment Illustrated in  FIG. 6   
       FIGS. 6  illustrates another embodiment of a drug delivery implant  40 ″. The drug delivery implant  40 ″ is similar to the drug delivery implant  40 ′ of  FIG. 5 , except as noted below. Thus, the reference numerals used to designate the various features of the drug delivery implant  40 ″ are identical to those used for identifying the corresponding features of the drug delivery implant  40 ′, except that a “″” has been added to the reference numerals. 
     In the illustrated embodiment, the drug delivery implant  40 ″ includes a shunt  41   a  that defines the lumen  48 ′, a first elongated body  41 b″ that has a recess  44 ″ at a proximal end  42   a  thereof, and a second elongated body  41   c ″ that has a recess  46 ″at a distal end  42   b  thereof, where the therapeutic agent  47 ′ can be disposed in the recesses  44 ″,  46 ″. In one embodiment, the lumen  48 ′, recess  44 ″ and recess  46 ″ can extend along the central axes of the shunt  41   a , first elongated body  41   b ″ and second elongated boy  41   c ″, respectively. 
     Preferably, at least two of the shunt  41   a  and first and second elongated bodies  41   b ″,  41   c ″ have the same length and can be coupled to each other along their lengths (e.g., via an interlocking mechanism defined on their outer surfaces) so as to define a unitary body. In one embodiment, the shunt  41   a  and first and second elongated bodies  41   b ″,  41   c ″ can be delivered sequentially to the implantation site and coupled together following implantation. In another embodiment, the shunt  41   a  and first and second elongated bodies  41   b ″,  41   c ″ can be coupled prior to implantation and delivered to the implantation site as a unitary body. The first and second elongated bodies  41   b ″,  41   c ″ can be oriented so that the therapeutic agents  47 ′ are directed in opposite directions (e.g., one toward the anterior chamber  20  and the second toward the suprachoroidal space  24 ). In another embodiment, the first and second elongated bodies  41   b ″,  41   c ″ can be oriented so that the therapeutic agents  47 ′ are directed in the same direction. 
     Embodiment Illustrated in  FIG. 7   
       FIGS. 7  illustrates another embodiment of a drug delivery implant  50 . In the illustrated embodiment, the drug delivery implant  50  includes a shunt  52   a  that defines a lumen  58  therethrough, and a first elongated body  52   b  that has a recess  56  at one end thereof, where a therapeutic agent  57  can be disposed in the recess  56 . In one embodiment, the lumen  58  and recess  56  can extend along the central axes of the shunt  52   a  and elongated body  52   b , respectively. The lumen  58  can be generally linear in one embodiment. In another embodiment, the lumen  58  can be non-linear. 
     Preferably, the shunt  52   a  and elongated body  52   b  have the same length and can be coupled to each other along their lengths (e.g., via an interlocking mechanism defined on their outer surfaces) so as to define a unitary body, prior to or following implantation. 
     Embodiment Illustrated in  FIGS. 8A-8B   
       FIGS. 8A-8B  illustrates another embodiment of a drug delivery implant  60 . In the illustrated embodiment, the drug delivery implant  60  includes an elongate body  62  that extends between a proximal end  62   a  and a distal end  62   b  and defines a lumen  64  that extends though the elongate body  62 . In the illustrate embodiment, the lumen  64  extends along a central axis of the elongate body  62 . However, in another embodiment, the lumen  64  can extend along an axis offset from the central axis of the body  62 . The lumen  64  can be generally linear. In another embodiment, the lumen  64  can be non-linear. 
     The drug delivery implant  60  also includes a first recesses  66  formed in the proximal portion  62   a  of the elongate body  62  about the lumen  64 . The drug delivery implant  60  also includes a second recesses  68  formed in the distal portion  62   b  of the elongate body  62  about the lumen  64 . The drug delivery implant  60  also includes a therapeutic agent  67  that can be disposed in the recesses  66 ,  68 . In one embodiment, the therapeutic agent  67  in the recesses  66 ,  68  can be the same. In another embodiment, the therapeutic agent  67  in the recesses  66 ,  68  can be different. 
     Advantageously, the drug delivery implant  60  allows for fluid flow therethrough via the lumen  64 , and said fluid flow is exposed to the therapeutic agent  67  and can carry it to a desired location. Where the implant  60  is implanted in the uveoscleral outflow pathway  24   a  so that the proximal end  62   a  is oriented toward the suprachoroidal space  24  and the distal end  62   b  is oriented toward the anterior chamber  20 , the lumen  64  allows for aqueous humor to flow from the anterior chamber  20 , through the elongate body  62  where the therapeutic agent  67  enters the fluid stream, and toward the suprachoroidal space  24 . 
     In one embodiment, the recesses  66 ,  68  can be circumferential recesses formed in the proximal and distal portions  62   a ,  62   b  of the elongate body  62 , respectively. In another embodiment, the recesses  66 ,  68  can each include two separate and distinct recesses at the formed in the elongate body  62  on radially opposite sides of the lumen  64 . In another embodiment, the drug delivery implant  60  can include only one circumferential recess at a proximal portion, distal portion, or central portion of the elongate body  62 . 
     Embodiment illustrated in  FIGS. 9A-9B   
       FIGS. 9A-9B  illustrate another embodiment of a drug delivery implant  70 . In the illustrated embodiment, the drug delivery implant  70  includes an elongate body  72  that extends between a proximal end  72   a  and a distal end  72   b  and defines a lumen  74  that extends though the elongate body  72 . In the illustrate embodiment, the lumen  74  extends along a central axis of the elongate body  72 . However, in another embodiment, the lumen  74  can extend along an axis offset from the central axis of the body  72 . The lumen  74  can be generally linear. In another embodiment, the lumen  74  can be non-linear. 
     The drug delivery implant  70  also includes a recesses  76  formed in the proximal portion  72   a  of the elongate body  72  about the lumen  74 . The drug delivery implant  70  also includes a first therapeutic agent  77  that can be disposed in the recess  76  and a second therapeutic agent  78  that can be disposed on an outer surface of the elongate body  72  at the distal portion  72   b  thereof. In one embodiment, the therapeutic agent  78  can be a film or a coating applied to the outer surface of the elongate body  72 . In one embodiment, the therapeutic agents  77 ,  78  are the same. In another embodiment, the therapeutic agent  78  can be different from the therapeutic agent  77 . 
     Advantageously, the drug delivery implant  70  allows for fluid to flow therethrough via the lumen  74 , and said fluid flow is exposed to the therapeutic agent  77  and can carry it to a desired location. Additionally, ocular tissue surrounding the drug delivery implant  70  can be exposed to the therapeutic agent  78  on the outer surface of the elongate body  72 . Where the implant  70  is implanted in the uveoscleral outflow pathway  24   a  so that the proximal end  72   a  is oriented toward the suprachoroidal space  24  and the distal end  72   b  is oriented toward the anterior chamber  20 , the lumen  74  allows for aqueous humor to flow from the anterior chamber  20 , through the elongate body  72  where the therapeutic agent  77  enters the fluid stream, and toward the suprachoroidal space  24 . 
     In one embodiment (not shown), the recess  76  can extend along the length of the elongate body  72  about the lumen  74 . In another embodiment, the recess  76  can include two separate and distinct recesses at the formed in the elongate body  72  on radially opposite sides of the lumen  74 . In another embodiment, the recess  76  can be located at a proximal portion, distal portion, or central portion of the elongate body  72 . Additionally, in one embodiment, the second therapeutic agent  78  can be disposed on the outer surface of the drug delivery implant  70  along the entire length of the elongate body  72 . 
     Embodiment illustrated in  FIG. 10   
       FIG. 10  illustrates another embodiment of a drug delivery implant  80 . In the illustrated embodiment, the drug delivery implant  80  includes an elongate body  82  that extends between a proximal end  82   a  and a distal end  82   b  and defines a lumen  84  that extends though the elongate body  82 . In the illustrate embodiment, the lumen  84  extends along a central axis of the elongate body  82 . However, in another embodiment, the lumen  84  can extend along an axis offset from the central axis of the body  82 . The lumen  84  can be generally linear. In another embodiment, the lumen  84  can be non-linear. 
     The drug delivery implant  80  also includes a first therapeutic agent  86  that can be disposed on the outer surface of the proximal portion  82   a  of the elongate body  82  and a second therapeutic agent  88  that can be disposed on an outer surface of the elongate body  82  at the distal portion  82   b  thereof. The therapeutic agents  86 ,  88  can be a film or a coating applied to the outer surface of the elongate body  82 . In one embodiment, the therapeutic agents  86 ,  88  are the same. In another embodiment, the therapeutic agent  86  can be different from the therapeutic agent  88 . 
     In the illustrated embodiment, the therapeutic agents  86 ,  88  extend circumferentially about the elongate body  82 . In another embodiment, the discreet portions of the therapeutic agents  86 ,  88  can be disposed on the elongate body  82  at diametrically opposite locations. 
     Advantageously, ocular tissue surrounding the drug delivery implant  80  can be exposed to the therapeutic agents  86 ,  88  on the outer surface of the elongate body  82 . Where the implant  80  is implanted in the uveoscleral outflow pathway  24   a  so that the proximal end  82   a  is oriented toward the suprachoroidal space  24  and the distal end  82   b  is oriented toward the anterior chamber  20 , the lumen  84  allows for aqueous humor to flow from the anterior chamber  20 , through the elongate body  82  and toward the suprachoroidal space  24 . Additionally, scleral, choroidal and/or ciliary tissue can be exposed to the therapeutic agents  86 ,  88  on the drug delivery implant  80 . 
     The drug delivery implant described in embodiments herein can be constructed of metals or plastics, or other suitable materials for implantation in ocular tissue. The drug delivery implant also need not have a unitary configuration; that is, be formed of the same material. For example, a portion of the drug delivery implant can be formed of a first material and another portion of the drug delivery implant can be formed of a second different material. 
     Procedures 
     For delivery of some embodiments of the ocular drug delivery implant, the implantation occurs in a closed chamber with or without viscoelastic. 
     The drug delivery implants may be placed using an applicator, such as a pusher, or they may be placed using a delivery instrument having energy stored in the instrument, such as disclosed in U.S. Patent Publication 2004/0050392, filed Aug. 28, 2002, the entirety of which is incorporated herein by reference and made a part of this specification and disclosure. In some embodiments, fluid may be infused through the delivery instrument or another instrument used in the procedure to create an elevated fluid pressure at the distal end of the shunt to ease implantation. 
       FIGS. 11A-12B  illustrate one embodiment of a surgical method for implanting the drug delivery implant into an eye, as described in the embodiments herein. A first incision or slit is made through the conjunctiva and the sclera  11  at a location rearward of the limbus  21 , that is, posterior to the region of the sclera  11  at which the opaque white sclera  11  starts to become clear cornea  12 . Preferably, the first incision is made about 3 mm posterior to the limbus  21 . Also, the first incision is made slightly larger than the width of the drug delivery implant. In one embodiment, a conventional cyclodialysis spatula may be inserted through the first incision into the supraciliary space to confirm correct anatomic position. 
     A portion of the upper and lower surfaces of the drug delivery implant proximate the back end of the body can be grasped securely by the surgical tool, for example, a forceps, so that the forward end of the implant is oriented properly. In one embodiment, the implant is oriented with a longitudinal axis of the implant being substantially co-axial to a longitudinal axis of the grasping end of the surgical tool. The drug delivery implant can then be disposed through the first incision and into the supraciliary space of the eye. In one embodiment, the drug delivery implant can have a shearing edge that can be advanced anteriorly in the supraciliary space and inserted into and through the anterior chamber angle of the eye. More particularly, the shearing edge of the insertion head of the implant can preferably pass between the scleral spur and the ciliary body  16  posterior to the trabecular meshwork. The drug delivery implant can be continually advanced anteriorly until a portion of its insertion head and the first end of the conduit is disposed within the anterior chamber  20  of the eye. Thus, the first end of the conduit is placed into fluid communication with the anterior chamber  20  of the eye. A back end of the elongate body of the drug delivery implant can be disposed into the suprachoroidal space  24  of the eye so that the second end of the conduit is placed into fluid communication with the suprachoroidal space  24 . 
     In the illustrated embodiment, a shoulder surface of the forward end of the drug delivery implant can be seated proximate an interior surface of the supraciliary space and is not introduced into the anterior chamber  20 . The shoulder surface advantageously aids in forming a tight seal to inhibit leakage of aqueous humor around the implant body as well as inhibit unwanted further anterior movement of the implant. In one embodiment, the shape of a cleft formed by the insertion head forms a tight seal about the exterior surface of the implant body, and, if used, the fusiform cross-sectional shape of the body inhibits gaping of the formed cleft on either elongate edge of the implant. 
     In one embodiment, the drug delivery implant can be sutured to a portion of the sclera  11  to aid in fixating the implant. In one embodiment, the first incision can subsequently be sutured closed. As one will appreciate, the suture used to fixate the drug delivery implant can also be used to close the first incision. In another embodiment, the drug delivery implant held substantially in place via the interaction of the implant body&#39;s outer surface and the tissue of the sclera  11  and ciliary body  16  without suturing the implant to the sclera  11 . Additionally, in one embodiment, the first incision can be sufficiently small so that the incision self-seals upon withdrawal of the surgical tool following implantation of the drug delivery implant without suturing the incision. 
     As discussed herein, in some embodiments the drug delivery implant can include a shunt comprising a lumen configured provide a drainage device between the anterior chamber  20  and the suprachoroidal space  24 . Upon implantation, the drainage device can form a cyclodialysis with the implant providing transverse communication of aqueous humor through the shunt along its length. Aqueous humor can thus be delivered to the suprachoroidal space where it can be absorbed, and additional reduction in pressure within the eye can be achieved. 
     The drug delivery implant can be made from any biological inert and biocompatible materials having the desired characteristics. The elongate body of the implant can in some embodiments be substantially rigid or may be substantially resilient and semi-rigid. Further, in one embodiment the exterior surface of the elongate implant body can be non-porous. Various medically suitable acrylics and other plastics are considered appropriate. The finish of the device preferably meets the standard for ophthalmic devices and does not irritate surrounding tissue. In one embodiment, the device may be made by conventional liquid injection molding or transfer molding process. 
     In some embodiments it is desirable to deliver the drug delivery implant ab interno across the eye, through a small incision at or near the limbus ( FIG. 13 a   ). The overall geometry of the system makes it advantageous that the delivery instrument incorporates a distal curvature, or a distal angle. In the former case, the drug delivery implant can be flexible to facilitate delivery along the curvature or can be more loosely held to move easily along an accurate path. In the latter case, the shunt can be relatively rigid. The delivery instrument can incorporate an implant advancement element (e.g. pusher) that is flexible enough to pass through the distal angle. 
     In some embodiments, the implant and delivery instrument can be advanced together through the anterior chamber  20  from an incision at or near the limbus  21 , across the iris  13 , and through the ciliary muscle attachment until the drug delivery implant outlet portion is located in the uveoscleral outflow pathway  24   a  (e.g. exposed to the suprachoroidal space  24  defined between the sclera  11  and the choroid  12 ), as shown in  FIG. 1 .  FIG. 13B  illustrates, a transocular implantation approach can be used with the delivery instrument inserted well above the limbus  21 . The incision, however, can be more posterior and closer to the limbus  21 . In other embodiments, the operator can then simultaneously push on a pusher device while pulling back on the delivery instrument, such that the drug delivery implant outlet portion maintains its location in the uveoscleral outflow pathway. The implant can be released from the delivery instrument, and the delivery instrument retracted proximally, as illustrated in  FIG. 13C . The delivery instrument then can be withdrawn from the anterior chamber through the incision. 
       FIG. 14  shows a meridional section of the anterior segment of the human eye and schematically illustrates another embodiment of a delivery instrument  1130  that can be used with embodiments of drug delivery implants described herein. In  FIG. 14 , arrows  1020  show the fibrous attachment zone of the ciliary muscle  16  to the sclera  11 . The ciliary muscle  16  is part of the choroid  28 . The suprachoroidal space  24  is the interface between the choroid  28  and the sclera  11 . Other structures in the eye include the lens  26 , the cornea  12 , the anterior chamber  20 , the iris  13 , and Schlemm&#39; s canal  22 . 
     In some embodiments, it is desirable to implant a drug delivery implant through the fibrous attachment zone, thus connecting the anterior chamber  20  to the uveoscleral outflow pathway  24   a , in order to reduce the intraocular pressure in glaucomatous patients. In some embodiments, it is desirable to deliver the drug delivery implant with a device that traverses the eye internally (ab interno), through a small incision in the limbus  21 . 
     The delivery instrument/implant assembly can be passed between the iris  13  and the cornea  12  to reach the iridocorneal angle. Therefore, the height of the delivery instrument/shunt assembly (dimension  1095  in  FIG. 14 ) preferably is less than about 3 mm, and more preferably less than 2 mm. 
     The suprachoroidal space  24  between the choroid  28  and the sclera  11  generally forms an angle α of about 55° with the optical axis X of the eye. This angle α, in addition to the height requirement described in the preceding paragraph, are features to consider in the geometrical design of the delivery instrument/implant assembly. 
     The overall geometry of the drug delivery implant system makes it advantageous that the delivery instrument  1130  incorporates a distal curvature  1140 , as shown in  FIG. 14 , or a distal angle  1150 , as shown in  FIG. 15 . The distal curvature ( FIG. 14 ) is expected to pass more smoothly through the corneal or scleral incision at the limbus  21 . However, in this embodiment, the drug delivery implant can be curved or flexible. Alternatively, in the design of  FIG. 15 , the drug delivery implant can be mounted on the straight segment of the delivery instrument, distal of the “elbow” or angle  1150 . In this case, the drug delivery implant can be straight and relatively inflexible, and the delivery instrument can incorporate a delivery mechanism that is flexible enough to advance through the angle. In some embodiments, the drug delivery implant can be a rigid tube, provided that the implant is no longer than the length of the distal segment  1160 . 
     The distal curvature  1140  of delivery instrument  1130  may be characterized as a radius of between about 10 to 30 mm, and preferably about 20 mm. The distal angle of the delivery instrument depicted in  FIG. 15  may be characterized as between about 90 to 170 degrees relative to an axis of the proximal segment  1170  of the delivery instrument, and preferably about 145 degrees. The angle incorporates a small radius of curvature at the “elbow” so as to make a smooth transition from the proximal segment  1170  of the delivery instrument to the distal segment  1160 . The length of the distal segment  1160  may be approximately 0.5 to 7 mm, and preferably about 2 to 3 mm. 
     In some embodiments, a viscoelastic can be injected into the suprachoroidal space to create a chamber or pocket between the choroid and sclera which can be accessed by a drug delivery implant. Such a pocket could expose more of the choroidal and scleral tissue area, and increase uveoscleral outflow in embodiments where the drug delivery implant includes a shunt, causing a lower intraocular pressure (TOP). In some embodiments, the viscoelastic material can be injected with a 25 or 27G cannula, for example, through an incision in the ciliary muscle attachment or through the sclera (e.g. from outside the eye). The viscoelastic material can also be injected through the shunt itself either before, during or after implantation is completed. 
     In some embodiments, a hyperosmotic agent can be injected into the suprachoroidal space. Such an injection can delay TOP reduction. Thus, hypotony can be avoided in the acute postoperative period by temporarily reducing choroidal absorption. The hyperosmotic agent can be, for example glucose, albumin, HYPAQUE™ medium, glycerol, or poly(ethylene glycol). The hyperosmotic agent can breakdown or wash out as the patient heals, resulting in a stable, acceptably low TOP, and avoiding transient hypotony. 
     Variations 
     In some embodiments, the drug delivery implant can facilitate delivery of a therapeutic agent. The therapeutic agent can be, for example, heparin, TGF-beta, an intraocular pressure-lowering drug, and an anti-proliferative agent. In some embodiments, the therapeutic agent is introduced concurrently with the drug delivery implant. The therapeutic agent can be part of the implant itself. For example, the therapeutic agent can be embedded in the material of the implant, or coat at least a portion of the implant. The therapeutic agent may be present on various portions of the implant. For example, the therapeutic agent may be present on the distal end of the implant and/or the proximal end of the implant. The implant can include combination of therapeutic agents. The different therapeutic agents can be separated or combined. One kind of therapeutic agent can be present at the proximal end of the drug delivery implant, and a different kind of therapeutic agent can be present at the distal end of the drug delivery implant. For example, an anti-proliferative agent may be present at the distal end of the implant to prevent growth, and a growth-promoting agent may be applied to the proximal end of the implant to promote growth. In some embodiments, the therapeutic agent is delivered through the implant to the desired location in the eye, such as the uveoscleral outflow pathway. 
     If desired, more than one drug delivery implant of the same or different type may be implanted. For example, the drug delivery implants disclosed herein may be used in combination with trabecular bypass shunts, such as those disclosed in U.S. Patent Publication 2004/0050392, and those described in U.S. Patent Publication 2005/0271704, filed Mar. 18, 2005, the entirety of which is incorporated herein by reference and made a part of this specification and disclosure. Such shunts may themselves include a therapeutic agent compounded with a biodegradable polymer such as PLGA, as discussed above. Additionally, implantation may be performed in combination with other surgical procedures, such as cataract surgery. In one embodiment, all or a portion of the drug delivery implant may be coated, e.g. with heparin, preferably in the flow path, to reduce blood thrombosis or tissue restenosis. 
     While certain embodiments of the disclosure have been described, these embodiments have been presented by way of example only, and are not intended to limit the scope of the disclosure. Indeed, the novel methods, systems, and devices described herein may be embodied in a variety of other forms. For example, embodiments of one illustrated or described shunt can be combined with embodiments of another illustrated or described shunt. Moreover, the shunts described above can be utilized for other purposes. For example, the shunts can be used to drain fluid from the anterior chamber to other locations of the eye or outside the eye. Furthermore, various omissions, substitutions and changes in the form of the methods, systems, and devices described herein may be made without departing from the spirit of the disclosure.