Bioabsorbable Ocular Drug Delivery Devices

Abstract

Provided are implantable intraocular drug delivery devices configured for targeted and / or controlled release of drugs to desired intraocular target tissues, as well as methods for implanting and using such devices for the treatment of ocular diseases and disorders. [Solution] An ocular implant configured to be implanted into a subject's eye, comprising an elongated outer shell comprising a bioerodible material and shaped to define an internal lumen, an internal plug positioned within the internal lumen and comprising a hydrogel, and a drug reservoir positioned within the internal lumen and comprising a drug, the ocular implant configured to pass through at least a portion of the internal plug which controls the elution of the drug through the outer shell.

Description

[Technical field]

[0001] <CROSS REFERENCE TO RELATED APPLICATIONS>

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 325,378, filed April 20, 2016, the entire contents of which are incorporated herein by reference.

[0003] The present disclosure relates to implantable intraocular drug delivery devices configured for targeted and / or controlled release of drugs to desired intraocular target tissues, and methods of using such devices for the treatment of ocular diseases and disorders. In certain embodiments, the present disclosure also relates specifically to the treatment of ocular diseases with drug delivery devices implanted in the eye, the device being made partially or essentially entirely of a biodegradable material. [Background technology]

[0004] The mammalian eye is a specialized sensory organ capable of receiving light and visual images. A number of pathologies, including ocular trauma, infection, degeneration, irregular blood vessels, and inflammatory problems, can impair or completely eliminate an individual's ability to perceive visual images. The central part of the retina is known as the macula. The macula is responsible for central vision, fine visualization, and color discrimination, and can be affected by age-related macular degeneration (wet or dry), diabetic macular edema, idiopathic choroidal neovascularization, or high myopic macular degeneration, among other pathologies.

[0005] Other conditions such as abnormal intraocular pressure may also affect vision. Approximately 2 percent of Americans suffer from glaucoma. Glaucoma is a group of eye diseases that encompass a wide range of clinical symptoms and etiologies, but are united by elevated intraocular pressure. Glaucoma results in lesions of the optic nerve found on the optic disc, resulting in corresponding visual field defects. If untreated, visual field defects can lead to blindness. Elevated intraocular pressure is the only treatable risk factor associated with glaucoma, and therefore reducing intraocular pressure is the primary treatment goal in all glaucoma, which can be achieved by drug therapy, surgery, or a combination of both.

[0006] Many ocular conditions progress due to the difficulty of administering therapeutic agents to the eye in sufficient amounts and / or for the duration required to ameliorate the symptoms of the condition. Often, drug absorption and processing occurs before the drug reaches the ocular target site. Because of this metabolism, systemic administration may require undesirably high concentrations of the drug to reach therapeutic levels at the ocular target site. This is not only impractical and expensive, but may also increase the incidence of side effects. Topical administration may be limited by limited diffusion through the cornea or dilution of the locally administered drug by the action of tears. Even drugs that pass through the cornea may be unacceptably depleted from the eye by ocular fluid flow and transition to the systemic circulation. Thus, a means of administering therapeutic agents to the eye in a controlled and targeted manner would confront the limitations of other delivery routes. Summary of the Invention [Means for solving the problem]

[0007] Various embodiments disclosed herein relate to a drug delivery ocular implant. The ocular implant includes an outer shell having a proximal end and a distal end, the outer shell being shaped to define an interior lumen. A drug can be located within the interior chamber.

[0008] In some embodiments, a drug delivery ocular implant or device is provided that includes an elongate shell having a proximal end, a distal end, the shell being shaped to define an internal lumen, and at least one first drug disposed within the internal lumen. The shell comprises a biodegradable polymer. The shell is preferably tubular or cylindrical.

[0009] According to the present disclosure, any of the described implants can include a shell of biodegradable polymeric materials, including homopolymers, polymer blends, and copolymers, such as random copolymers, block copolymers, and the like.

[0010] Suitable biodegradable materials for the manufacture of implants and their components include the following: poly(esters), poly(ester amides) (PEA), poly(ester carbonates) (PEC), polylactic acid (PLA), poly(L-lactide) (PLLA), poly(D-lactide) (PDLA), poly(DL-lactic acid) (PDLLA), polyglycolide (PGA), polycaprolactone (PCL), copolymers such as polylactic acid-co-glycolide (PLGA), poly(hydroxyalkanoates), poly(3-hydroxybutyrate) (PHB), PHB copolymerized with 3-hydroxyvalerate (PHBV), poly(propylene glycolate ... Poly(butylene fumarate) (PPF), poly(anhydrides) (PAA), poly(butylene succinate) (PBS), poly(ethylene succinate) (PES), poly(hydroxyalkanoates) (PHAs), poly(cyanoacrylates) (PCAs), polyacetals, polyorthoesters (POE), polycarbonates including poly(trimethylene carbonate) (PTMC), polyphosphazenes, polyphosphates, as well as blends, copolymers and combinations of the above, and modified polysaccharides, such as natural polymers including, but not limited to, starch, cellulose, and chitosan.

[0011] In some embodiments, the length of the device can be 1-7 mm, including 2-5 mm. In some embodiments, the device has a tip that tapers near the distal end of the implant. In other embodiments, the length of the device can be about 15-30 mm, including about 15-18 mm, about 18-21 mm, about 21-23 mm, about 23-25 ​​mm, about 25 mm-27 mm, about 27-30 mm, and overlapping ranges thereof. In some embodiments, the outer shell of the device can be flexible and / or curved.

[0012] In some embodiments, an ocular implant can be implanted into the eye of a subject. The implant can include an elongated outer shell that includes a bioerodible material and is shaped to define an inner lumen, an inner plug located within the inner lumen and that includes a hydrogel, and a drug reservoir located within the inner lumen and that includes a drug. The drug can pass through at least a portion of the inner plug that controls elution of the drug through the outer shell.

[0013] In some embodiments, the drug reservoir is located adjacent to the internal plug. In some embodiments, the internal plug is located adjacent to a distal-most end of the internal lumen. In some embodiments, the elongate shell includes one or more orifices located near a distal end of the shell, the orifices configured to control elution of the drug through the hydrogel and out of the implant. In some embodiments, the implant includes a coating surrounding at least a portion of the shell.

[0014] In some embodiments, the implant includes a proximal obstruction. The proximal obstruction can form an end cap at the proximal end of the shell. In some embodiments, the proximal obstruction is located near the proximal side of the drug reservoir within the shell.

[0015] In some embodiments, the outer shell is configured to begin to bioerode after all or nearly all of the drug has eluted from the internal lumen of the implant. In some embodiments, the outer shell is configured to begin to bioerode while at least a portion of the drug that elutes from the internal lumen of the implant remains in the internal lumen. In some embodiments, the implant further comprises a fluid flow path. In some embodiments, the implant is configured for implantation into the eye of a subject, and the fluid flow path drains ocular fluid to a physiological outflow space. In some embodiments, the hydrogel surrounds at least a portion of the drug within the internal lumen.

[0016] The ocular implant may include one or more retention features configured to secure or anchor the ocular implant to ocular tissue. Such retention protrusions optionally include one or more ridges, ribs, and / or barbs. In some embodiments, the retention protrusions are flexible.

[0017] The implants described herein are optionally fixed (e.g., any mechanism or element that allows the implant to be permanently or transiently anchored, fixed, or attached) to intraocular tissues such as the ciliary muscle, ciliary tendon, ciliary fibrous band, trabecular meshwork, iris, iris root, lens cortex, lens epithelium, to or within the lens capsule, sclera, scleral promontory, choroid, or to or within Schlemm's canal.

[0018] The ocular implant can be configured to be positioned within the supraciliary space, the suprachoroidal space, Schlemm's canal, the anterior chamber, the vitreous humor, or the lens capsule. The ocular implant can be positioned within the supraciliary space, the suprachoroidal space, Schlemm's canal, the anterior chamber, the vitreous humor, or the lens capsule.

[0019] In some embodiments, the shell has a substantially uniform thickness. In some embodiments, the shell is permeable or semi-permeable to the drug contained therein, such that at least about 5%, 10%, 15%, 20% or more of the total elution of the first drug can occur through the portion of the shell having the first thickness. In some embodiments, all or nearly all of the total elution of the drug occurs through the shell. In other embodiments, the shell is impermeable or nearly impermeable to the drug contained within the device, such that less than 5%, including less than 2%, less than 1%, or nearly zero, elution occurs through the shell.

[0020] In some embodiments, the shell includes one or more regions that have different drug release rates from the bulk of the shell. Such regions can increase or decrease drug release relative to the bulk of the shell. Such regions can be characterized, for example, by the presence or absence of a coating that retards drug release, or by being thinner or thicker to alter drug release rates. In embodiments having regions of reduced shell thickness, such regions can be formed by any suitable means, including one or more of ablation, stretching, etching, grinding, and shaping. The regions can be any pattern on or around the implant, including spiral patterns, patches, rings, and / or bands.

[0021] In some embodiments, the wall of the shell comprises at least one opening, orifice or hole. In some embodiments, the wall of the shell comprises a plurality of openings, orifices or holes, which may be arranged randomly or in a patterned array. The openings, orifices or holes in the wall of the shell may be open or may be covered with one or more coatings or membranes. In some embodiments where the device comprises a plurality of openings, orifices or holes through the shell, at least a portion of the plurality may be closed with a membrane permeable to the drug.

[0022] In some embodiments, elution of the drug (e.g., protein therapeutic) is regulated by diffusion from the device through an orifice (as described above), another opening, hole, channel, hole, or preferably micropore provided through the tube wall, or through a cap, plug, or membrane at the end of the tube. The diameter of such elution regulating features is configured to be large enough to allow the passage of protein drug molecules. In some embodiments, these features are at least about 0.05, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3 μm (or more) in diameter. In some embodiments, the thickness of the tube wall, cap, plug, or membrane can be about 10 μm to about 2 mm, e.g., about 10 μm to about 50 μm, about 50 to about 100 μm, about 100 to about 150 μm, about 150 to about 200 μm, and any range therebetween. In some preferred embodiments, the range is about 50 to about 200 μm.

[0023] In some embodiments, the elution or diffusion of a drug through an elution feature (such as an opening, hole, channel, pore, preferably a micropore) generally follows the Fick equation at any given time, where the elution rate is proportional to the concentration gradient from the inside of the device to the outside of the device. In some embodiments, the combined open area of ​​the elution features and the diffusion coefficient of the protein drug define the rate, while the elution rate is inversely proportional to the length and curvature of the elution feature.

[0024] Eluting features can be formed, in some embodiments, by laser machining, or by extraction of a highly soluble material of appropriate particle size blended into a bioabsorbable matrix, or by sintering a bioabsorbable powder.

[0025] The elution feature is designed to provide an elution rate of the protein drug that, combined with the clearance rate from the eye, results in a therapeutic concentration of the protein drug in the eye. Such elution rates can range from about 0.1 to about 20 μg / week, including about 0.5 to about 20 μg, about 1.0 to about 20 μg, about 5.0 to about 20 μg, about 10.0 to about 20 μg, about 10.0 to about 15 μg, about 7 to about 15 μg, about 2 to about 10 μg, and preferably about 0.1 to about 20 μg / week, including 2 to 6 μg / week. Other amounts between the above ranges are also achieved in some embodiments.

[0026] In some embodiments, surface erosion of the bioabsorbable material of the implant provides a self-cleaning function, allowing adherent proteins, polysaccharides, cells or other biomaterial to be shed from the device so that the elution features are not blocked.

[0027] In some embodiments disclosed herein, a coating is formed, preferably a polymeric coating that is biodegradable. In some embodiments, two or more polymeric coatings are located on the surface of the shell, and in some such embodiments, each coating has a unique biodegradation rate in ocular fluid (including being substantially non-biodegradable). In some embodiments, the coating alters (increases or decreases) the release rate of the drug and / or alters (increases or decreases) the biodegradation rate of the material covered by the coating.

[0028] Embodiments of the device may elute one or more drugs through the shell only, through one or more caps (containing drug release elements) only, through one or more open apertures or perforations in the shell and / or cap membranes, or through any combination of the above.

[0029] In some embodiments, at least the distal most about 5 mm to about 10 mm of the inner lumen contains the drug.

[0030] In some embodiments, elution of the first drug from the implant continues for a period of at least one year, including at least two, three, four, five or more years.

[0031] In some embodiments described herein, the drug elutes from the implant with zero order or pseudo-zero order kinetics.

[0032] In some embodiments, the implants described herein optionally further comprise a lumen configured to transport ocular fluid from a first location in the eye to one or more other locations, thereby reducing intraocular pressure. In some such embodiments, the shell comprises two lumens, which may be coaxial or parallel, one lumen being an internal lumen for containing at least one drug, and the other lumen serving as a conduit to facilitate delivery of aqueous humor from the anterior chamber to another location in the eye, such as the suprachoroidal space, Schlemm's canal, etc., to reduce intraocular pressure.

[0033] In some embodiments, the device includes a cap structure for releasing or eluting one or more drugs. In some embodiments, the cap is a special type of cap, referred to herein as a drug release element. The cap can be located at either or both the proximal or distal end of the device's shell. Some embodiments include one or two caps or drug release elements. Depending on the placement of the elements, the device can deliver drugs to the anterior, posterior, or both. Thus, the device can treat anterior and / or posterior ocular conditions.

[0034] In some embodiments, the implant includes a cap configured for reversible or irreversible interaction with the proximal end of the shell. The cap includes at least one opening, and in some embodiments, multiple openings are provided. The total surface area of ​​the one or more openings can be selected, in a particular embodiment, based on the desired elution rate of the first drug from the implant.

[0035] In some embodiments, placement of the cap on the proximal end of the shell can hold the membrane between the cap and the proximal end of the shell. In some embodiments, the cap is a press-fit cap, while other embodiments employ a crimp cap, a screw cap, or another type of cap. In some embodiments, the membrane is permeable to the at least one first drug and ocular fluid (and / or the aqueous component of ocular fluid). In some embodiments, the membrane (when the cap is placed) closes the at least one opening, and elution of the at least one first drug occurs only through the membrane (e.g., compression of the membrane by the cap serves to seal the implant from other routes of unintended drug release). In some embodiments, a distally located seal is located within the lumen to limit fluid communication between the internal lumen and the ocular space only through the membrane. In some embodiments, the selected combination of membrane and opening dimensions (e.g., surface area) is tailored to a particular desired elution rate of the first active agent. In some embodiments, the membrane has a thickness of about 50 to about 100 microns.

[0036] The ocular implant may include a special type of cap, referred to herein as a drug release element, configured to release a drug from an internal chamber, also referred to herein as an inner lumen or internal lumen. The drug release element may include a distal seal member including at least one opening, a proximal seal member including at least one opening, and a membrane compressed between the distal seal member and the proximal seal member. The retainer may be configured to hold the drug release element in place relative to the outer shell. The drug release element may be configured such that the drug passes through the at least one opening in the distal seal member, through the compressed membrane, through the at least one opening in the proximal seal member, and out the proximal end of the outer shell.

[0037] The retainer can include one or more tabs that can be folded to mate with the proximal seal member. In some embodiments, the one or more tabs can be folded to mate with the membrane. The outer shell can include one or more grooves, and the retainer can extend into the one or more grooves and be located proximal to the proximal seal member. The retainer can have a lateral extent that exceeds an inner diameter of the interior chamber adjacent the retainer and is equal to or less than an outer diameter of the exterior shell adjacent the retainer. In some embodiments, the interior chamber can include a shelf, and the distal seal member can be located on the shelf.

[0038] The membrane of the cap or drug release element can include ethylene vinyl acetate, which can have a vinyl acetate concentration of about 10% to about 30%, although other concentrations can be used as described herein. Alternative membranes can be used, including membranes that are biodegradable. The membrane can also have a biodegradable or non-biodegradable coating. The ocular implant can be configured such that the membrane has a thickness in a compressed state of about 75 microns to about 125 microns and / or the membrane is compressed an amount of about 20 microns to about 40 microns from the uncompressed state, although other thicknesses and amounts of compression can be used as described herein.

[0039] The drug release element can have an elution rate of about 15 nanograms per day to about 35 nanograms per day, although other elution rates can be used. The ocular implant can be configured to hold a volume of drug of about 40 nanoliters to about 150 nanoliters, although other volumes can be used.

[0040] In some embodiments, there is a valve within the outer shell, which can be reversibly opened and closed to allow the at least one first drug to pass into the inner lumen. In some embodiments, there is a valve disposed at the distal most end of the outer shell, which can be reversibly opened and closed to allow the at least one first drug to pass from the inner lumen to a target site outside the implant.

[0041] Various embodiments of the implants disclosed herein can include one or more obstructions disposed within the internal lumen that limit the forward (or, in some embodiments, rearward) elution of a drug, and / or an obstruction including a one-way valve disposed to allow fluid to pass through the implant in a proximal to distal direction. In some embodiments having one or more obstructions disposed within the internal lumen, the one or more obstructions can facilitate the simultaneous (or sequential) elution of one or more drugs into the anterior and / or posterior chambers for a desired effect.

[0042] In some embodiments, the first drug is a beta adrenergic receptor antagonist. The beta adrenergic receptor antagonist can be a selective beta adrenergic antagonist or a non-selective beta adrenergic receptor antagonist. In some embodiments, the selective beta adrenergic receptor antagonist is selected from the group consisting of betaxolol and levobetaxolol, and combinations thereof. In some embodiments, the non-selective beta adrenergic antagonist is selected from the group consisting of timolol, levobunolol, carteolol, metipranolol, and combinations thereof. In some embodiments, at least one drug is used, and in some embodiments, the at least one first drug is timolol.

[0043] In some embodiments, the drug may be formulated as an oil.

[0044] In some embodiments, the drug may include a prostaglandin, a prostaglandin analog, a prostaglandin inhibitor, a beta-adrenergic receptor antagonist, or a combination thereof, although other drugs may be used as described herein. In some embodiments, the drug may include travoprost and / or a prodrug thereof. In other embodiments, the drug may include alprostadil and / or a variant or prodrug thereof.

[0045] Additionally, in some embodiments, a second agent may optionally be provided. In some embodiments, the second (or third, etc.) agent provides a synergistic effect when combined with the first agent. In other embodiments, the second agent reduces one or more side effects associated with the first agent.

[0046] In some embodiments, one or more drugs are contained within a micellar or vesicular structure, or formulated with a biodegradable polymer configured to release the drug at a known rate.

[0047] In some embodiments, the first drug is present as one or more micro-tablets, the micro-tablets having a density of about 0.7 g / cc to about 1.6 g / cc, a length to diameter aspect ratio of about 2.8 to 3.6, and / or a minor axis of about 0.28 to 0.31 mm and a major axis of about 0.8 to 1.1 mm. In some embodiments, the first drug is present in an amount of at least 70% by weight of the total weight of the one or more micro-tablets. In some embodiments, the micro-tablets have a surface area to volume ratio of about 13 to 17. In some embodiments, the micro-tablets are sized to permit passage of the micro-tablets through a conduit having an inner diameter of about 23 to 25 gauge.

[0048] In further embodiments, the micro-tablets are optionally coated with a coating that modulates the release of the first drug from the micro-tablets. In some embodiments, the coating is a polymer coating.

[0049] Also provided herein is a method for treating an ocular condition or disorder in an intraocular target tissue, comprising connecting an opening in the lateral eye to the anterior chamber, advancing a delivery device coupled to a drug delivery ocular implant through the opening across the anterior chamber, inserting the drug delivery ocular implant into the ocular tissue, placing the implant at a desired location in the eye, and withdrawing the delivery device from the eye. The drug elutes from the implant in an amount sufficient to treat the ocular condition or disorder. In some embodiments, the therapeutic effect is obtained for a period of at least one year to up to five years.

[0050] In some embodiments, the device is positioned such that at least one of the one or more drug release regions or the cap structure is in proximity to an intraocular target. In some embodiments, the intraocular target is in the posterior chamber. In some embodiments, the intraocular target is selected from the group consisting of the macula, retina, optic nerve, ciliary body, and intraocular vasculature. In some other embodiments, the intraocular target is in the anterior chamber.

[0051] In some embodiments, inserting the drug delivery ocular implant into an ocular tissue comprises positioning at least a portion of the implant in a portion of the eye selected from the group consisting of the uveoscleral pathway, the suprachoroidal space, the anterior chamber, the lens capsule, the vitreous humor, and Schlemm's canal.

[0052] These and other features, aspects and advantages of the present disclosure will now be described with reference to the drawings of embodiments, which are illustrative of the present disclosure and are not intended to limit the present disclosure. Those skilled in the art will readily appreciate that the features shown in the illustrative embodiments can be combined in both a foreseen manner, although not explicitly shown, and in a manner disclosed herein. [Brief description of the drawings]

[0053] [Figure 1] FIG. 1 is a schematic cross-sectional view of an eye. [Figure 2A] 13A-13C show further drug delivery implants incorporating shunts according to embodiments disclosed herein. [Figure 2B] 1 illustrates a cross-sectional view of one embodiment of a retention feature on a drug delivery implant according to embodiments disclosed herein. [Figure 3A] 1A-1D illustrate various drug delivery implants according to embodiments disclosed herein. [Figure 3B] 1A-1D illustrate various drug delivery implants according to embodiments disclosed herein. [Figure 3C] 1A-1D illustrate various drug delivery implants according to embodiments disclosed herein. [Figure 3D]1A-1D illustrate various drug delivery implants according to embodiments disclosed herein. [Figure 4A] FIG. 1 is a cross-sectional view of one embodiment of a drug delivery implant according to embodiments disclosed herein. [Figure 4B] FIG. 1 is a cross-sectional view of one embodiment of a drug delivery implant according to embodiments disclosed herein. [Figure 4C] FIG. 1 is a cross-sectional view of one embodiment of a drug delivery implant according to embodiments disclosed herein. [Figure 5A] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 5B] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 6A] 1A-1C illustrate various features of an elongate delivery device according to some embodiments disclosed herein. [Figure 6B] 1A-1C illustrate various features of an elongate delivery device according to some embodiments disclosed herein. [Figure 6C] FIG. 1 illustrates one embodiment of a delivery device according to embodiments disclosed herein. [Figure 6D] FIG. 1 illustrates an implantation structure of a drug delivery device according to embodiments disclosed herein. [Figure 7] FIG. 1 illustrates an apparatus for implanting a drug delivery device according to embodiments disclosed herein. [Figure 8] FIG. 1 illustrates an apparatus for implanting a drug delivery device according to embodiments disclosed herein. [Figure 9] 1 is a schematic cross-sectional view of an eye with a delivery device containing an implant advanced across the anterior chamber, the size of the implant being exaggerated for illustrative purposes. [Figure 10] 1 illustrates another implantation procedure according to some embodiments disclosed herein, with the size of the implant exaggerated for illustrative purposes. [Figure 11] 1 is a schematic cross-sectional view of an eye with a delivery device advanced adjacent to the anterior chamber angle, with the size of the implant exaggerated for illustrative purposes. [Figure 12] FIG. 1 is a schematic cross-sectional view of an eye in which a delivery device is implanting an implant that extends from the anterior chamber through the suprachoroidal space and terminates just proximal to the macula. [Figure 13A] FIG. 2 is a distal exploded perspective view of a drug release element. [Figure 13B] FIG. 13B is a proximal exploded perspective view of the drug release element of FIG. 13A. [Figure 14] FIG. 1 is a cross-sectional view of an implant including a drug release element. [Figure 15] FIG. 1 is a partial cross-sectional view of an implant including a drug release element. [Figure 16] FIG. 1 is a perspective view of one exemplary embodiment of a seal for use with a drug delivery ocular implant. [Figure 17] 1 is a perspective view of one exemplary embodiment of a proximal seal member for use with a drug delivery ocular implant. [Figure 18] FIG. 1 is a perspective view of an exemplary embodiment of an ocular implant. [Figure 19] FIG. 19 is a side view of one exemplary embodiment of the ocular implant of FIG. 18. [Figure 20] 19 is a cross-sectional view of an exemplary embodiment of the ocular implant of FIG. 18. [Figure 21A] 1 shows drug concentration and elution data according to some embodiments herein. FIG. 2 shows the change in drug concentration over time. [Figure 21B] 1 shows drug concentration and elution data according to some embodiments herein, and illustrates the drug elution rate over time from a predicted prophetic implant. [Figure 22A] 1 illustrates drug elution data according to some embodiments herein, showing the rate of drug elution from an implant over time. [Figure 22B] 1 illustrates drug elution data according to some embodiments herein, showing the rate of drug elution from an implant over time. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0054] 1 is an anatomical diagram of the eye, including 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 behind the iris 13, the ciliary body 16, and Schlemm's canal 22. The eye also includes the uveoscleral pathway, which serves to remove some of the fluid from the anterior chamber, and includes the suprachoroidal or supraciliary space, which is located between the choroid 28 and the sclera 11. The eye also includes a posterior region 30, which includes the macula 32.

[0055] Achieving localized ocular administration of drugs may require direct injection or application, but may also involve the use of drug-eluting implants, a portion of which may be placed in close proximity to the target site of action within the eye or chamber (e.g., anterior chamber, posterior chamber, or both simultaneously) where the target site is located. Drug-eluting implants may also be used to target delivery of drugs to specific ocular tissues, such as the macula, retina, ciliary body, optic nerve, etc., or to vascularize specific areas of the eye. Drug-eluting implants may also provide the opportunity to administer a controlled amount of drug for a desired time, depending on the condition. For example, some conditions may require the drug to be released at a constant rate for only a few days. Other conditions may require the drug to be released at a constant rate for up to several months. Still other conditions may require periodic or different release rates over a period of time. Furthermore, other conditions may require periods of no release (e.g., "drug holiday").

[0056] In some cases, the implant may serve additional functions, such as maintaining patency of a fluid flow path within the orbit after drug delivery is complete, acting as a reservoir for future administration of the same or a different therapeutic agent, or may also serve to maintain patency of a fluid passageway or flow path from a first location to a second location, for example, functioning as a stent. Conversely, it may be desirable for the implant to be partially or completely biodegradable so that it is removed from the eye after delivery of all or nearly all of the drug.

[0057] For bioabsorbable drug delivery of protein drugs, such as anti-VEGF proteins and / or monoclonal antibodies or antibody fragments, among others, for example protein molecules blended with bioabsorbable polymers such as PLA, PLGA, polyvinyl alcohol (PVA), cross-linked polyacrylic acid (Carbopol), hydroxypropyl methylcellulose (HPMC), other polyesters or polyetheramides, various methods exist. Various structures have been previously disclosed, including rods, gels, micelles, nanoparticles, and combinations of these materials. Applicants have found these approaches to be disadvantageous, for example, due to the possibility of protein inactivation and aggregation when manufacturing these formulations. Aggregation can be disadvantageous, for example, by inhibiting the desired elution profile, shortening the lifespan of the delivered protein drug. Also, such approaches may not significantly extend the residence time of the protein in the eye compared to the clearance rate of the protein alone.

[0058] However, in some embodiments disclosed herein, bioabsorbable (e.g., biodegradable or bioerodible) devices overcome these limitations. In some embodiments, the bioabsorbable materials used to construct the entire device (or substantially the entire device or a portion thereof) can include PLA, PLGA, polycaprolactone, other polyesters, polyetheramides, or other polyamides. Combinations can also be used in some embodiments. The bioabsorbable material can be a hydrogel that includes one or more of polyethylene glycol, polyethylene oxide, polyethylene oxide-co-propylene oxide, co-polyethylene oxide block or random copolymers, polyacrylamide, and polyvinyl alcohol, poly(vinylpyrrolidinone). The hydrogel can alternatively or additionally include one or more polymers such as hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, polyvinyl acetate, polyvinyl alcohol, gelatin, polyvinylpyrrolidone, and the like. Such polymers can form, for example, interpenetrating networks. In some embodiments, the polymers can help increase the mechanical strength of the hydrogel. In some embodiments, the permeability of the hydrogel can be adjusted by selecting a particular polymer. In some embodiments, the hydrogel is advantageously non-toxic, water-soluble, bioerodible, hydrophilic, highly absorbent, and / or flexible. In some embodiments, the hydrogel is optically transparent, which can reduce or minimize interference with the patient's vision.

[0059] Hydrogels can be made by a variety of methods and can be implemented in a variety of forms. In some embodiments, hydrogels can be formed from synthetic (e.g., poly(ethylene glycol), poly(hydroxyethyl methacrylate)) and / or natural polymers (e.g., collagen, hyaluronan, heparin). Depending on the reactivity of the constituent materials, gelation can be induced by pH, temperature, Coulombic interactions, covalent bonds, non-covalent interactions, and / or polymerization, among other methods. For example, covalent bonds and / or polymerization can be achieved by chemical reactions such as free radical polymerization of vinyl groups, amide bond formation between amine and ester groups (e.g., active esters using n-hydroxysuccinimide), and / or Diels-Alder reactions of furan and maleimide moieties. The reactive components can be delivered into a mold or tube. For example, the hydrogel can be formed in the shape of the mold (e.g., in the shape of a tube). In some embodiments, the hydrogel can be removed from the mold and / or extruded from the tube. In some embodiments, the hydrogel can be transferred into the outer shell of the implant. In some embodiments, the reactive components can be delivered directly into the outer shell. For example, a hydrogel can be formed within the shell.

[0060] In some embodiments, the hydrogel can form a coating material that covers the implant (all or part) and / or any orifices (all or part). In some embodiments, the implant can include a plug of hydrogel, as discussed in more detail below. For example, the drug can pass through the hydrogel. In some embodiments, the hydrogel can be formed ex vivo or in situ. In some embodiments, the drug is embedded in the hydrogel. For example, the hydrogel-drug mixture can include separate solutions of the polymer and the protein stabilizer. The hydrogel composition can be selected based on several factors, such as crosslink density (e.g., the ratio of the mass of the crosslinker to the mass of the selected monomer), porosity, thickness, curvature, volume fraction of the polymer in the hydrogel, and / or diffusion permeability of the protein drug.

[0061] Some examples of protein stabilizers include gelatin, sugars (e.g., trehalose, sucrose, among others), amino acids, non-ionic surfactants (e.g., poloxamer), and / or buffer salts, among others. Protein stabilizers can advantageously prevent and / or limit aggregation and degradation of protein drugs. This can improve the life span of protein drugs, as described above. Various formulations can be produced by mixing individual solutions of polymers and protein stabilizers. For example, anti-VEGF drug components and / or proteins can be added to the formulation, and protein drug molecules can be embedded in a polymer hydrogel matrix.

[0062] Exemplary formulations comprising embedded protein drug molecules can be freeze-dried. In some embodiments, the freeze-dried material can be directly compressed into tablets of suitable size for injection as a soluble implant into the vitreous cavity of the human eye. For example, the tablet can generally be in the shape of one or more cylindrical and / or rectangular disks and / or tiles. The compression force applied to the freeze-dried material, including the formulations described herein, can be controlled or adjusted. Advantageously, the density of the tablet can be adjusted by adjusting the applied compression force. For example, the dissolution rate of a tablet can be related to its density, so that the dissolution rate of the tablet can be controlled by adjusting the compression force. For example, the compression force can be translated into a controlled release rate of the protein drug molecule.

[0063] In some embodiments, the implant can be injected by a specially designed insertion device. In some embodiments, one or more tablets can be placed in a reservoir that contains an elution-controlling membrane or gel material that controls the rate of dissolution and diffusion and / or contains the material that is delivered into the eye. Advantageously, this can minimize the impact on vision. Once injected, the implant slowly dissolves, for example, into the uveoscleral pathway, the suprachoroidal space, the anterior chamber, the capsular bag, the vitreous humor, and / or Schlemm's canal. The implant slowly releases the protein drug at a concentration that can treat the patient. In some embodiments, the concentration of the protein drug may be in the range of about 100 to about 150 mg / mL, about 150 to about 200 mg / mL, about 200 to about 250 mg / mL, about 250 to about 300 mg / mL, about 300 to about 350 mg / mL, about 350 to about 400 mg / mL, about 400 to about 450 mg / mL, about 450 to about 500 mg / mL, and / or concentrations therebetween. In some preferred embodiments, the concentration is in the range of about 200 to about 300 mg / mL. The release rate may be for an extended period of time, for example, 1 to 2 hours, 2 to 6 hours, 6 to 12 hours, 12 to 24 hours, 1 to 2 days, 1 to 7 days, 1 to 2 months, 1 to 6 months, 6 to 12 months, and / or 12 to 24 months or more. The implants can be used to treat a variety of posterior ocular diseases, such as age-related macular degeneration, diabetic macular edema, and / or diabetic retinopathy, among other diseases.

[0064] In some embodiments, a hybrid structure is employed in the delivery device that includes both bioabsorbable and non-bioabsorbable materials. In some embodiments, possible non-bioabsorbable components include, but are not limited to, steel, titanium, or non-bioabsorbable polymer frit materials. In some embodiments, the non-bioabsorbable materials may form the tubular portion, or end caps, or membranes of the device, as discussed in more structural detail below. In such embodiments, the bioabsorbable materials may optionally form the remaining portions of the device.

[0065] As discussed in more detail below, some embodiments of the present invention provide near zero order elution of protein drugs for extended periods of time while utilizing a bioabsorbable shell to allow patients to receive multiple doses in succession without significant debris accumulation in the eye.

[0066] The implants according to the embodiments disclosed herein are preferably implanted with devices that do not require osmotic or ionic gradients for the release of drugs, and can be used to reduce ocular morbidity by minimizing trauma to healthy ocular tissues, and / or deliver one or more drugs in a targeted and controlled release manner to treat multiple or single ocular conditions and their symptoms. However, in some embodiments, an osmotic or ionic gradient is used to trigger, control (in whole or in part), or regulate the release of a drug (or drugs) from the implant. In some embodiments, the osmotic pressure is balanced between the interior of the implant and the ocular fluid, resulting in no appreciable gradient (either osmotic or ionic). In such embodiments, a variable amount of solute is added to the drug in the device to balance the pressure.

[0067] As used herein, "drug" generally refers to one or more drugs that can be administered alone, in combination and / or in admixture with one or more pharma- ceutically acceptable excipients (e.g., binders, disintegrants, fillers, diluents, lubricants, drug release-controlling polymers, other agents, etc.), adjuvants, or compounds that can be contained within the implants described herein. The term "drug" is a broad term that can be used interchangeably with "therapeutic agent" and "pharmaceutical agent" or "drug" and includes so-called small molecule drugs, as well as macromolecular drugs and biological agents, including, but not limited to, proteins, nucleic acids, antibodies, etc., whether such drugs are natural, synthetic, or recombinant. Drug may refer to a drug alone or in combination with an excipient as described above. Drug may also refer to an active pharmaceutical agent or a prodrug, salt, or derivative thereof.

[0068] As used herein, "patient" shall have its ordinary meaning and shall refer to mammals in general. The term "mammal" includes, but is not limited to, humans, dogs, cats, rabbits, rodents, pigs, sheep, and primates, among others. Additionally, throughout this specification, ranges of values ​​are given along with lists of values ​​for particular parameters. It should be noted that in these cases, such disclosures include not only the values ​​in the list, but also the ranges of values, including integer and fractional values ​​between any two of the values ​​in the list.

[0069] "Biodegradable," as used herein, generally refers to the property of materials to be broken down and generally eliminated from the site of implantation after they are implanted in the human or animal body by any natural process occurring therein. Biodegradable includes, but is not limited to, bioerodible, bioresorbable, and bioabsorbable.

[0070] In some embodiments, a biocompatible drug delivery ocular implant is provided that includes an outer shell that is shaped to define at least one internal lumen that contains a drug for release into the ocular cavity. The outer shell is polymeric in some embodiments and is generally uniform in thickness in some embodiments. The outer shell is preferably elongated, tubular or cylindrical. In some embodiments, a cap is located at one or both ends of the shell and serves to regulate drug delivery in whole or in part. The outer shell may include one or more holes or openings and / or areas of increased or decreased thickness to modify or adjust the rate of drug delivery from the implant.

[0071] In some embodiments, a single layer or multiple layers of coating material can be used to cover (wholly or partially) the implant and any orifices (wholly or partially) to further control the drug release rate from the implant. For example, in some embodiments, a hydrogel can form a single layer or multiple layers of coating material covering (wholly or partially) the implant and / or any orifices (wholly or partially) as described above to further control the drug release rate from the implant. In some instances, the hydrogel forms a single layer of coating material along the inner wall of the implant. In some embodiments, the hydrogel forms a membrane and the drug must pass through the membrane to elute. In some embodiments, multiple layers of coating material can be used to further control the drug release rate from the implant. Each layer of coating material allows the drug to diffuse through each layer at a different rate. Additionally, in some embodiments, a combination of one or more orifices, a single layer or multiple layers covering one or more orifices, and a region of reduced thickness is used to tailor the drug release rate from the implant.

[0072] In some embodiments, the wall of the shell comprises at least one opening, orifice or hole. In some embodiments, the wall of the shell comprises a plurality of openings, orifices or holes, which may be arranged randomly or in a patterned array. The openings, orifices or holes in the wall of the shell may be open or may be covered with one or more coatings or membranes. In some embodiments where the device comprises a plurality of openings, orifices or holes through the shell, at least a portion of the plurality may be closed with a membrane permeable to the drug.

[0073] In some embodiments, elution of the drug (e.g., protein therapeutic) is regulated by diffusion out of the device through an orifice (as described above), another opening, hole, channel, hole, or preferably micropore provided through the tube wall, or through a cap, plug, or membrane at the end of the tube. The diameter of such elution regulating features is configured to be large enough to allow the passage of protein drug molecules. In some embodiments, these features are at least about 0.05, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3 μm (or more) in diameter.

[0074] In some embodiments, the orifice and / or elution hole can be tapered. Thus, the diameter of the orifice need not be constant. A tapered orifice can adjust and / or regulate the elution of the drug (e.g., protein therapeutic) depending on the degree of tapering of the orifice. In some embodiments, the taper of the orifice forms a cone-like shape. In some examples, the orifice can taper outward from the inner wall of the shell to the outer wall of the shell. For example, the tapered orifice can have an inner diameter along the inner wall of the shell and an outer diameter along the outer wall of the shell. The inner diameter of the orifice can be about 0.025, about 0.05, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3 μm (or more) in diameter. The outer diameter of the orifice can be about 0.025, about 0.05, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3 μm (or larger) in diameter.

[0075] The inner diameter can be smaller than the outer diameter of the orifice. For example, the taper of the orifice can extend radially outward from the inner diameter to the outer diameter. In some embodiments, the taper angle of a tapered orifice can be determined using the following formula:

[0076]

number

[0077] In some embodiments, the value of tan θ can range from about 0 to 1.73. In some embodiments, the taper angle can include an angle of about 0 to 5, about 5 to 10, about 10 to 15, about 15 to 20, about 20 to 25, about 25 to 30, about 30 to 35, about 35 to 40, about 40 to 45, about 45 to 50, about 50 to 55, about 55 to 60, and / or about 60 to 65 degrees relative to the axis extending from the proximal end to the distal end of the implant. This shape can control the drug elution rate after the implant is implanted in the eye. For example, the amount of drug eluted from the implant can be more effectively controlled by adjusting the inner and / or outer diameter of the orifice and / or the taper angle. In some cases, when the taper angle is larger, the drug elutes at a faster rate than when the taper angle is smaller. The size of the inner orifice diameter and the outer orifice diameter can be selected based on the flow rate or elution rate of the drug as it passes through the tapered orifice. In some embodiments, the elution or diffusion of the drug through the tapered orifice generally follows a modified Fick's equation such that at any given time, the rate of flow through the tapered orifice is a multiple of the rate of flow through a constant diameter orifice, as shown below:

[0078]

number

[0079] After implantation at a desired site in the eye, the drug is released from the implant in a targeted and controlled manner, preferably for an extended period of time, based on the design of various aspects of the implant. The implants and related methods disclosed herein can be used to treat conditions that require drug administration to specific tissues in the eye, such as the posterior chamber, anterior chamber, or macula, ciliary body, and other ocular target tissues. In some embodiments, the implant is configured to be placed in the punctum of a subject's eye to deliver one or more therapeutic agents. In some embodiments, the implant is placed in the punctum to deliver therapeutic agents to the tear film to target the cornea or anterior chamber and / or other ocular and / or orbital regions.

[0080] <General>

[0081] In some embodiments functioning as a sole drug delivery device, the implant is configured to deliver one or more drugs to the anterior region of the eye in a controlled manner, while in other embodiments, the implant is configured to deliver one or more drugs to the posterior region of the eye in a controlled manner. In yet other embodiments, the implant is configured to simultaneously deliver drugs to both the anterior and posterior regions of the eye in a controlled manner. In yet other embodiments, the implant is configured such that the drug is released in a targeted manner to a particular intraocular tissue, such as the macula or the ciliary body. In some embodiments, the implant delivers the drug to the ciliary process and / or the posterior chamber. In some other embodiments, the implant delivers the drug to one or more of the ciliary muscle and / or tendon (or fibrous band). In some embodiments, the implant delivers drugs to one or more of Schlemm's canal, trabecular meshwork, episcleral vein, lens cortex, lens epithelium, lens capsule, sclera, scleral promontory, vitreous humor, choroid, suprachoroidal space, retinal artery and vein, optic disc, central retinal vein, optic nerve, macula, fovea, and / or retina. In yet another embodiment, delivery of drugs from the implant targets the entire ocular chamber. In some embodiments, the implant is configured to be placed in the punctum to deliver one or more therapeutic agents (which can target the anterior chamber and / or another ocular region) or to be placed in the punctum to deliver to the tear film to target the cornea or anterior chamber and / or another ocular and / or orbital region. It should be understood that each of the embodiments described herein can target one or more of these regions, and are optionally combined with a shunt function (described below).

[0082] In some embodiments, the implant comprises an outer shell. In some embodiments, the outer shell is tubular and / or elongated. In some embodiments, the shell is formed with at least a first internal lumen. In certain embodiments, the lumen can run the entire length of the outer shell. In some embodiments, the lumen is subdivided. In further shunting embodiments, the shell can have one or more additional lumens within the portion of the device, with at least one such lumen acting as a shunt.

[0083] In a preferred embodiment, the outer shell is biodegradable. In a further embodiment, one or more or all additional parts of the device are also biodegradable, including but not limited to caps, membranes, clips and sealing members.

[0084] Suitable biodegradable materials for the manufacture of implants and their components include poly(esters), poly(ester amides) (PEA), poly(ester carbonates) (PEC), polylactic acid (PLA), poly(L-lactide) (PLLA), poly(D-lactide) (PDLA), poly(DL-lactic acid) (PDLLA), polyglycolide (PGA), poly(glycolide-co-lactide) (PGALA), poly(glycolic acid-co-lactic acid); polycaprolactone (PCL), copolymers such as polylactic acid-co-glycolide (PLGA), poly(hydroxyalkanoates), poly(3-hydroxybutyrate) (PHB), PHB copolymerized with 3-hydroxyvalerate (PHBV), These include, but are not limited to, natural polymers including, but not limited to, poly(propylene fumarate) (PPF), poly(anhydrides) (PAA), poly(butylene succinate) (PBS), poly(ethylene succinate) (PES), poly(hydroxyalkanoates) (PHAs), poly(acyanoacrylates) (PCA), polyacetals, polyorthoesters (POE), polycarbonates including poly(trimethylene carbonate) (PTMC), polyphosphazenes, polyphosphate esters, as well as blends, copolymers and combinations of the above, and modified polysaccharides, such as, for example, natural polymers including, but not limited to, starch, cellulose, and chitosan.

[0085] The degree, rate or timing of biodegradation can be modified or adjusted by any method or combination of methods to suit a specific application. A shorter biodegradation time can be achieved, for example, by increasing the surface-to-volume ratio of the shell, decreasing the wall thickness, modifying the surface topography by drilling, grooving or roughening, including holes or pores in the shell, making the shell more porous, and selecting a material that biodegrades more rapidly. A longer biodegradation time can be achieved, for example, by decreasing the surface-to-volume ratio of the shell, increasing the wall thickness, making the outer shell with a smooth surface topography, making the shell with minimal or no porosity, adding inner and / or outer membranes of a material that dissolves more slowly, and selecting a material that biodegrades more slowly. The degree, rate or timing of biodegradation can also be adjusted based on the placement of the implant. For example, for an implant placed in the punctum of the eye, a certain biodegradation rate of the implant may be desired. That rate may or may not be different from the desired biodegradation rate of an implant configured to be located, for example, within the eye (e.g., within the suprachoroidal space). Thus, in some embodiments, biodegradation of the punctal implant upon delivery of all or nearly all of its therapeutic load is desired, but the rate can be specifically tailored to suit the implant / patient, etc. In some embodiments, implant bioerosion is tailored to begin after delivery of all or nearly all of the drug load. In some embodiments, implant bioerosion is tailored to begin at least partially overlapping with drug elution.

[0086] In some embodiments, the drug (or drugs) is placed in the internal lumen (or internal lumens) of the implant shell. In some embodiments, the drug is preferentially placed in the more distal portion of the lumen. In some embodiments, the distal most 15 mm of the implant lumen (or lumens) contain the drug (or drugs) to be released. In some embodiments, the distal most 10 mm, including 1, 2, 3, 4, 5, 6, 7, 8, and 9 mm of the internal lumen, contain the drug to be released. In some embodiments, the drug is preferentially placed in the more proximal portion of the lumen. In some embodiments, the drug is placed approximately evenly throughout the lumen.

[0087] In some embodiments, the drug diffuses through the shell into the intraocular environment. In some embodiments, the outer shell material is permeable or semi-permeable to the drug (or drugs) disposed within the inner lumen, and therefore at least a portion of the total elution of the drug occurs through the shell itself in addition to any areas of increased permeability, reduced thickness, orifices, etc. In some embodiments, about 1% to about 50% of the drug elution occurs through the shell itself. In some embodiments, about 10% to about 40%, or about 20% to about 30% of the drug elution occurs through the shell itself. In some embodiments, about 5% to about 15%, about 10% to about 25%, about 15% to about 30%, about 20% to about 35%, about 25% to about 40%, about 30% to about 45%, or about 35% to about 50% of the drug elution occurs through the shell itself. In certain embodiments, about 1% to 15%, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14%, of the total elution of the drug (or drugs) occurs through the shell. The term "permeable" and related terms (e.g., "impermeable" or "semi-permeable") are used herein to refer to a material that is somewhat permeable (or not permeable) to one or more drugs or therapeutic agents and / or ocular fluids. The term "impermeable" does not necessarily mean that there is no elution or permeation of drugs through the material, but instead such elution or other permeation is negligible or negligible, e.g., less than about 3%, including less than about 2% and less than about 1% of the total elution.

[0088] In some embodiments, the implant includes a polymer coating on the exterior surface of the shell. In another embodiment, the implant includes a polymer coating on the interior surface of the shell. In yet another embodiment, the polymer coating is on both the interior and exterior surfaces. In yet another embodiment, the polymer coating is biodegradable. Some embodiments include a non-polymer coating (e.g., heparin) instead of or in addition to the polymer coating. Additionally, some embodiments use a combination of one or more orifices, a single layer or multiple layers covering the one or more orifices, and regions of reduced thickness to tailor the rate of drug release from the implant.

[0089] In some embodiments, the internal lumen containing the drug is separated from the proximal portion of the implant by a proximal obstruction in the internal lumen that prevents elution of the drug into the anterior portion of the eye. In some embodiments, the internal lumen containing the drug is separated from the proximal portion of the implant by a one-way valve in the internal lumen. The one-way valve prevents elution of the drug into the anterior portion of the eye but allows ocular fluid from the anterior portion of the eye to reach the internal lumen containing the drug.

[0090] In some embodiments, the implant further comprises a proximal portion configured to reload / refill the implant with the same or additional therapeutic agents, multiple drugs, or one or more adjuvant compounds.

[0091] In some embodiments including a shunt, the shunt portion drains fluid from the ocular chamber to a physiological outflow space after implantation at the implantation site, reducing intraocular pressure. In some embodiments, the implant is dimensioned such that when the proximal or distal end of the implant is at the implantation site near the target tissue for drug delivery, the outflow port of the implant drains ocular fluid to a remote area and / or physiological outflow pathway. For example, the punctal implants disclosed herein (and U.S. Provisional Patent Application No. 62 / 054833, filed Sep. 24, 2014, which is incorporated herein by reference in its entirety) can also include one or more drainage cavities that drain tears to the nasolacrimal duct. Other implants disclosed herein can be configured to drain ocular fluid from the anterior chamber, for example, to the suprachoroidal space. Drainage is not included in some embodiments of punctal implants and is not included in some embodiments of implants for intraocular placement.

[0092] For example, in some embodiments, the implant is dimensioned such that after implantation, the distal end of the implant is close enough to the macula that drugs delivered by the implant reach the macula. In some embodiments incorporating a shunting feature, the implant is dimensioned such that when the distal end of the implant is placed close enough to the macula, the proximal end of the implant extends into the anterior chamber. In these embodiments, the outflow outlet of the implant, described in more detail below, is positioned to drain aqueous humor into the uveoscleral pathway or other physiological outflow pathway.

[0093] In yet another embodiment, the combined drug delivery and shunt implant can be placed in any physiological location that requires simultaneous drug delivery and fluid transport from a first physiological site to a second site (which can be a physiological site or external to the patient). In some embodiments, the shunt function works in conjunction with the drug delivery function to enhance the therapeutic effect of the delivered agent. In another embodiment, the therapeutic effect of the delivered agent may be accompanied by undesirable side effects such as fluid accumulation, swelling, etc. In some embodiments, the shunt function reduces the side effects of the delivered agent. It is understood that the dimensions and functions of the implants disclosed herein can be tailored to target and / or control delivery to various regions of the eye while maintaining communication with physiological outflow pathways.

[0094] For example, in some embodiments, the implant is dimensioned such that after implantation, 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. In some embodiments, drug eluted from the implant elutes from the proximal end of the implant into the anterior chamber. In some embodiments incorporating a shunting feature, one or more outlets of the implant are positioned to allow aqueous humor to drain into the uveoscleral pathway. In some embodiments, aqueous humor drains from the anterior chamber into the suprachoroidal space.

[0095] The delivery device, described in more detail below, can be used to facilitate delivery and / or implantation of the drug delivery implant to a desired location in the eye. The delivery device can be used to place the implant in a desired location, such as any length of the suprachoroidal space, including up to and near the macula, from the anterior chamber to the suprachoroidal space, or any other intraocular region, by applying a continuous implantation force, by tapping the implant into position with a distal portion of the delivery device, by activation of a stored energy source in the delivery device, or by a combination of these methods. The design of the delivery device can take into account, for example, the implantation angle and the location of the implant relative to the incision. For example, in some embodiments, the delivery device can have a fixed shape, can be shaped adjustable, or can be actuated. In some embodiments, the delivery device can have ancillary or auxiliary functions, such as, for example, injection of dyes and / or viscoelastic fluids, incision, use as a guidewire, etc. The term "incision" as used herein shall have its ordinary meaning and may also refer to an incision, an opening, a slit, a notch, a puncture, and the like.

[0096] In certain embodiments, the drug delivery implant can include one or more drugs that may or may not be mixed with a biodegradable polymer or a biodegradable polymer and at least one additional agent.

[0097] <Drug delivery implants>

[0098] The present disclosure relates to an ocular drug delivery implant that, after implantation at an implantation site, controls and releases one or more drugs to a desired target area within the eye, over an extended period of time. Although various embodiments of the implant are illustrated and referenced herein, it will be understood by those skilled in the art that the present invention is not limited to the illustrated embodiments, and that the features of the illustrated embodiments are interchangeable and / or may be substituted or further comprised by features disclosed herein.

[0099] The outer shell of the implant can be manufactured by extrusion, stretching, injection molding, micromachining, laser machining, or any combination thereof. Other suitable manufacturing and assembly methods known in the art can also be used. In some embodiments, the outer shell is elongated, cylindrical or tubular, and includes at least one internal lumen. In some embodiments, the internal lumen is defined by the outer shell and a partition. In some embodiments, the partition is impermeable, and in other embodiments, the partition is permeable or semi-permeable. In some embodiments, the partition allows the implant to be reloaded with a new dose of drug. In some embodiments, the thickness of the outer shell is approximately uniform. In other embodiments, the thickness varies in certain areas of the shell. Depending on the desired implantation site in the eye, thicker areas of the outer shell are located where necessary to maintain the structural integrity of the implant. In some embodiments, the implant is made of a flexible material.

[0100] In some embodiments, the shell also has one or more specific regions of drug release or one or more specific regions of enhanced drug release compared to the remainder of the shell. In some embodiments, the drug release regions are of reduced thickness compared to the adjacent and surrounding thickness of the shell. In some embodiments, the reduced thickness regions are formed by one or more of ablation, stretching, etching, grinding, molding, and other similar techniques that remove material from the shell. In other embodiments, the drug release regions are formed with a different thickness (e.g., some embodiments are thinner and some are thicker) compared to the surrounding shell, but with a higher permeability to one or more of the drug and ocular fluid. In yet other embodiments, the shell is constructed with materials that are uniform or nearly uniform in thickness, but with different permeability to the ocular fluid and drug in the lumen. Thus, these embodiments have distinct regions of drug release from the implant. The drug release regions can be of any shape necessary to adequately deliver the drug to a specific target tissue of the eye.

[0101] In some embodiments, the implant is self-trepanning. In some embodiments, the distal end of the implant is sharp enough to penetrate ocular tissue, such as the cornea, limbus, or near the scleral promontory of the eye. In other embodiments, the distal end is rounded, blunt, or not sharp, but is still suitable for performing blunt dissection of two tissue planes, preferably non-invasively, or for penetrating certain internal ocular tissue. In either case, the distal portion can be sufficiently blunt so as not to substantially penetrate the scleral tissue of the eye.

[0102] In some embodiments, the implant incorporates flexible outwardly extending extensions, e.g., fixation or retention features such as ridges, ribs, barbs, ridges, threads, or protrusions that extend from the outer surface of the implant to inhibit migration of the implant from its implanted location. In some embodiments, inwardly extending features such as grooves help to retain the implant. Such features extend around the entire circumference of the implant or around only a portion of the circumference. The extensions can be separate parts attached to the implant, can be integrally formed with the implant, or can be added in a separate manufacturing step. The extensions can be located at the proximal or distal ends or regions of the implant, or both, to prevent the implant from being extruded or migrating from its intended location in the eye. In some embodiments, the extensions are longitudinally disposed along the implant. The spacing between the extensions can be regular or irregular. The flexibility of the retention features may facilitate entry through the corneal incision and through the ciliary muscle attachment tissue or other tissue. In some embodiments, the irregular surface serves to prevent host tissue growth (e.g., fibrous growth) into or onto the implant, which may reduce drug elution efficiency in some embodiments.

[0103] In some embodiments, the implant has an outer diameter that allows the implant to be fitted into a 23 gauge needle during implantation. The implant can also have a diameter designed for insertion with a larger needle. For example, the implant can be delivered with an 18 gauge, 19 gauge or 20 gauge needle. In another embodiment, a smaller gauge applicator, such as 23 gauge or smaller, is used. In some embodiments, the implant has a generally constant cross-sectional shape throughout the majority of its length. Alternatively, the implant can have a portion of decreasing or increasing cross-sectional size (e.g., diameter) along its length. In some embodiments, the distal end of the implant has a tapered portion, or a portion of continuously decreasing radial dimension relative to the luminal axis along the length of the shaft. The tapered portion preferably terminates in a smaller radial dimension at the distal end in some embodiments. During implantation, the tapered portion can be manipulated to form, expand and / or increase the size of the incision or puncture formed in the tissue. The diameter of the tapered portion can be about 30 gauge to about 23 gauge, preferably about 25 gauge. As described herein, in some embodiments, the device can be tubular and can be injected into the vitreous through a needle (although other shapes are used in some embodiments). The diameter of such tubular implants can range from about 0.1 to about 0.8 mm, about 0.2 to about 0.8 mm, about 0.3 to about 0.8 mm, about 0.4 to about 0.8 mm, preferably about 0.3 to about 0.6 mm. In some embodiments, the device can range in length from about 1 to about 15 mm, including about 2 to about 15 mm, about 4 to about 15 mm, about 5 to about 15 mm, about 5 to about 15 mm, about 5 to about 14 mm, about 5 to about 13 mm, about 5 to about 12 mm, about 5 to about 11 mm, about 2 to about 11 mm, about 3 to about 11 mm, preferably 5 to 10 mm long. Diameter and length ranges in between are also contemplated.

[0104] In some embodiments, the drug is formulated or compounded with additional compounds. In some embodiments, the drug is in the form of a drug-containing pellet. Some embodiments of the therapeutic or therapeutic agent include a drug mixed with a polymer formulation. In certain embodiments, the polymer formulation includes poly(lactic-co-glycolic acid), i.e., PLGA copolymer, or other biodegradable (e.g., bioerodible, bioabsorbable) polymers.

[0105] Drugs are generally disposed within the lumens of the implants described herein and are omitted from most figures for clarity in illustrating other features of the implant, however, it should be understood that all embodiments herein optionally include one or more drugs.

[0106] In some embodiments, the implant further comprises a coating that can be disposed at various locations in or on the implant. In some embodiments, the coating is a polymer coating. The coating is optionally biodegradable. Some other embodiments can include an implant made entirely of a biodegradable material, where the entire implant degrades over time. In some embodiments, the coating is disposed over the entire implant (e.g., encases the implant), while in other embodiments, only a portion of the implant is covered. In some embodiments, the coating is on the exterior surface of the implant. In some embodiments, the coating is disposed on the lumen wall within the implant instead of, or in addition to, the exterior of the implant or shell. Similarly, in some embodiments where the coating is disposed on the interior of the implant, the coating covers the entire interior surface of the lumen, while in other embodiments, only a portion of the interior surface is covered.

[0107] In addition to functioning as a drug delivery device, some embodiments of the implant may also include a shunt. As used herein, the term "shunt" is a broad term having its ordinary meaning to one of ordinary skill in the art (not limited to any particular or specific meaning) and refers to, but is not limited to, a portion of the implant that defines one or more flow paths for transporting fluid from a first, often undesirable location to one or more other locations. In some embodiments, the shunt can be configured to be a fluid flow path that drains aqueous humor from the anterior chamber to an outflow pathway to reduce intraocular pressure.

[0108] The shunt portion of the implant can have an inflow portion and an outflow portion. The inflow portion or inlet can be located at or near the proximal end of the implant. The inlet can include one or more openings. The shunt outflow portion can be located at or near the distal end of the implant and can include one or more openings. In some implants, especially longer implants configured to extend to the macula or another structure at the back of the eye, the outflow portion can be present in the middle section of the implant, or both the middle and distal sections. In some embodiments, when the implant is deployed, the inflow portion can be sized and configured to be present in the anterior chamber, and the outflow portion can be sized and configured to be present in the supraciliary or suprachoroidal space. In some embodiments, the outflow portion can be sized and configured to be present in the supraciliary region of the uveoscleral pathway, the suprachoroidal space, another portion of the eye, or another physiological space susceptible to fluid attachment.

[0109] In some embodiments, at least one lumen extends through the shunt portion of the implant. In some embodiments, there is at least one lumen that serves to direct fluid through the shunt portion of the implant. In certain embodiments, each lumen extends along the lumen axis from the inflow end to the outflow end. In some embodiments, a lumen extends substantially through the longitudinal center of the shunt such that it is coaxial with the drug lumen. In other embodiments, a lumen can be offset from the longitudinal center of the shunt such that it and the drug lumen are in a side-by-side arrangement.

[0110] In some embodiments of the implant, including implants that extend far into the posterior segment, the shunt section of the implant and the drug delivery section of the implant are separate, with the drug delivery section toward the distal end and the shunt section toward the proximal end. In such embodiments, the most proximal outflow orifice on the implant is located at or within 10 mm of the proximal end of the implant. The outflow orifice can be located anywhere distal to the inflow location. In some embodiments, the shunt section and the drug section overlap to some extent and can have a coaxial or parallel arrangement as described above.

[0111] FIG. 2A shows an embodiment of a drug-eluting implant 430 that includes a coaxial shunt that can serve to drain fluid from the anterior chamber to a natural outflow pathway, such as the uveoscleral pathway (e.g., the suprachoroidal space). The internal lumen 436 of the implant 430 can communicate with an inflow or inlet 432 and an outflow or outlet 434. The drug can be located in the space between the internal lumen and the outer shell. There can be a wall separating the drug from the drainage space, or they can be in contact with a solid drug or formulation, forming the wall of the internal lumen. When implanted, the inflow 432 is sized and configured to be located in the anterior chamber, and the outflow 434 is sized and configured to be located in the suprachoroidal space. The drug can be eluted directly from the inflow, or through a cap (not shown) and / or through the wall of the implant. As the drug elutes from the implant, the fluid can be directed through the internal lumen 436 of the implant.

[0112] The implant 430 can be sized with an outer diameter that allows the implant 430 to be fitted into a 21 or 23 gauge needle or hollow instrument during implantation, although larger or smaller gauge instruments or another dedicated delivery device can be used. The implant 430 can also have a diameter designed for delivery with a larger needle. For example, the implant 430 can be delivered with an 18, 19 or 20 gauge needle. The implant 430 can have a constant diameter throughout the majority of its length. In some embodiments, the implant 430 includes a retention feature 446 that acts to mechanically lock or secure the implant 430 in place when implanted. In some embodiments, the retention feature 446 includes a reduced diameter portion, e.g., an annular groove, between the proximal end 438 and the distal end 440. In some embodiments, the retention feature 446 includes barbs or other projections extending from the outer surface of the implant 430 to prevent the implant 430 from migrating from its implanted position, as described above.

[0113] 2B, for example, some embodiments of the implant 430 have a plurality of annular ribs 448 formed on an outer surface of the implant 430. The annular ribs 448 can be longitudinally spaced along the implant 430 between the proximal end 438 and the distal end 440. The spacing of the annular ribs 448 can be regular or irregular.

[0114] The outflow section 434 of the implant 430 is preferably located at or near the distal end 440 of the implant 430. In the embodiment shown in FIG. 2A, the outflow section 434 is a tapered distal section 444, but can have other shapes, including a non-tapered or more gradually tapered shape. The tapered distal section 444 terminates in a smaller radial dimension at the outflow end or outlet 440. During implantation, the tapered section 444 can act alone or in cooperation with a guidewire, trocar, or other portion of a delivery instrument disposed within the internal lumen 436 that is flush with or extends beyond the end of the implant, to form, enlarge, and / or increase the size of an incision or puncture made in tissue. For example, the distal end 440 can function as a trocar to pierce or make an incision in tissue. After the distal end 440 of the implant 430 has been advanced, the tapered portion 444 may be advanced through the puncture or incision. As the tapered portion 444 advances through tissue, it acts to widen or expand the tissue surrounding the puncture or incision to accommodate the increasing size of the tapered portion 444. Some embodiments of the implant (for intraocular or intrapunctal placement) do not include drainage.

[0115] The tapered portion 444 may also facilitate proper placement of the implant 430 in the supraciliary or suprachoroidal space. For example, the implant 430 is preferably advanced through tissue in the anterior chamber angle during implantation. This tissue is generally fibrous or porous and is relatively easy to pierce or cut with a surgical device such as the tip of the implant 430. The implant 430 may advance through this tissue and extend into the uveoscleral tract to abut the sclera. As the implant 430 abuts the sclera, the tapered portion 444 preferably provides a generally rounded edge or surface that facilitates sliding of the implant 430 in the suprachoroidal space along the inner wall of the sclera. For example, as the implant 430 advances into the uveoscleral tract to abut the sclera, the implant 430 may be oriented at an angle relative to the inner wall of the sclera. As the tip of the implant 430 enters the sclera, the tip preferably has a radius that allows the implant 430 to slide along the sclera instead of perforating or substantially penetrating the sclera. As the implant 430 slides along the sclera, the tapered portion 444 provides an edge that the implant 430 can abut against the sclera, reducing the likelihood that the implant 430 will perforate the sclera.

[0116] For ease of understanding, only a few of the possible embodiments of the various retention projections are shown, and it should be understood that any implant embodiment may be readily combined with any of the retention projections disclosed herein.

[0117] 3A-3D show examples of implants. The implants may include the same or similar features as other implants described herein. As discussed above, the implants may include an outer shell 54. The outer shell 54 may include one or more orifices. For example, in some embodiments, one or more orifices 56a across the thickness of the outer shell 54 provide a pathway of communication between the environment outside the implant and the inner lumen 58 of the implant (FIGS. 3A-3D). The one or more orifices are formed through the implant shell by drilling holes in the various shells of the individual implants or by any other technique known in the art. The orifices may be of any shape, such as spherical, cubic, ellipsoidal, etc. The number, location, size, and shape of the orifices formed in a given implant will determine the ratio of orifice to implant surface area. This ratio may vary depending on the desired release profile of the drug delivered by a particular embodiment of the implant, as shown below. In some embodiments, the surface area ratio of the orifice to the implant is greater than about 1:100. In some embodiments, the surface area ratio of the orifice to the implant ranges from about 1:10 to about 1:50, from about 1:30 to about 1:90, from about 1:20 to about 1:70, from about 1:30 to about 1:60, from about 1:40 to about 1:50. In some embodiments, the surface area ratio of the orifice to the implant ranges from about 1:60 to about 1:100, including about 1:70, 1:80, and 1:90.

[0118] In some embodiments, the shell may include one or more orifices 56b at or near the distal tip of the implant, as shown, for example, in Figures 3A-3D. The shape and size of the orifices may be selected based on the desired elution profile. Yet another embodiment includes a combination of a distal orifice and multiple orifices located more proximally in the shell. Yet another embodiment includes a combination of distal orifices, proximal orifices and / or drug release regions (and possibly one or more coatings) in the shell. Yet another embodiment has a closed distal end. In such embodiments, the drug release regions (based on shell thickness / permeability, orifices, coatings, drug placement, etc.) may be aligned along the long axis of the implant. Such a configuration is advantageous in reducing the amount of tissue damage resulting from the advancing distal end during some embodiments of the implantation procedures disclosed herein.

[0119] In some embodiments, the distal orifice comprises a biodegradable or bioerodible plug 61 having multiple orifices 56b that maintains drug elution from the implant if one or more of the orifices become blocked by tissue during insertion / implantation. In other embodiments, the orifice may comprise a permeable or semi-permeable membrane, porous film or sheet, or the like. In some such embodiments, the permeable or semi-permeable membrane, film or sheet may be on the outside of the shell and cover the orifice, on the inside of the shell and cover the orifice, or both. The permeability of the material determines in part the rate of drug release from the implant, as described in more detail below. Such membranes, sheets or films are useful in embodiments where the outer shell orifice is elongated.

[0120] In some embodiments, an additional structure or structures within the lumen can at least partially control the elution of the drug from the implant. In addition to or instead of a single or multiple layers of permeable or semi-permeable material that can be used to encase the drug, FIGS. 3A-3D show an implant. The implant can have an outer shell, an inner plug 210, and a drug reservoir that is at least partially filled with the drug 62. In some embodiments, the inner plug 210 is located between the drug 62 and the various orifices 56a, 56b of the outer shell 54. For example, the inner plug 210 need not completely surround the drug. However, as discussed below, in some embodiments, the inner plug 210 at least partially or entirely surrounds the drug 62. In some embodiments, the material of the inner plug 210 is different from the shell 54, and in some embodiments, the material of the inner plug 210 is the same material as the shell 54. Suitable materials for the inner plug include, but are not limited to, agarose or hydrogels, among others. As discussed above, the hydrogel may include, among others, polyacrylamide, polymethylmethacrylate, HEMA (hydroxyethyl methacrylate), polyethylene glycol, polyethylene oxide, polyethylene oxide-co-propylene oxide, co-polyethylene oxide block or random copolymers, polyvinyl alcohol, poly(vinylpyrrolidinone), hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, polyvinyl acetate, gelatin, and / or polyvinylpyrrolidone. Additional materials disclosed herein for use in the shell or other portions of the implant may be suitable for the inner plug in certain embodiments.

[0121] In some embodiments, the size, density, porosity, or permeability of the hydrogel plug 210 may differ from the shell 54. In some embodiments, the hydrogel is formed in place (i.e., within the internal lumen of the implant), for example, by polymerizing, molding, or solidifying in situ a dispensed liquid, powder, crystal, or gel. In some embodiments, the hydrogel plug is preformed outside the shell and placed within the shell prior to implantation. In such embodiments, a customized implant can be constructed and the selection of the preformed internal plug can be optimized based on the individual drug, patient, implant, and / or disease being treated.

[0122] In some embodiments, the hydrogel plug can be dehydrated or partially shrunken / dehydrated before being placed in the shell 54 prior to implantation. For example, in a dehydrated state, the hydrogel plug can be shrunken to only about 10% of its fully hydrated volume, and in other embodiments, it is 95%, 90%, 85%, 80% or 75% of its fully hydrated volume in the implant. In some embodiments, the hydrogel can be hydrated and swelled within the shell 54 prior to implantation and / or before being placed within the shell 54. In some embodiments, the hydrogel plug can include a "fugitive" material or solvent, such as plasticizers, glycerin, among others, that are biocompatible. The fugitive material flows out of the implant after implantation and is replaced by ocular fluid. The material can thus trigger the flow and / or elution of the drug from the implant. For example, the flow of the material can cause the plug to become more permeable to the drug, allowing the drug to pass through the hydrogel plug. In some embodiments, the material can prevent and / or minimize shrinkage or degradation of the drug prior to and / or during elution, or while the implant is stored and transported prior to use.

[0123] As discussed above, in some embodiments, the hydrogel plug can be biodegradable or bioerodible. In some other embodiments, the hydrogel plug is durable (e.g., neither biodegradable nor bioerodible). In some embodiments, the hydrogel plug is advantageously non-toxic, water soluble, bioerodible, hydrophilic, highly absorbent, and / or flexible.

[0124] As shown in FIGS. 3A-3D , a hydrogel plug 210 can be located within the outer shell 54. In some embodiments, the hydrogel plug can be located adjacent to the drug 62. The hydrogel plug 210 can be located adjacent to a distal-most end of the outer shell 54. For example, the drug can be located adjacent to the plug 210 and / or proximal to the plug 210. As discussed herein, the drug 62 can be partially or completely surrounded by the hydrogel plug. In some embodiments, the plug 210 can include a mixture of a hydrogel and a drug.

[0125] Various amounts of hydrogel and drug can be implemented in certain embodiments of the implant. For example, the volume ratio of drug to hydrogel located within the eluting implant is greater than about 1:1. In some embodiments, the volume ratio of drug to hydrogel located within the eluting implant ranges from about 1:1 to about 2:1, about 2:1 to about 5:2, about 5:2 to about 3:1, about 3:1 to about 7:2, about 7:2 to about 4:1, about 4:1 to about 9:2, and / or other ranges. In some embodiments, the volume ratio of drug to hydrogel located within the eluting implant ranges from about 1:1 to about 1:2, about 1:2 to about 1:3, about 1:3 to about 1:4, among other ranges. As discussed above, the drug can be dispersed within the hydrogel. In such configurations, all or a portion of the drug can be dispersed within the hydrogel. For example, at least 50% of the volume of the mixture can include the drug, as discussed above.

[0126] In some embodiments, the internal plug may be attached or bonded adjacent to the inner wall of the shell. For example, the hydrogel plug is preferably permeable to the drug, thereby allowing the drug to pass through the plug and through the orifice to the target tissue. In some embodiments, the hydrogel plug is also permeable to bodily fluids, allowing fluids from outside the implant to reach the drug. The overall drug release rate from the device may be controlled by the physical properties of several aspects of the implant components, including, but not limited to, the area and volume of the orifice, the surface area of ​​any drug release regions, the composition and / or size or location of the hydrogel plug relative to both the drug and the orifice and / or the drug release regions, and the permeability of the hydrogel plug to the drug and bodily fluids. Additionally, in some embodiments, the hydrogel plug increases the path length between the drug and the orifice and / or the drug release region, thereby providing an additional control point for the drug release rate. For example, the drug may be configured to pass through all and / or a portion of the hydrogel plug 210 toward the target tissue. Elution of the drug through the hydrogel may occur for a period of between 2 weeks and 1 year. In some embodiments, elution of the drug through the hydrogel can occur for periods of 2 weeks to 3 years, 1 day to 1 week, 1 week to 2 weeks, 2 weeks to 4 weeks, 1 month to 2 months, 2 months to 4 months, 4 months to 8 months, 4 months to 6 months, 6 months to 1 year, 1 year to 2 years, 2 years to 3 years, and / or longer.

[0127] In some alternative embodiments, the hydrogel plug 210 may be more loosely attached to the inner lumen of the shell, thereby allowing flow or transport of the drug around the plug (see FIG. 3B). In yet other embodiments, the hydrogel plug may include two or more pieces or portions. In some embodiments, the drug may elute from the implant by passing through gaps between the hydrogel plug and the inner wall of the shell. The drug may also elute from the implant by passing through gaps in a portion or portion of the hydrogel plug. The drug may also elute from the implant by passing through a permeable inner plug. Similarly, bodily fluids may enter the implant from outside the implant and reach the drug by any of these or other routes. Elution of the drug may occur as a result of any combination of these passages or permeation routes.

[0128] As shown in FIG. 3A, the implant can include a proximal obstruction 64a. In some embodiments, the proximal obstruction 64a is located proximal to the drug 62 (see FIGS. 3A-3D). The proximal obstruction 64a can be located adjacent to the drug, hydrogel plug, and / or hydrogel-drug mixture. In some embodiments, the proximal obstruction 64a can form the proximal end of the implant. In some embodiments, the proximal obstruction 64a is located within the implant. In some embodiments, the proximal obstruction 64a can include an optional shunt feature. The optional shunt feature can include an outflow opening 66 in communication with a proximal inflow lumen 68 located in the proximal region 52 of the implant. In some embodiments, the optional shunt feature can include an outflow opening in communication with a portion of the eye. For example, in some embodiments, the opening 66 can allow the implant to drain fluid when the implant is implanted within the eye. In some embodiments, elution of the drug from the implant can cause a spike and / or increase in intraocular pressure. Evacuation of fluid from the proximal end of the implant through openings 66 can, for example, help reduce swelling and / or intraocular pressure. In some embodiments, evacuation of fluid through openings 66 can help accelerate the elution of drug 62.

[0129] In some embodiments, the orifice 56a is covered (wholly or partially) with one or more eluting membranes 100 that provide an obstacle to the release of the drug 62 from the inner lumen 58 of the implant shell 54. In some embodiments, the eluting membrane is permeable to the therapeutic agent, bodily fluids, or both. In some embodiments, the membrane is elastic and comprises silicone. In other embodiments, the membrane can be coated wholly or partially with a biodegradable or bioerodible material to control the influx of bodily fluids or the initiation of release of the therapeutic agent from the implant. In some embodiments, the membrane is impregnated with additional agents that are beneficial, such as anti-fibrotic agents, vasodilators, anti-thrombotic agents, or permeability control agents. Additionally, in some embodiments, the membrane includes one or more layers 100a, 100b, and 100c that can, for example, exhibit specific permeability.

[0130] In some embodiments, the outer shell 54 can be coated with a coating. In some embodiments, the coating is a polymer coating. The coating can be biodegradable in some cases. Some other embodiments can include an implant made entirely of a biodegradable material, with the entire implant degrading over time. In some embodiments, the coating is placed over the entire implant (e.g., encases the implant), while in other embodiments, only a portion of the implant is covered. In some embodiments, the coating is on the outer surface of the implant. In some embodiments, the coating is placed on the luminal wall within the implant instead of, or in addition to, the exterior of the implant or shell, as discussed below. The coating can help control the elution of the drug through the shell. In some embodiments, the coating can help extend the life of the implant (e.g., the shell). For example, in some embodiments, the coating can bioerode over time. The coating can bioerode and / or dissolve at the same or similar rate as the drug elutes through the shell. In some embodiments, the coating bioerodes at a faster rate than the drug elutes through the shell. In some embodiments, the coating can inhibit and / or prevent the shell from bioeroding. For example, in some embodiments, the coating can help to prevent or inhibit biodegradation of part or all of the shell until all or part of the drug elutes through the shell (e.g., after all or part of the treatment has been provided to the patient). For example, in some embodiments, the coating can cause the shell 54 to bioerode or dissolve at a slower rate while the drug is being administered to the patient and / or at a faster rate once the treatment is complete or nearly complete.

[0131] As with the hydrogel plugs and drug release regions described herein, the properties of the elution membrane at least partially determine the release rate of the therapeutic agent from the implant. Thus, the overall drug release rate from the implant can be controlled by the physical properties of the implant, including, but not limited to, the area and volume of the orifice, the surface area of ​​any drug release region, the size and location of any hydrogel plug relative to both the drug and the orifice and / or the drug release region, and the permeability of any layer covering any orifice or drug release region to drug and body fluids.

[0132] In some embodiments, the implants described herein can be sized and shaped to be implanted in or through various regions of the eye. For example, the implant can be located in the supraciliary space, the suprachoroidal space, Schlemm's canal, the anterior chamber, the vitreous humor, or the lens capsule. In some embodiments, the implant can be located entirely in the anterior and / or posterior chamber. In some embodiments, the implant is located partially in the anterior and / or posterior chamber. In some embodiments, the implant is positioned in the vitreous humor or cavity such that the implant is not located in the optical axis or visual axis.

[0133] Some embodiments disclosed herein are dimensioned to be entirely contained within the subject's eye, and the dimensions can be obtained for each subject by standard ophthalmic techniques. After completion of the implantation procedure, in some embodiments, the proximal end of the device can be located at or near the anterior chamber, and the distal end of the implant can be located anywhere within the suprachoroidal space. In some embodiments, the distal end of the implant is located near the limbus. In other embodiments, the distal end of the implant is located near the macula in the posterior region of the eye. In other embodiments, the proximal end of the device can be located at or near another region of the eye, such as the vitreous chamber, the vitreous cavity, etc. In some such embodiments, the distal end of the device can also be located at or near another region of the eye. The term "near" is sometimes used interchangeably herein with "at," but depending on the context, it can refer to a distance close enough for the drug to diffuse from the implant to the target tissue. In yet another embodiment, the implant is dimensioned to span the distance between a first non-ocular physiological space and a second non-ocular physiological space.

[0134] In one embodiment, the drug delivery implant is positioned in the suprachoroidal space by advancing it through the ciliary attachment tissue posterior to the scleral spur. The ciliary attachment tissue is generally fibrous or porous and is relatively easy to pierce, cut or separate from the scleral spur using a delivery instrument disclosed herein or another surgical device. In such an embodiment, the implant is advanced through this tissue and abuts or contacts the sclera as it extends into the uveoscleral pathway. The implant is advanced along the inner wall of the sclera within the uveoscleral pathway until it reaches the desired implantation site within the posterior portion of the pathway.

[0135] In some embodiments, the total length of the implant is 1-30 mm in length. In some embodiments, the length of the implant is 2-25 mm, 6-25 mm, 8-25 mm, 10-30 mm, 15-25 mm, or 15-18 mm. In some embodiments, the length of the implant is about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mm, and the delivery device containing the implant can be inserted and advanced through the cornea to the iris, creating only a self-sealing puncture in the cornea, and in some embodiments, the outer diameter of the implant is about 100-600 microns. In some embodiments, the diameter of the implant is about 150-500 microns, about 125-550 microns, or about 175-475 microns. In some embodiments, the diameter of the implant is about 100, 125, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 460, 470, 475, 480, 490, or 500 microns. In some embodiments, the inner diameter of the implant is about 50-500 microns. In some embodiments, the inner diameter is about 100-450 microns, 150-500 microns, or 75-475 microns. In some embodiments, the inner diameter is about 80, 90, 100, 110, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 410, 420, 425, 430, 440 or 450 microns.

[0136] The implant can be sized to have an outer diameter that allows the implant to be fitted into a 23-25 ​​gauge needle or hollow instrument during implantation, although larger or smaller gauge instruments or another dedicated delivery device can be used. For example, the implant can be sized to have an outer diameter that allows the implant to be fitted into an 18 gauge needle, 19 gauge needle, 20 gauge needle, 21 gauge needle, 22 gauge needle, 23 gauge needle, 24 gauge needle, 25 gauge needle, 26 gauge needle, 27 gauge needle, 28 gauge needle, 29 gauge needle, and / or 30 gauge needle. The implant can have a constant diameter throughout all or a portion of its length. In some embodiments, the implant can be sized and shaped to be fitted into a thin walled needle, such as an ultra thin walled needle. Implant embodiments can have a maximum outer diameter of about 0.1-0.5 mm, including 0.15-0.45 mm, 0.2-0.4 mm, and 0.25-0.35 mm.

[0137] In further embodiments, the internal lumen of the implant may be coated with a layer of hydrophilic material to increase the rate of contact between ocular fluid and the therapeutic agent or agents disposed within the lumen. In one embodiment, the hydrophilic material is permeable to ocular fluid and / or drugs. Conversely, the internal lumen may be coated with a layer of hydrophobic material to cooperatively inhibit contact between ocular fluid and the therapeutic agent or agents disposed within the lumen. In one embodiment, the hydrophobic material is permeable to ocular fluid and / or drugs.

[0138] 4A-4C show additional embodiments of an implant 50 that may be particularly suitable for placement directly in the vitreous cavity. These embodiments are similar or identical to those described above in many respects, including but not limited to, materials, elution rates, drugs, orifices, configurations, delivery, sizes, coatings, etc., and the above statements, including but not limited to those in the preceding 21 paragraphs related to FIGS. 3A-3D, also apply to FIGS. 4A-4C. FIG. 4A is a cross-sectional view of another embodiment of an implant 50. The implant shown in FIG. 4A may include any one or any combination of the implant features described herein. As discussed above, the implant may be bioerodible or bioabsorbable. As shown, the implant may be capsule-shaped. For example, the implant may include a distal end 65b and a proximal end 65a. The distal end 65b and the proximal end 65a may be rounded. Such a configuration may help prevent or inhibit injury to the patient when the implant is placed in the patient's eye. The rounded ends of the implant may aid in easier insertion of the implant into various areas of the patient's eye, such as the supraciliary space, suprachoroidal space, Schlemm's canal, anterior chamber, vitreous humor, posterior chamber, and / or lens capsule.

[0139] As shown in FIG. 4A, the implant can include an outer shell 54. The outer shell 54 can include one or more orifices 56a, 56b. The orifices 56a, 56b can be located at or near the distal end 65b of the implant. As described above, the implant can include an internal or hydrogel plug 210 and a drug 62. In some embodiments, the hydrogel plug 210 is located near the distal end 65b of the implant and / or the orifices 56a, 56b. The drug 62 can be located adjacent to the hydrogel plug 210. For example, the drug 62 can be located at or near the proximal end 65a of the implant. In some embodiments, the drug 62 is included in a drug reservoir.

[0140] In some embodiments, the proximal end 65a of the implant forms a closed end. In some embodiments, the proximal end 65a of the implant includes a cap. For example, the proximal end 65a of the implant can limit or prevent elution of the drug 62 through the proximal end 65a of the implant. For example, the hydrogel plug 210 and drug 62 can be located within the outer shell 54 such that the drug 62 passes through at least a portion of the distal region of the implant. In some embodiments, the drug 62 passes through at least a portion of the hydrogel plug 210 before passing through the outer shell 54. Thus, the hydrogel plug 210 can help control the elution of the drug 62.

[0141] In some embodiments, as described above, the orifices 56a, 56b may help control the elution of the drug 62 through the hydrogel plug 210 and the outer shell 54. As described above, the drug 62 may be located within the outer shell 54 such that the drug 62 passes through the hydrogel plug 210 before eluting. In some embodiments, the orifices 56a, 56b may allow the drug 62 to pass through the outer shell 54 after passing at least a portion of the hydrogel plug 210. In some embodiments, the orifices may be sized and shaped to control the elution rate of the drug through the hydrogel plug 210 and / or the outer shell 54 of the implant, as described herein.

[0142] As discussed above, the implant can include various volumes of hydrogel plug and drug in certain embodiments of the implant. For example, the volume ratio of drug 62 to hydrogel located within the eluting implant can be greater than about 1:1. For example, in some embodiments, at least 50% of the interior volume of the shell 54 is filled with drug 62 before the drug is eluted from the implant. In some embodiments, the volume ratio of drug to hydrogel plug located within the eluting implant ranges from about 1:1 to about 2:1, from about 2:1 to about 5:2, from about 5:2 to about 3:1, from about 3:1 to about 7:2, from about 7:2 to about 4:1, from about 4:1 to about 9:2, and / or other ranges. In some embodiments, the volume ratio of drug to hydrogel located within the eluting implant ranges from about 1:1 to about 1:2, from about 1:2 to about 1:3, from about 1:3 to about 1:4, among other ranges.

[0143] Figure 4B is a cross-sectional view of another embodiment of an implant 50. The implant shown in Figure 4B is similar or identical in many respects to the implants described herein. The implant shown in Figure 4B can include any one or any combination of the features of the implants described herein.

[0144] As shown in FIG. 4B, the implant can include an outer shell 54. The outer shell 54 can include one or more orifices 56a, 56b. The orifices 56a, 56b can be located at or near the distal end 65b of the implant. In some embodiments, the outer shell 54 can optionally include one or more orifices 56c located at or near the proximal end 65a of the implant. As described above, the implant can include an interior or hydrogel plug 210 and a drug 62. As shown, all or a portion of the drug 62 can be dispersed within and / or mixed with the hydrogel plug 210 to form a hydrogel-drug mixture. The hydrogel-drug mixture can be preformed. For example, the hydrogel and drug can be mixed prior to being inserted into the interior space of the outer shell 54. In some embodiments, at least 50% of the volume of the hydrogel-drug mixture can include a drug, as described above. As discussed above, the orifices 56 a , 56 b and / or the hydrogel may help control the elution rate of the drug through the shell 54 .

[0145] Figure 4C is a cross-sectional view of another embodiment of an implant 50. The implant shown in Figure 4C is similar or identical in many respects to the implants described herein. The implant shown in Figure 4C can include any one or any combination of the features of the implants described herein.

[0146] As shown in FIG. 4C, the implant can include an outer shell 54. The outer shell 54 can include one or more orifices 56a, 56b. The orifices 56a, 56b can be located at or near the distal end 65b of the implant. In some embodiments, the outer shell 54 can include one or more orifices 56c, optionally located at or near the proximal end 65a of the implant. As described above, the implant can include an interior or hydrogel plug 210 and a drug 62. As shown, the hydrogel plug 210 can surround at least a portion of the drug 62. As described above, the orifices 56a, 56b and / or hydrogel can help control the elution rate of the drug through the outer shell 54. The drug 62 can pass through all or a portion of the hydrogel plug 210 before eluting through the outer shell 54.

[0147] As shown diagrammatically in Figures 6A and 6B, an elongate implant can include multiple features as disclosed herein. For example, Figure 6A shows an elongate implant having a proximal end 52 and a distal end 50 that includes multiple pellets of a therapeutic agent 62. As discussed in more detail herein, the therapeutic agent can be in various forms, such as pellets, micropellets, vesicles, micelles, or other membranous binding structures, oils, emulsions, gels, slurries, etc., depending on the embodiment. The implant includes regions of drug release 56. Additionally, the embodiment shown in Figures 6A and 6B includes a fluid inflow pathway 38k and an outflow pathway 56k, thus combining delivery of a therapeutic agent with fluid guidance to an ocular outflow pathway (e.g., the suprachoroidal space).

[0148] 6D is a schematic diagram of an eye in which an embodiment of an elongated implant has been positioned in accordance with some embodiments disclosed herein. As shown, a proximal end 52 of the implant is near the anterior of the eye and a distal end 50 of the implant is in a more posterior position. The implant may be implanted in the suprachoroidal space in one embodiment, and a drug release region 56 may be positioned to elute a therapeutic agent 58 from the implant in the posterior region of the eye. Although not explicitly shown here, it should be understood that the implant may optionally include fluid inflow and outflow pathways as described herein.

[0149] Another embodiment of the ocular implant may be configured to be disposed at least partially in the supraciliary and / or suprachoroidal space and may include one or more caps or drug release elements as discussed in the following sections. Figure 18 is a perspective view of an exemplary embodiment of an ocular implant 900 having a drug release element. Figure 19 is a side view of an exemplary embodiment of an ocular implant 900. Figure 20 is a cross-sectional view of an exemplary embodiment of an ocular implant 900. Various features of the ocular implant 900 are similar or the same as the features shown in or described in connection with Figures 2A-2B and described above.

[0150] The ocular implant 900 can include an outer shell 906. The outer shell and possibly other components of the implant are preferably made of a biodegradable material. The outer shell 906 can define an inner chamber 908, which can be a drug reservoir that holds one or more drugs as described herein. The outer shell 906 can be configured to be implanted in the supraciliary and / or suprachoroidal space of a patient's eye. The outer shell 906 can have a generally straight shape, or the implant can be pre-curved to a curvature that generally matches the supraciliary and / or suprachoroidal space. The outer shell 906 can be flexible in some embodiments, e.g., such that the ocular implant can have a generally straight shape when in the delivery device and a curved shape when implanted in the eye (e.g., the supraciliary and / or suprachoroidal space). The outer shell 906 can include a distal end 902, which can be tapered to facilitate insertion into the supraciliary and / or suprachoroidal spaces.

[0151] The outer shell 906 can include a proximal end 904 that can include a drug release element 930. In some embodiments, the proximal end 904 can have an increased outer diameter such that a step or ridge 905 is formed between the proximal end 904 and a center of the outer shell 906. In some embodiments, the ocular implant 900 can be inserted into the eye (e.g., the supraciliary and / or suprachoroidal space) until the step or ridge 905 contacts ocular tissue adjacent the insertion site (e.g., ciliary tissue). The step or ridge 905 can help prevent overinsertion of the ocular implant 900. The ocular implant 900 can be configured to release (e.g., elute) a drug, such as from a proximal end of the ocular implant 900, for example, into the anterior chamber 20, as described herein. The drug release location (e.g., the proximal end) can be spaced a distance 907 from the step or ridge 905 to prevent ocular tissue adjacent the insertion site from covering or blocking the drug release location of the ocular implant 900. By way of example, the distance can be about 25 microns, about 50 microns, about 75 microns, about 100 microns, about 150 microns, about 200 microns, about 300 microns, about 400 microns, about 500 microns, about 750 microns, about 1000 microns, about 1250 microns, about 1500 microns, or any value therebetween, including a range bounded by any of these distances. In some embodiments, the step or ridge 905 can extend laterally outwardly farther than shown in FIGS. 18-20. The step or ridge 905 can extend laterally outward a distance that can be about 25 microns, about 50 microns, about 75 microns, about 100 microns, about 150 microns, about 200 microns, about 300 microns, about 400 microns, about 500 microns, about 750 microns, about 1000 microns, or any value therebetween, including a range defined by any of these distances.

[0152] The ocular implant 900 may include one or more retention features 910 configured to secure the implant in place when implanted in the eye. The one or more retention features 910 may include one or more annular ribs on the outer surface of the outer shell 906. The ribs may have angled distal sides and / or may be barbed to facilitate insertion of the ocular implant 900 into the eye while preventing the ocular implant 900 from unintentionally dislodging from the ocular tissue. In some embodiments, the ribs may have an outer diameter approximately the same as the outer diameter of the proximal end 904 to facilitate placement in a delivery device. In some embodiments, the one or more retention features 910 may be configured to engage with ocular tissue adjacent the insertion site. For example, the one or more retention features 910 may be present at or near the proximal end 904, or at or near the shoulder or ridge 905. In some embodiments, the retention features 910 may be omitted and the outer shell 906 may be held in place by friction with the surrounding ocular tissue.

[0153] The ocular implant 900 may include a drug release element 930. Drug release elements are discussed further in the following section.

[0154] In some embodiments, the implant includes a punctal plug. In some such embodiments, the physical location of the drug within the implant is advantageous for the timing of drug delivery. Such an approach is useful, in some embodiments, when treating dry eye with a combination of steroids and cyclosporine. Many current therapies for dry eye employ initial treatment with steroid eye drops for a first period (e.g., 2 weeks). After the initial period, cyclosporine eye drops are added to the treatment regimen. Thereafter, the steroid is then tapered, ending on day 60, and cyclosporine therapy is continued alone for as long as necessary. However, according to an embodiment disclosed herein, the punctal implant can deliver the steroid and cyclosporine in a timely manner to provide a near-constant, zero-order drug administration. Such an administration profile is generally believed to be more efficient than bolus delivery, such as that provided by eye drops. In some embodiments, the punctal plug is configured to bioerode as the drug load is released, as disclosed herein, and in some embodiments, is completely bioerode as all or nearly all of the drug load is released.

[0155] In some embodiments employing multiple agents, the second (or third, etc.) agent provides a synergistic effect when combined with the first agent, hi other embodiments, the second agent reduces one or more side effects associated with the first agent.

[0156] Accordingly, some embodiments provide an implant for insertion into a lacrimal punctum of a subject's eye, the implant including an outer shell having a proximal end and a distal end, the outer shell shaped to define an internal lumen and dimensioned for insertion into the lacrimal punctum of the subject's eye, at least one first active drug disposed within the internal lumen, a proximal portion of the shell with at least one region of drug release, and a distal closure member within the internal lumen that prevents elution of the first active drug from the distal end of the implant.

[0157] In some such embodiments, the first active drug is eluted from the lumen into the tear film of the eye of the subject by passing through at least one drug release region.In some embodiments, the implant is dimensioned to be implanted with the distal end of the shell located in the lacrimal duct.In some embodiments, the implant is dimensioned to be implanted with the distal end of the shell located in the lacrimal sac.In some embodiments, the implant is dimensioned to be implanted with the distal end of the shell located in the nasolacrimal duct.

[0158] In some embodiments, a punctal implant is also provided that is configured to be inserted into a lacrimal punctum of a subject's eye and deliver two or more active drugs to the subject's eye, the punctal implant comprising: (i) an outer shell comprising a proximal end comprising at least one drug release region and a flange; (ii) a closed distal end; and (iii) an inner lumen comprising at least two active drugs located within the lumen.

[0159] In some embodiments, there is also provided a punctal implant configured to be inserted into a lacrimal punctum of a subject's eye and deliver two or more active drugs to the subject's eye, the implant comprising an outer shell including (i) a proximal end including at least one drug release region and a flange, (ii) a closed distal end, and (iii) an inner lumen including at least two active drugs located within the lumen, the drug release region including an opening through an annular ring located at a proximal-most portion of the inner lumen, the opening providing for elution of the two or more active drugs only through the closure member, the dimensions of the opening at least in part defining the elution rates of the two or more active drugs, the flange configured to rest on a surface of the eyelid when the implant is inserted into the punctum, and the first and second active drugs elute from the lumen into the tear film of the subject's eye by passing through the at least one drug release region.

[0160] In some embodiments, the at least one region of drug release comprises at least one opening. Additionally, in some embodiments, the implant further comprises at least one membrane closing the at least one opening, the membrane being permeable to the at least one first active drug such that elution of the at least one first active drug occurs only through the at least one membrane.

[0161] In some embodiments, the at least one region of drug release comprises a plurality of openings disposed in a random or patterned array through the shell across the proximal portion of the implant, at least a portion of the plurality of openings being closed with a membrane permeable to the first active drug, as previously described.

[0162] In some embodiments described herein, the drug (or drugs) elutes from the implant with zero order or pseudo-zero order kinetics.

[0163] In some embodiments, the intraocular target is the posterior chamber, the anterior chamber, both the anterior and posterior chambers, or the macula, retina, optic nerve, ciliary body, and intraocular vasculature.

[0164] In some embodiments, the drug acts on intraocular target tissues to provide a long-term therapeutic effect. In one embodiment, the drug comprises a steroid. In such embodiments, the implant comprises a total steroid dose of about 10 to about 1000 μg, the steroid is released from the implant at a rate of about 0.05 to about 10 μg / day, and / or the steroid acts on the diseased or damaged target tissue at a concentration of about 1 to about 100 nanomolar. In some embodiments, the steroid further produces side effects associated with the accumulation of physiological fluid, and the optional shunt transports the accumulated fluid from the first location to a remote second location (e.g., from the anterior chamber to an existing physiological outflow pathway, such as Schlemm's canal, nasolacrimal duct, etc.).

[0165] In some embodiments, the at least one drug release region comprises a closure member that is permeable to the two or more active drugs, and the closure member allows the elution of the two or more active drugs to occur only through the closure member. In some embodiments, the thickness of the closure member at least partially defines the elution rate of the active drug (or active drugs). In some embodiments having a flange, the flange is configured to rest on the surface of the eyelid when the implant is inserted into the punctum. In some embodiments, the active drug (or active drugs) elutes from the lumen into the tear film of the subject's eye by passing through the at least one drug release region.

[0166] In some embodiments, the occlusive membrane is sized based on the permeability of the occlusive member to the first active drug (and second or more), the desired relative timing, and duration of elution of the first active drug and second active drug. In some embodiments, the occlusive member is about 0.0001-0.0005 inches thick. In certain embodiments, the occlusive member is integrally formed with the outer shell of the implant. In some embodiments, the occlusive member further comprises random or patterned holes through the occlusive membrane.

[0167] In some embodiments, the first active drug is located proximal to the location of the second active drug within the internal lumen. In some embodiments, a third active drug is included, and in certain such embodiments, the first and second active drugs are located adjacent to each other, and both the first and second active drugs are located proximal to the location of the third active drug within the internal lumen.

[0168] In some embodiments, the active drug (or drugs) are formulated as a tablet, a nanodispersion, or a combination thereof. In some embodiments, a first active drug is formed as a discontinuous first phase and a second active drug is formulated as a dispersion of liquid or solid particles within which the first active drug is dispersed.

[0169] In some embodiments, the device can be filled with the protein drug in the form of an amorphous solid, a powder, or a crystalline solid, or in the form of a suspension thereof, or in the form of a solution. When filling the device with a suspension or solution, the initial concentration of the protein drug can be in the range of about 100 to about 500 mg / mL, or a concentration between the above, including about 100 to about 150 mg / mL, about 150 to about 200 mg / mL, about 200 to about 250 mg / mL, about 250 to about 300 mg / mL, about 300 to about 350 mg / mL, about 350 to about 400 mg / mL, about 400 to about 450 mg / mL, and about 450 to about 500 mg / mL, depending on the case. In some preferred embodiments, the concentration is in the range of about 200 to about 300 mg / mL.

[0170] In some embodiments, the drug may contain an excipient such as trehalose that stabilizes the protein drug during pre-processing (such as lyophilization) or during its use in the eye. Depending on the concentration of trehalose, an osmotic gradient may be created from the inside of the device to the outside of the device, and moisture from the vitreous will tend to enter the device and displace some of the drug. This event may be intentional if an initial burst of dissolution is desired. Otherwise, the concentration of trehalose may be reduced to an isotonic level, or a polymer with multiple hydroxyl residues may be utilized to reduce the osmolality and slow the loss due to dissolution.

[0171] Other excipients may include buffers that maintain a neutral pH when the bioabsorbable material hydrolyzes. Such buffers may also be polymers that retard their loss by elution.

[0172] In some embodiments, the outer shell of the implant includes a bulge in the distal region to secure the implant to the punctum.

[0173] In some embodiments, the first active drug elutes from the implant for 1 to 75 days and the second active drug elutes from about 1 to about 24 months after the first active drug elutes.

[0174] In some embodiments, the implants disclosed herein are about 0.5 to about 2.5 mm in length. Some implant embodiments are about 1.4 to about 1.6 mm in length. Some implant embodiments are about 0.2 to about 1.5 mm in diameter. Some implant embodiments are about 0.2 to about 0.6 mm in diameter.

[0175] In some embodiments, the first active drug can be a steroid. In some such embodiments, the steroid is selected from the group consisting of loteprednol etabonate, dexamethasone, and triamcinolone acetonide. In some embodiments, the second active drug is cyclosporine, optionally formulated as a nanodispersion. In some embodiments, the first active drug is cyclosporine A. In some embodiments, the first active drug promotes tear production.

[0176] Some embodiments optionally include retention protrusions configured to secure the implant at the implantation site (e.g., the punctum). Such retention protrusions optionally include one or more of swellings, ridges, claws, threads, flexible ribs, tack-like features, flexible barbs, barbed tips, expandable materials (such as hydrogels), and biocompatible adhesives. In some embodiments, the expandable material is disposed on the outer surface of the implant shell and expands upon contact with a solvent, such as intraocular fluid, tear film, and the like.

[0177] In some embodiments, the outer shell of the punctal plug implant comprises a bioerodible material. As discussed in more detail elsewhere in this disclosure, in some embodiments, the bioerodible material is configured to erode at a rate that results in the entire implant (including the punctal insert and other implant locations) being completely or substantially bioeroded. This can be configured to mimic the timing of drug release, in some cases, such that the implant itself is completely or substantially eroded simultaneously with the elution of all or nearly all of the drug load from the implant (including the punctal implant). However, in some embodiments, bioerosion of the implant is timed to begin only after all or nearly all of the drug load has been delivered.

[0178] It is understood that any of the devices described herein, including those in Figures 2A and 2B or 5A and 5B, can be fitted with any cap including a drug release element, or the caps shown in Figures 5A, 5B and 12-17, discussed below, and the drug delivery implants shown in Figures 18-20 can be fitted with the caps shown in Figures 5A and 5B, or can not include a cap. Additionally, any of the embodiments disclosed and illustrated herein can include a cap including a drug release element at the distal end instead of the proximal end, or they can include them at both ends. If the implant has caps at both ends, the type of cap at each end can be the same or different, and each can deliver the same drug from the same lumen, the same drug from the same lumen where the lumen is separated into two compartments by an obstruction within the lumen, the same drug from different lumens, different drugs from a lumen that includes an obstruction separating the two drugs, or different drugs from different lumens. When two caps are present, the timing and / or rate of drug delivery may be the same or different, and if different timing, they may overlap or be separated.Similarly, an implant similar to Figures 5A and 5B or 18-20 may include a drainage cavity, such as that of Figures 2A and 2B, or as described elsewhere herein.

[0179] It is further understood that possible features and materials of the implants of Figures 2A and 2B, 5A and 5B, and 18-20 are discussed throughout this specification, including in this section and the previous section, including, but not limited to, biodegradable materials, sizes, lengths, diameters, retention features, shunts, pores, coatings, distal end shapes, etc. Physical separations in the specification are not intended and, as will be understood by those of skill in the art, should not be construed as meaning that each idea is separate and cannot be applied to the various device embodiments described herein.

[0180] <Cap containing drug release element>

[0181] In some embodiments, the implant can include one or more caps. In such embodiments, one or more portions of the implant are manufactured separately and then combined (e.g., assembled cap and implant shell) for a final implant that can be directly inserted into the target site. For example, as shown in FIG. 5A, implant 53, in some embodiments, includes implant shell 54, separate cap 54a (shown in different shading for ease of viewing, but possibly constructed of the same or different material as the implant shell). Any of a variety of cap configurations can be used with any of the implant shells, of course, sized to allow for interaction between the parts.

[0182] As shown in FIG. 5A, the cap 54a includes a central opening, thereby forming a drug release region 56. In some embodiments, the assembly of certain such embodiments takes advantage of the elastic or semi-elastic properties of the membrane 60 through which the drug (or drugs) contained within the implant elute. Advantageously, in some embodiments, the elasticity of the membrane 60 allows the cap of the implant to be press-fit onto the implant shell and then held by pressure applied to the cap by the elastic rebound of the membrane (e.g., an "auto-lock" feature). Thus, in some embodiments, the membrane 60 not only serves to define the release rate of the drug (or drugs), but also serves as a gasket that seals the interior of the implant from the external environment, thus limiting fluid communication between the interior and the exterior to that occurring through the membrane 60. The membrane 60 can be constructed of any material or materials suitable for drug elution. For example, the membrane 60 in one embodiment comprises ethylene vinyl acetate, while in another embodiment the membrane comprises silicone or another partially or semi-permeable material, homopolymers, polymer blends, and copolymers such as random copolymers, block copolymers, polyethylene, polyurethane, polyethersulfone, polyamide, poly(carbonate urethane), poly(ether urethane), silicone poly(carbonate urethane), silicone poly(ether urethane), PurSil™, Elasthane™, CarboSil™, and / or Bionate™. The biodegradable materials mentioned above for the shell can also be used for the membrane, cap, and other components. The choice of membrane material and its dimensions (e.g., its thickness) are guided, at least in part, by the drug of choice, the form in which it is placed within the implant (free acid, prodrug, oil, solid, micelle, etc.), whether ocular fluid is to be excluded from the device, and the like.

[0183] 5B is an exploded view of one embodiment of an implant disclosed herein. The implant 53 includes at least one internal lumen 58 that contains a therapeutic agent(s). As mentioned above, the implant further includes a cap 54a and a membrane 60 that, when assembled together, form a (membrane-based) drug release region 56 tailored to a particular therapeutic agent(s) of interest.

[0184] In various embodiments, the thickness of the membrane 60 (together with the particular therapeutic agent or agents of choice) ranges from about 30 to about 200 μm, including about 50 to about 200 μm, about 70 to about 200 μm, about 90 to about 200 μm, about 30 to about 100 μm, about 30 to about 115 μm, about 50 to about 125 μm, about 63 to about 125 μm, about 84 to about 110 μm, about 57 to about 119 μm, and overlapping ranges thereof. In some embodiments, the thickness of the membrane 60 also at least partially limits the elution rate of the drug (or drugs) of interest. The size of the opening in the cap also contributes to the elution rate.

[0185] Numerous alternatives and variations are possible. For example, in some cases, assembly of the embodiment shown in Figures 5A and 5B can include providing an outer shell 54 and loading a drug reservoir. A cap 54a having a membrane 60 can be applied to the proximal end of the shell 54. In some embodiments, the cap 54a can be advanced distally until a desired amount of membrane compression is achieved (e.g., 30 microns, or any other suitable amount described herein), and then the cap 54a can be reversibly or irreversibly crimped or secured to the shell 54. In some embodiments, a micrometer can be used to measure the amount of membrane compression.

[0186] One particular type of cap is referred to herein as a drug release element. FIG. 13A is a distal exploded perspective view of a drug release element 530. FIG. 13B is a proximal exploded perspective view of a drug release element 530. The drug release element 530 can be configured to slowly elute a drug as described herein. The drug release element 530 can be located at or near the proximal end 504 of the implant 500. In another embodiment, it can be located at or near the distal end of the implant, or at both ends. The shell 506 can include a shelf 548. A proximal portion of the interior of the shell 506 proximal to the shelf 548 can be larger in diameter than a portion distal to the shelf 548. In some embodiments, the shelf 548 can include a fixed annular size about its circumference. In some embodiments, the shelf 548 does not have a fixed annulus about its circumference, and in some cases the shelf 548 can be one or more protrusions that form a stop for a distal seal member, as described herein. The shell 506 can include one or more grooves 550, as described herein, that can be configured to receive the retainer 532. In some embodiments, the shell 506 can include two grooves 550 that are positioned substantially opposite each other.

[0187] The drug release element 530 can include a distal seal member 552, a membrane 554, and a proximal seal member 556. The distal seal member 552 can be mounted on the shelf 548 on the shell 506. The distal seal member 552 can have an outer diameter that is larger than a distal portion of the interior of the shell (distal to the shelf 548) and smaller than a proximal portion of the interior of the shell (proximal to the shelf 548). The distal seal member 552 can be generally annular and / or have an opening 558 extending therethrough. The proximal seal member 556 can have an outer diameter that is larger than a distal portion of the interior of the shell (distal to the shelf 548) and smaller than a proximal portion of the interior of the shell (proximal to the shelf 548). The proximal seal member 556 can be inserted into the proximal end 504 of the shell 506. The proximal seal member 556 can be generally disc-shaped. The proximal seal member 556 can include at least one opening 560 extending therethrough. In the illustrated embodiment, the proximal seal member 556 includes two openings 560. The membrane 554 can be located between the distal seal member 552 and the proximal seal member 556, and in some embodiments, the membrane 554 can be compressed between the distal seal member 552 and the proximal seal member 556. The retention portion 532 can hold the drug release element 530 in a compressed state (e.g., with the membrane 554 compressed), as described herein. The distal seal member 552 can include a step 562. FIG. 14 shows the membrane 554 in an undeformed state. When compressed, the membrane 554 can deform to fill the space of the step 562.

[0188] The distal seal member 552 and / or the proximal seal member 556 can be made of various biocompatible materials, such as ceramics, metals (e.g., titanium), as described herein. In some embodiments, forming the members 552 and / or 556 from a ceramic material can be advantageous for creating details on the part. In some embodiments, one or both of the seal members 552 and 556 can be made of a resilient biocompatible material (e.g., silicone) that is impermeable or nearly impermeable to the drug. The membrane 554 can be made of a variety of suitable materials that allow the drug to be eluted from the implant 500. In some embodiments, the membrane can be made of ethylene vinyl acetate (EVA). The elution rate of the drug can depend at least in part on the % concentration of vinyl acetate in the EVA material. The vinyl acetate concentration can be about 40% or less, about 30% or less, about 25% or less, at least about 10%, at least about 20%, at least about 25%, and / or at least about 30%, with values ​​outside of these ranges being used in some embodiments. The vinyl acetate concentration can be about 10% to about 30%, about 20% to about 30%, or about 25% to about 30% of the EVA material. In some embodiments, the vinyl acetate concentration can be about 25% or about 28% of the EVA material.

[0189] As described herein, the membrane 554 can be compressed between the distal seal member 552 and the proximal seal member 556. The proximal seal member 556 can be compressed distally to compress the membrane 554, and the retainer 532 can be inserted through the groove 550 such that the retainer is proximal to the proximal seal member 556. The retainer 532 can have a length greater than the inner diameter of the proximal portion inside the shell and less than or equal to the outer diameter of the shell 506 at the groove 550. When inserted, the retainer 532 can extend into the two opposing grooves 550. The force from the compressed membrane 554 can compress the retainer 532 proximally, and the grooves 550 can hold the retainer in place to maintain the membrane 554 in the compressed shape. The retainer 532 can have a generally hourglass shape, although other shapes can be used in some embodiments. The retainer can include one or more tabs 564 that can be folded to secure the retainer 532. 14 is a cross-sectional view showing the retainer 532 inserted with the tab 564 facing up. FIG. 15 is a partial cross-sectional view showing the retainer 532 inserted with the tab 564 folded over to engage the proximal seal member 556. When folded, the tab 564 can enter one or more openings 560 and engage the proximal seal member 556, thereby preventing or inhibiting the retainer 532 from moving (e.g., sliding out of the groove 550). In some embodiments, when the membrane 554 is compressed, a portion of the membrane 554 is pushed proximally into the one or more openings 560, and the folded tab 564 engages the membrane 554, facilitating securing the membrane 554.

[0190] The drug may elute from the proximal end of the implant 500. The drug may pass from the internal chamber 508 through at least one opening 558 in the distal seal member 552 and into the membrane 554. The membrane 554 may be configured to allow the drug to pass through the membrane 554 at a desired elution rate. The drug may pass through at least one hole 560 in the proximal seal member 556, through the retention portion 532, and out the proximal end 504 of the implant 500. In FIG. 15, the elution of the drug is indicated by two arrows. In some embodiments, the thickness and / or compression of the membrane 554 may at least partially affect the elution rate of the drug. In some embodiments, the membrane 554 can have a compressed thickness of at least about 50 microns, at least about 75 microns, at least about 80 microns, at least about 90 microns, at least about 95 microns, at least about 100 microns, not more than about 200 microns, not more than about 150 microns, not more than about 125 microns, not more than about 110 microns, not more than about 105 microns, not more than about 100 microns, not more than about 95 microns, and / or not more than about 90 microns, although values ​​outside these ranges can be used in some embodiments. The compressed thickness 566 of the membrane 554 can be from about 75 microns to about 125 microns, from about 85 microns to about 105 microns, or from about 90 microns to about 100 microns. In some embodiments, the compressed thickness 566 of the membrane 554 can be about 95 microns. The membrane can be compressed by at least about 10 microns, at least about 20 microns, at least about 30 microns, at least about 40 microns, less than about 50 microns, less than about 40 microns, less than about 30 microns, and / or less than about 20 microns, although values ​​outside these ranges can be used in some embodiments. The membrane 554 can be compressed by an amount between about 20 microns and about 40 microns, or between about 25 microns and about 35 microns. The membrane 554 can be compressed by about 30 microns in some embodiments. Compression of the membrane 554 can improve the long-term operation of the membrane 554 for several years.

[0191] The amount of compression applied to the membrane 554 is set by the dimensions of the implant 500 components, not by human decisions during assembly, and therefore can be reliably applied without relying on human decisions. By way of example, the longitudinal distance 568 between the shelf 548 and the proximal end of the groove 550 can be approximately 235 microns. The distal seal member 558 can have a longitudinal thickness 570 of approximately 65 microns. The proximal seal member 556 can have a longitudinal thickness 572 of approximately 50 microns. The retainer 532 can have a longitudinal thickness of approximately 25 microns. The membrane 554, having a longitudinal thickness of approximately 125 microns, can be compressed to a longitudinal thickness 566 of approximately 95 microns (or less), and the retainer 532, having a longitudinal thickness 574 of approximately 25 microns, can be inserted to maintain the membrane 554 in the compressed configuration. Thus, as defined by the dimensions of the respective components, the membrane 554 is compressed by 30 microns from a thickness of 125 microns to a thickness of 95 microns.

[0192] Many variations are possible. For example, FIG. 16 is a perspective view of one exemplary embodiment of an alternative seal 576 that may be used in place of seal 528 in some embodiments. Seal 576 may be a single integral part and may be formed of a resilient material (e.g., silicone) that is impermeable or nearly impermeable to the drug. Seal 576 may include a distal expansion portion 578 and a proximal expansion portion 580, both of which may be configured to seal against an inner wall of interior chamber 508. FIG. 17 is a perspective view of one exemplary embodiment of an alternative upper seal member 582 that may be used in place of upper seal member 556 described herein. Upper seal member 582 is generally annular or ring-shaped. Upper seal member 582 includes a single relatively large hole 584 in place of the two relatively small holes 560 of upper seal member 556 described herein. The larger hole 584 may result in a faster elution rate than the two smaller holes 560. Similarly, the size and number of holes in distal seal member 552 may at least partially affect the elution rate of the drug. The implant 500 can be configured to have an elution rate of about 100 nanograms / day or less, about 75 nanograms / day or less, about 50 nanograms / day or less, about 40 nanograms / day or less, about 30 nanograms / day or less, about 25 nanograms / day or less, about 20 nanograms / day or less, at least about 10 nanograms / day, at least about 15 nanograms / day, at least about 20 nanograms / day, at least about 25 nanograms / day, at least about 30 nanograms / day, and / or at least about 40 nanograms / day, although values ​​outside these ranges can be used in some embodiments. The elution rate can be about 15 nanograms / day to about 35 nanograms / day, or about 20 nanograms / day to about 30 nanograms / day. The elusion rate can be about 25 nanograms / day in some cases.The drug elution rate and volume can provide drug delivery for a period of at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, at least about 10 years, up to about 15 years, up to about 12 years, up to about 10 years, up to about 8 years, up to about 6 years, and / or up to about 4 years, although values ​​outside these ranges can be used in some embodiments.

[0193] Drug delivery ocular implants can be manufactured to hold a variety of different drug volumes. The implants can hold at least about 30 nanoliters, at least about 40 nanoliters, at least about 50 nanoliters, at least about 60 nanoliters, at least about 70 nanoliters, at least about 80 nanoliters, at least about 90 nanoliters, at least about 100 nanoliters, at least about 110 nanoliters, at least about 120 nanoliters, at least about 130 nanoliters, at least about 140 nanoliters, at least about 150 nanoliters, about 200 nanoliters or less, about 175 nanoliters or less, about 150 nanoliters or less, about 130 nanoliters or less, about 120 nanoliters or less, about 110 nanoliters or less, about 100 nanoliters or less, about 90 nanoliters or less, about 80 nanoliters or less, about 70 nanoliters or less, about 60 nanoliters or less, and / or less than about 50 nanoliters, although values ​​outside these ranges can be used in some embodiments. The implant may hold a volume of drug from about 40 nanoliters to about 150 nanoliters, or from about 50 nanoliters to about 120 nanoliters.

[0194] Various alternative embodiments disclosed herein can include drug release elements that can be similar or the same as drug release elements 530 and / or 730 or other drug release elements shown and described herein. For example, in some embodiments, an ocular implant can include a drug release element that can be configured to at least partially locate in the supraciliary space and / or the suprachoroidal space and have similar or the same features as the drug release elements disclosed herein (e.g., drug release elements 530 and / or 730). FIG. 18 is a perspective view of an exemplary embodiment of an ocular implant 900. FIG. 19 is a side view of an exemplary embodiment of an ocular implant 900. FIG. 20 is a cross-sectional view of an exemplary embodiment of an ocular implant 900. Various features of the ocular implant 900 are similar or the same as the features shown in or described in connection with FIGS. 2A, 2B and described above.

[0195] The ocular implant 900 can include an outer shell 906. The outer shell and possibly other components of the implant are preferably made of a biodegradable material. The outer shell 906 can define an inner chamber 908, which can be a drug reservoir that holds one or more drugs as described herein. The outer shell 906 can be configured to be implanted in the supraciliary and / or suprachoroidal space of a patient's eye. The outer shell 906 can have a generally straight shape, or the implant can be pre-curved to a curvature that generally matches the supraciliary and / or suprachoroidal space. The outer shell 906 can be flexible in some embodiments, e.g., such that the ocular implant can have a generally straight shape when in the delivery device and a curved shape when implanted in the eye (e.g., the supraciliary and / or suprachoroidal space). The outer shell 906 can include a distal end 902, which can be tapered to facilitate insertion into the supraciliary and / or suprachoroidal spaces.

[0196] The outer shell 906 can include a proximal end 904 that can include a drug release element 930. In some embodiments, the proximal end 904 can have an increased outer diameter such that a step or ridge 905 is formed between the proximal end 904 and a center of the outer shell 906. In some embodiments, the ocular implant 900 can be inserted into the eye (e.g., the supraciliary and / or suprachoroidal space) until the step or ridge 905 contacts ocular tissue adjacent the insertion site (e.g., ciliary tissue). The step or ridge 905 can help prevent overinsertion of the ocular implant 900. The ocular implant 900 can be configured to release (e.g., elute) a drug, such as from a proximal end of the ocular implant 900, for example, into the anterior chamber 20, as described herein. The drug release location (e.g., the proximal end) can be spaced a distance 907 from the step or ridge 905 to prevent ocular tissue adjacent the insertion site from covering or blocking the drug release location of the ocular implant 900. By way of example, the distance can be about 25 microns, about 50 microns, about 75 microns, about 100 microns, about 150 microns, about 200 microns, about 300 microns, about 400 microns, about 500 microns, about 750 microns, about 1000 microns, about 1250 microns, about 1500 microns, or any value therebetween, including a range bounded by any of these distances. In some embodiments, the step or ridge 905 can extend laterally outwardly farther than shown in FIGS. 18-20. The step or ridge 905 can extend laterally outward a distance that can be about 25 microns, about 50 microns, about 75 microns, about 100 microns, about 150 microns, about 200 microns, about 300 microns, about 400 microns, about 500 microns, about 750 microns, about 1000 microns, or any value therebetween, including a range defined by any of these distances.

[0197] The ocular implant 900 may include one or more retention features 910 configured to secure the implant in place when implanted in the eye. The one or more retention features 910 may include one or more annular ribs on the outer surface of the outer shell 906. The ribs may have angled distal sides and / or may be barbed to facilitate insertion of the ocular implant 900 into the eye while preventing the ocular implant 900 from unintentionally dislodging from the ocular tissue. In some embodiments, the ribs may have an outer diameter approximately the same as the outer diameter of the proximal end 904 to facilitate placement in a delivery device. In some embodiments, the one or more retention features 910 may be configured to engage with ocular tissue adjacent the insertion site. For example, the one or more retention features 910 may be present at or near the proximal end 904, or at or near the shoulder or ridge 905. In some embodiments, the retention features 910 may be omitted and the outer shell 906 may be held in place by friction with the surrounding ocular tissue.

[0198] The ocular implant 900 can include a drug release element 930. The drug release element can include a distal seal member 952, a membrane 954, and a proximal seal member 956 that are the same as or similar to the other distal seal members, membranes, and proximal seal members discussed and illustrated herein. What is disclosed herein for other embodiments that include a drug release element also applies to the ocular implant 900 and will not be repeated here. The membrane 954 can be compressed between the distal seal member 952 and the proximal seal member 956, as described herein. The retainer 932 can hold the drug release element 930 in place, as described herein. The outer shell 906 can include one or more grooves 950, and the retainer 932 can mate with one or more grooves 950 proximal to the proximal seal member 956. Two grooves 950 can be located on opposite sides of the outer shell 906, and the retainer 930 can be inserted through one groove 950, across the interior chamber 908, and into the other groove 950. The distal seal member 952 can be seated on a ledge within the interior chamber 908. A compressed membrane 954 can apply a force that presses the distal seal member 952 against the ledge and the proximal seal member 956 against the retainer 932.

[0199] It should be understood that the above elements should not be construed as limiting the implant to the specific combinations or embodiments described, but rather the features discussed are freely interchangeable to allow flexibility in constructing a drug delivery implant according to the present disclosure.

[0200] <Delivery device>

[0201] Another aspect of the systems and methods described herein relates to a delivery device for implanting an implant for delivering drugs to the eye and possibly draining fluid from the anterior chamber to a physiological outflow space. In some embodiments, the implant is inserted into the eye at a site across the eye from the implantation site. The delivery device is long enough to advance the implant across the eye from the insertion site, through the anterior chamber, to the implantation site. At least a portion of the device can be flexible. The device can include multiple members that are longitudinally movable relative to one another. In some embodiments, the multiple members include one or more slidable guide tubes. In some embodiments, at least a portion of the delivery device is curved. In some embodiments, one portion of the delivery device is rigid and another portion of the device is flexible.

[0202] In some embodiments, the delivery instrument has a distal curvature. The distal curvature of the delivery instrument can be characterized as having a radius of about 10-30 mm in some embodiments. In some embodiments, the radius of the distal curvature is about 20 mm.

[0203] In some embodiments, the delivery instrument has a distal angle 88 (having a magnitude shown as χ in FIG. 22). The angle χ can be characterized as about 90 to 180 degrees relative to the proximal segment 94 of the delivery instrument. In some embodiments, the angle χ can be characterized as about 145 to about 170 degrees. In some embodiments, the angle is about 150 to about 170 degrees, or about 155 to about 165 degrees. The angle can introduce a small radius of curvature into the "elbow" to provide a smooth transition from the proximal segment to the distal segment of the delivery instrument. The length of the distal segment can be about 0.5 to 7 mm in some embodiments, and in some other embodiments, the length of the distal segment is about 2 to 3 mm.

[0204] In other embodiments, a curved distal end is generally preferred. In such embodiments, the height of the delivery device / shunt assembly (dimension 90 in FIG. 8) is less than about 3 mm in some embodiments, and less than 2 mm in other embodiments.

[0205] In some embodiments, the instrument has a sharp feature at the leading end and is self-trepelling, i.e., self-penetrating, so as to pass through tissue without preforming an incision, hole, or opening. In some embodiments, the self-trepelling instrument is configured to only penetrate corneal and / or limbal tissue. In other embodiments, the self-trepelling instrument is configured to penetrate internal ocular tissue, such as in the anterior chamber angle, to deliver the implant. Alternatively, a separate trocar, scalpel, spatula, or similar instrument can be used to preform an incision in the ocular tissue (cornea / sclera or more internal tissue) before passing the implant through such tissue. In some embodiments, the implant is rounded at the distal end to aid in blunt dissection of the ocular tissue (thus reducing the risk of tissue damage). However, in other embodiments, the implant is also sharp, tapered, or configured to penetrate ocular tissue to aid in implantation.

[0206] To deliver some embodiments of the drug eluting ocular implant, the instrument has a cross-section small enough so that when the instrument is withdrawn from the eye, the insertion site self-seals without sutures. The outer dimensions of the delivery instrument are preferably no larger than about 18 gauge and no smaller than about 27 or 30 gauge.

[0207] To deliver some embodiments of the drug-eluting ocular implant, an incision is made in the corneal tissue using a hollow needle through which the implant passes. The needle has a small diameter size (e.g., 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27 gauge) so that the incision is self-sealing, and implantation is performed in a closed chamber with or without viscoelastic properties. Self-sealing incisions can also be made by a traditional "tunneling" procedure in which a spatula-shaped scalpel is used to make a roughly inverted V-shaped incision through the cornea. In a preferred aspect, the instrument used to make the incision through the cornea remains in place (i.e., extends through the corneal incision) during the procedure and is not removed until after implantation. Such an incision-making instrument can be used to place the ocular implant or can function in conjunction with a delivery instrument that allows implantation through the same incision without withdrawing the incision-making instrument. Of course, in alternative embodiments, various surgical tools may be passed multiple times through one or more corneal incisions.

[0208] Some embodiments include a spring-loaded propulsion system. In some embodiments, the spring-loaded pusher includes a button operably connected to a hinged rod device. The rod of the hinged rod device engages a recess in the pusher surface, holding the pusher spring in a compressed configuration. When a user presses the button, the rod disengages from the recess, thereby allowing the spring to decompress and advance the pusher.

[0209] In some embodiments, an over-the-wire system is used to deliver the implant. The implant can be delivered over the wire. In some embodiments, the wire is self-treplenishing. The wire can also function as a trocar. The wire can be superelastic, flexible, or relatively stiff to the implant. The wire can be preformed to have a shape. The wire can be curved. The wire can have shape memory or be elastic. In some embodiments, the wire can be a pull wire. The wire can also be a steerable catheter.

[0210] In some embodiments, the wire is placed within a lumen of the graft. The wire is capable of axial movement within the lumen. The lumen may or may not contain a valve or other flow regulating device.

[0211] In some embodiments, the delivery device is a trocar. The trocar may be bent or curved. In some embodiments, the trocar is flexible. In other embodiments, the trocar is relatively rigid. In other embodiments, the trocar is rigid. In embodiments where the trocar is rigid, the implant is relatively flexible. The trocar has a diameter of about 0.001 inches to about 0.01 inches. In some embodiments, the trocar has a diameter of 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, or 0.01 inches.

[0212] In some embodiments, the implant is delivered by applying a motive force at or near the proximal end of the implant. The motive force can be a pulling or pushing force applied to the end of the implant.

[0213] The device may include a seal or coating to prevent aqueous humor from passing through the delivery device and / or between the components of the device when in the eye. The seal helps prevent backflow. In some embodiments, the device is coated with a coating and a hydrophilic or hydrophobic drug. In some embodiments, one area of ​​the device is coated with a coating and a hydrophilic drug and another area of ​​the device is coated with a coating and a hydrophobic drug. The delivery device may further include seals between the various components that make up the device. The seal may include a hydrophobic or hydrophilic coating between slip-fit ​​surfaces of the components of the device. The seal may be located proximal to the implant when carried by the delivery device. In some embodiments, the seal is present on at least one section of each of the two devices machined to fit closely together.

[0214] The delivery instrument can be configured to deliver multiple implants, and in some such embodiments, the implants can be arranged vertically (or sequentially if the number of implants is greater than two) within the device.

[0215] In some embodiments, the delivery device has a generally straight needle or cannula having a sharpened tip, about 21-30 gauge, including 23-25 ​​gauge, and / or an inner diameter of about 0.15-0.45 mm, including 0.25-0.35 mm. The needle or cannula is operatively connected to a handpiece having a trigger, plunger or actuator that, when actuated, expels the implant from the distal end of the delivery device. The implant is preferably preloaded into the delivery device by the manufacturer.

[0216] <Procedure>

[0217] To deliver some embodiments of the ocular implant, the implant is placed in a closed chamber, with or without viscoelastic properties.

[0218] The implant can be deployed using an applicator such as a pusher, or can be deployed using a delivery device with energy stored in the device, such as that disclosed in U.S. Patent No. 7,331,984, issued February 19, 2008, which is incorporated by reference in its entirety and made a part of the specification and this disclosure. In some embodiments, fluid can be injected through the applicator to generate high fluid pressure at the leading end of the implant to facilitate implantation.

[0219] In one embodiment of the present invention, a delivery device (or "applicator") similar to those used to place trabecular stents through the trabecular meshwork of the eye is used. Certain embodiments of such delivery devices are disclosed in U.S. Patent No. 7,331,984, issued February 19, 2008, U.S. Patent Application Publication No. 2002 / 0133168, entitled APPLICATOR AND METHODS FOR PLACING A TRABECULAR SHUNT FOR GLAUCOMA TREATMENT, and U.S. Provisional Patent Application No. 60 / 276,609, filed March 16, 2001, entitled APPLICATOR AND METHODS FOR PLACING A TRABECULAR SHUNT FOR GLAUCOMA TREATMENT, each of which is incorporated by reference in its entirety and made a part of this specification and this disclosure.

[0220] In one embodiment, a delivery device 2000 includes a hand piece, an elongated tip, a retainer, and an actuator, and is shown diagrammatically in FIG. 6C. The hand piece 1000 has a distal end 1002 and a proximal end 1004. The elongated tip 1010 is connected to the distal end of the hand piece. The elongated tip has a distal portion and is configured to pass through a corneal incision and be placed in the anterior chamber. A retainer 1020 (e.g., an insertion tube) is attached to the distal portion of the elongated tip. The retainer is configured to retain and release the drug delivery implant. An actuator 1040 is on the hand piece and actuates the retainer to release the drug delivery implant from the retainer. In one embodiment, the deployment mechanism in the delivery device includes a push-pull type plunger.

[0221] In some embodiments, the retainer comprises a clamp. In some embodiments, the device further comprises a spring in the handpiece configured to be loaded when the drug delivery implant is retained by the retainer, the spring being at least partially unloaded upon actuation of the actuator to release the drug delivery implant from the retainer. In various embodiments, the clamp comprises a plurality of claws configured to apply a clamping force to at least a proximal portion of the drug delivery implant. The retainer may also include a plurality of flanges.

[0222] In some embodiments, the distal portion of the elongate tip is made of a flexible material. It can be a flexible wire. The distal portion can have a deflection range, preferably about 45 degrees from the long axis of the handpiece. The delivery device can further include an irrigation port in the elongate tip.

[0223] In some embodiments, the method includes using a delivery device including a hand piece having a distal end and a proximal end and an elongate tip connected to the distal end of the hand piece. The elongate tip has a distal portion and is configured to be placed through a corneal incision into the anterior chamber. The device further includes a retainer attached to the distal portion of the elongate tip and an actuator on the hand piece for actuating the retainer to release the drug delivery implant from the retainer, the retainer configured to retain and release the drug delivery implant.

[0224] The delivery instrument can be advanced through an insertion site in the cornea and advanced across or posterior to the globe into the anterior chamber angle to position itself at its base. Using the anterior chamber angle as a reference point, the delivery instrument can be further advanced generally posteriorly to advance the implant into the anterior chamber angle onto the iris.

[0225] In some cases, depending on the implant structure, the implant can be positioned within the anterior chamber angle and assume a curved shape that matches the annular shape of the anterior chamber angle.

[0226] In some embodiments, the implant can be positioned adjacent to tissue of the anterior chamber angle or iris tissue, and the pusher tube can be advanced axially toward the distal end of the delivery instrument. As the pusher tube advances, the implant also advances. Once the implant has been advanced through the tissue and is no longer in the lumen of the delivery instrument, the delivery instrument is retracted, leaving the implant in the ocular tissue.

[0227] Positioning and implantation of the implant can be performed using a gonioscopic or other conventional imaging device. In some embodiments, a delivery instrument is used to move the implant to the desired location by applying a continuous implantation force, by tapping the implant into place with a distal portion of the delivery instrument, or by a combination of these methods. Once the implant is in the desired location, it can be further seated by tapping with a distal portion of the delivery instrument.

[0228] FIG. 9 illustrates one embodiment of a surgical method for implanting a drug delivery implant into an eye as described in embodiments herein. A first incision or slit is made in the conjunctiva and sclera 11 at a location posterior to the limbus 21, i.e., posterior to the area of ​​the sclera 11 where the milky white sclera 11 begins to become the transparent cornea 12. In some embodiments, the first incision is posterior to the limbus 21, including about 3 mm posterior to the limbus. In some embodiments, the incision is made to allow the surgical tool to be inserted into the anterior chamber at a shallow angle (relative to the anterior-posterior axis), as shown in FIG. 9. In another embodiment, the first incision can be made to allow for a larger angle of insertion of the tool (see, e.g., FIGS. 10-12). Additionally, the first incision is made slightly larger than the width of the drug delivery implant. In one embodiment, a conventional cyclodissection spatula can be inserted into the supraciliary space through the first incision to confirm the correct anatomical location.

[0229] A portion of the upper and lower surfaces of the drug delivery implant can be firmly grasped with a surgical tool, such as forceps, so that the front end of the implant is properly oriented. The implant can also be secured by viscoelasticity or by mechanical interlocking with the wall of the pusher tube or implant delivery device. In one embodiment, the implant is oriented so that the long axis of the implant is approximately coaxial with the long axis of the gripping end of the surgical tool. The drug delivery implant is placed through the first incision.

[0230] The delivery instrument can be advanced from the insertion site across the eyeball into the anterior chamber angle to a location near the scleral promontory. Using the scleral promontory as a reference point, the delivery instrument can be further advanced generally posteriorly to advance the implant toward the iris into the ocular tissue at a location just medial to the scleral promontory.

[0231] In some cases, depending on the implant structure, the shear edge of the implant's insertion head can pass between the scleral promontory and the ciliary body 16 posterior to the trabecular meshwork.

[0232] The drug delivery implant can be advanced continuously backwards until a portion of its insertion head and the first end of the conduit are located within the anterior chamber 20. Thus, the first end of the conduit is in fluid communication with the anterior chamber 20. The distal end of the elongated body of the drug delivery implant can be positioned in the suprachoroidal space of the eye such that the second end of the conduit is in fluid communication with the suprachoroidal space. Alternatively, the implant can be positioned adjacent to tissue in the anterior chamber angle, and the pusher tube can be advanced axially toward the distal end of the delivery instrument. As the pusher tube advances, so does the implant. Once the implant has been advanced through the tissue and no longer in the lumen of the delivery instrument, the delivery instrument is retracted to deposit the implant in the ocular tissue.

[0233] Positioning and implantation of the implant can be performed using a gonioscopic or other conventional imaging device. In some embodiments, a delivery instrument is used to move the implant to the desired location by applying a continuous implantation force, by tapping the implant into place with a distal portion of the delivery instrument, or by a combination of these methods. Once the implant is in the desired location, it can be further seated by tapping with a distal portion of the delivery instrument.

[0234] In one embodiment, the drug delivery implant is sutured to a portion of the sclera 11 to aid in fixation of the implant. In one embodiment, the first incision is then sutured closed. It should be understood that the suture material used to fix the drug delivery implant can also be used to close the first incision. In another embodiment, the drug delivery implant is held in place substantially without suturing the implant to the sclera 11 due to interaction of the outer surface of the implant body with the tissue of the sclera 11 and the ciliary body 16 and / or choroid 12. Additionally, in one embodiment, the first incision is small enough that the incision self-seals upon withdrawal of the surgical tools following implantation of the drug delivery implant without suturing the incision.

[0235] As discussed herein, in some embodiments, the drug delivery implant further comprises a shunt including a lumen configured to provide a drainage device between the anterior chamber 20 and the suprachoroidal space. Upon implantation, the drainage device can form a cyclodialysis, and the implant provides a sustained, patent communication of aqueous humor through the shunt along its length. Thus, aqueous humor can be delivered to the suprachoroidal space where it can be absorbed, further reducing intraocular pressure.

[0236] In some embodiments, it is desirable to deliver the drug delivery implant abinterno across the eyeball through a small incision at or near the limbus (FIG. 10). Depending on the overall system geometry, it is advantageous for the delivery instrument to include a distal curve (as in FIG. 8) or a distal angle (as in FIG. 7). In the former case, the drug delivery implant can be flexible to facilitate delivery along the curve, or it can be held more loosely to facilitate movement along a precise path. In the latter case, the implant can be relatively rigid. The delivery instrument can incorporate an implant advancement element (e.g., a pusher) that is flexible enough to pass through the distal angle.

[0237] In some embodiments, the implant and delivery device are advanced together from an incision at or near the limbus 21, through the anterior chamber 20, past the iris 13, through the ciliary muscle attachment, until the drug delivery implant exit is located in the uveoscleral pathway (e.g., adjacent the suprachoroidal space defined between the sclera 11 and the choroid 12). FIG. 10 illustrates a transocular implantation approach that may be used to insert the delivery device well above the limbus 21. In other embodiments (see, for example, FIG. 11), the incision may be made more posteriorly, closer to the limbus 21. In one embodiment, the incision is made on the nasal side of the eye, providing an implantation location for the drug delivery implant 40 on the temporal side of the eye. In another embodiment, the incision may be made on the temporal side, providing an implantation location for the drug delivery implant on the nasal side of the eye. In some embodiments, the operator pulls back on the delivery instrument while simultaneously pushing the pusher device to maintain the drug delivery implant outlet in the posterior region of the suprachoroidal space near the macula 34, as shown in Figure 12. The implant is released from the delivery instrument, and the delivery instrument is retracted proximally. The delivery instrument is withdrawn from the anterior chamber through the incision.

[0238] In some embodiments, to reduce intraocular pressure in glaucoma patients, it is desirable to implant a drug delivery implant that allows aqueous humor to continuously drain through the fibrous attachment zone, connecting the anterior chamber 20 to the uveoscleral pathway. In some embodiments, it is desirable to deliver the drug delivery implant using a device that traverses the eye from the inside (abinterno) through a small incision at the limbus 21.

[0239] In some embodiments, a microinvasive method of implanting a drug delivery implant is provided. In some such embodiments, an ab externo technique is utilized. In some embodiments, the technique is non-penetrating, thereby limiting the invasiveness of the implantation method. As discussed herein, in some embodiments, the implanted drug delivery device includes a shunt. In some embodiments, such an implant facilitates the removal of fluid from a first location while simultaneously delivering a drug. In some embodiments, the implant passes fluid from the anterior chamber to the suprachoroidal space to remove fluid (e.g., aqueous humor) from the anterior chamber and help prevent pressure buildup in the anterior chamber.

[0240] 8 shows a longitudinal section of the anterior segment of a human eye and diagrammatically illustrates another embodiment of a delivery device 38 that can be used with the drug delivery implant embodiments described herein. In FIG. 8, arrow 82 indicates the fibrous attachment zone of the ciliary muscle 84 and the sclera 11. The ciliary muscle 84 is coextensive with the choroid 28. The suprachoroidal space is the interface of the choroid 28 and the sclera 11. Other structures of the eye include the lens 26, cornea 12, anterior chamber 20, iris 13, and Schlemm's canal 22.

[0241] The delivery device / implant assembly can pass between the iris 13 and the cornea 12 to reach the iridocorneal angle. Thus, the height of the delivery device / shunt assembly (dimension 90 in FIG. 8) is less than about 3 mm in some embodiments, and less than 2 mm in other embodiments.

[0242] The suprachoroidal space between the choroid 28 and the sclera 11 generally forms an angle 96 of approximately 55 degrees with the optical axis 98 of the eye. This angle, in addition to the height requirements described in the previous paragraph, is a feature to be considered in the geometric design of the delivery device / implant assembly.

[0243] Depending on the overall geometry of the drug delivery implant system, it is advantageous for the delivery device 38 to incorporate a distal curve 86 as shown in FIG. 8, a distal angle, or a combination thereof. The distal curve (FIG. 9) is expected to pass more smoothly through the corneal or scleral incision at the limbus. In this embodiment, the drug delivery implant may be curved or flexible. Alternatively, the drug delivery implant may be mounted on a straight segment of the delivery device, distal to the "elbow" or angle. In this case, the drug delivery implant may be straight and relatively stiff, and the delivery device may incorporate a delivery mechanism that is flexible enough to advance through the angle. In some embodiments, the drug delivery implant may be a rigid tube, provided that the implant is no longer than the length of the distal segment.

[0244] The distal curve 86 of the delivery instrument 38 may be characterized as having a radius of about 10-30 mm in some embodiments, and about 20 mm in some embodiments. The distal angle of the delivery instrument in one embodiment having a straight section and a single corner near the distal end may be characterized as about 90-170 degrees relative to the axis of the proximal segment 94 of the delivery instrument. In another embodiment, the angle may be about 145 to about 170 degrees. The corner includes a small radius of curvature at the "elbow" to provide a smooth transition from the proximal segment 94 to the distal segment 92 of the delivery instrument. The length of the distal segment 92 may be about 0.5-7 mm in some embodiments, and about 2-3 mm in some embodiments.

[0245] In some embodiments, a viscoelastic or other fluid is injected into the suprachoroidal space to form a chamber or pocket between the choroid and the sclera that is accessible to the drug delivery implant. In embodiments where the drug delivery implant includes a shunt to reduce intraocular pressure (IOP), such a pocket exposes more of the choroidal and scleral tissue area, providing lubrication and tissue protection during implantation and increasing uveoscleral flow. In some embodiments, a 25G or 27G cannula is used to inject the viscoelastic material, for example, through an incision at the ciliary muscle attachment or through the sclera (e.g., from outside the eye). The viscoelastic material can also be injected through the implant itself before, during, or after implantation is complete.

[0246] In some embodiments, hyperosmolar agent is injected into the suprachoroidal space. Such injection can delay the fall of IOP. Thus, by temporarily lowering choroidal absorption, hypotony in the acute postoperative period can be avoided. Hyperosmolar agent can be, for example, glucose, albumin, HYPAQUE™ medium, glycerol or poly(ethylene glycol). Hyperosmolar agent can be decomposed or flushed out as the patient recovers, resulting in a stable and tolerable low IOP, and can avoid transient hypotony.

[0247] In some embodiments, the distal portion of the delivery device is sharpened like a needle and can form an opening in the sclera of the eye, allowing for direct placement of the implant, such as the implants of Figures 4A-4C, into the vitreous cavity of the eye after a plunger or actuator on the handpiece is pushed or pressed to expel the implant from the distal end of the device. In such embodiments, a straight needle or cannula may be preferred for delivering the implant.

[0248] Controlled Drug Release

[0249] The drug delivery implants described herein function to contain a drug and elute the drug from the implant in a controlled manner over an extended period of time, based on the design of the various components of the implant. The various elements of the implant composition, the physical properties of the implant, the location of implantation in the eye, and the composition of the drug work together to create a desired drug release profile.

[0250] As mentioned above, in some embodiments, the drug delivery implant is made of one or more biodegradable materials that degrade by bioerosion, bioresorption, bioabsorption, etc. after implantation in the eye and delivery of all or nearly all of the drug. Such materials can be permeable, semi-permeable, or impermeable to the drug delivered from the device. The materials can be formulated or manufactured to be porous or substantially non-porous. Suitable biodegradable materials can optionally have one or more additional physical properties, such as flexibility, hydrophilicity, hydrophobicity, elasticity, etc.

[0251] In some embodiments, the implant is engineered to control the rate of drug release from the device. In some such embodiments, the outer shell of the device controls almost entirely the rate of drug delivery. In other such embodiments, the outer shell controls a portion of the drug delivery rate, with the remainder being controlled by a drug-permeable membrane, which may be part of one or more membrane cap systems, such as drug release elements, as described above. In other embodiments, one or more membrane cap systems substantially or entirely control the rate of drug delivery.

[0252] Suitable biodegradable materials for the manufacture of implants and their components include the following: poly(esters), poly(ester amides) (PEA), poly(ester carbonates) (PEC), polylactic acid (PLA), poly(L-lactide) (PLLA), poly(D-lactide) (PDLA), poly(DL-lactic acid) (PDLLA), polyglycolide (PGA), polycaprolactone (PCL), copolymers such as polylactic acid-co-glycolide (PLGA), poly(hydroxyalkanoates), poly(3-hydroxybutyrate) (PHB), PHB copolymerized with 3-hydroxyvalerate (PHBV), poly(propylene glycolate ... Poly(butylene fumarate) (PPF), poly(anhydrides) (PAA), poly(butylene succinate) (PBS), poly(ethylene succinate) (PES), poly(hydroxyalkanoates) (PHAs), poly(cyanoacrylates) (PCAs), polyacetals, polyorthoesters (POE), polycarbonates including poly(trimethylene carbonate) (PTMC), polyphosphazenes, polyphosphates, as well as blends, copolymers and combinations of the above, and modified polysaccharides, such as natural polymers including, but not limited to, starch, cellulose, and chitosan.

[0253] The material may be coated on all or part of the inside and / or outside, on one or both sides. The coating may serve any of a variety of purposes, including, but not limited to, modifying the elution rate of the drug through the material (accelerating or slowing down the elution rate), modifying the degradation rate of the material (accelerating or slowing down the degradation rate), modifying water resistance or permeability (increasing or decreasing resistance or permeability), or other properties. The coating is preferably biodegradable.

[0254] The coating can be any suitable material, including, but not limited to, poly(lactic acid), polyethylene vinyl acetate, poly(lactic acid-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 polymers or copolymers. Suitable atomic or inorganic materials can also be used. As discussed above, various materials, coastings, and mechanisms for tailoring the elution profile of the drug from the device can be applied to any type of implant disclosed herein, including implants for intraocular placement and implants for punctal placement. Similarly, the use of bioerodible materials for the body of the implant can be used for implants for intraocular placement and implants for punctal placement. The ability of the implant to substantially or completely erode, whether for intraocular placement or for punctal placement, is advantageous in some embodiments. In some embodiments, erosion of the implant occurs after all or nearly all of the drug has been released from the implant. In some embodiments, erosion of the implant overlaps with at least a portion of the drug release. In some embodiments, erosion of the implant occurs simultaneously with drug release, and when all or nearly all of the drug has been released from the implant, the implant is substantially eroded.

[0255] In some ocular diseases, treatment may require a well-defined kinetic profile for administering a drug to the eye, such as zero-order release, pseudo-zero-order release, etc. From the above discussion of various embodiments, it should be understood that the ability to tailor the rate of drug release from the implant can be used to obtain a desired kinetic profile as well. For example, the composition of the shell and any polymeric coating can be manipulated to provide a particular kinetic profile of drug release. Furthermore, the design of the implant itself, including the thickness of the shell material, and the presence and composition of any caps, including drug release elements, are included in the method to provide a means to create a particular drug release profile. Similarly, PLGA copolymers and / or other controlled release materials and excipients can be used to provide a particular kinetic profile of the release of the formulated drug. In some embodiments, the zero-order release of the drug can be achieved by manipulating any of the above features and / or variables, alone or in combination.

[0256] In connection with controlled release of a drug to a target tissue, it is desirable to have a dose of the drug (or drugs) over a period of time in some embodiments. That is, in some embodiments, the total drug load delivered to the target tissue over the life of the implant is in the range of about 10 to about 1000 μg. In some embodiments, the total drug load is in the range of about 100 to about 900 μg, about 200 to about 800 μg, about 300 to about 700 μg, or about 400 to about 600 μg. In some embodiments, the total drug load is in the range of about 10 to about 300 μg, about 10 to about 500 μg, or about 10 to about 700 μg. In other embodiments, the total drug load is in the range of about 200 to about 500 μg, about 400 to about 700 μg, or about 600 to about 1000 μg. In yet other embodiments, the total drug loading ranges from about 200 to about 1000 μg, about 400 to about 1000 μg, or about 700 to about 1000 μg. In some embodiments, the total drug loading ranges from about 500 to about 700 μg, about 550 to about 700 μg, or about 550 to about 650 μg, including 575, 590, 600, 610, and 625 μg. It is understood that other drug ranges bordering, overlapping, or included in the above ranges are also used in certain embodiments.

[0257] Similarly, in another embodiment, the controlled drug delivery amount is calculated based on the drug elution rate from the implant. In certain such embodiments, the drug elution rate is about 0.05 μg / day to about 10 μg / day. In another embodiment, an elution rate of about 0.05 μg / day to about 5 μg / day, about 0.05 μg / day to about 3 μg / day, or about 0.05 μg / day to about 2 μg / day is obtained. In another embodiment, an elution rate of about 2 μg / day to about 5 μg / day, about 4 μg / day to about 7 μg / day, or about 6 μg / day to about 10 μg / day is obtained. In another embodiment, an elution rate of about 1 μg / day to about 4 μg / day, about 3 μg / day to about 6 μg / day, or about 7 μg / day to about 10 μg / day is obtained. In yet other embodiments, dissolution rates of about 0.05 μg / day to about 1 μg / day are obtained, including 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 μg / day. It is understood that other drug ranges bordering, overlapping, or included in the above ranges are also used in some embodiments.

[0258] Instead of or in addition to one or more of the above parameters, the release of the drug from the implant can be controlled based on a desired concentration of the drug in the target tissue. In some embodiments, the desired concentration of the drug in the target tissue is in the range of about 1 nM to about 100 nM. In other embodiments, the desired concentration of the drug at the site of action is in the range of about 10 nM to about 90 nM, about 20 nM to about 80 nM, about 30 nM to about 70 nM, or about 40 nM to about 60 nM. In yet other embodiments, the desired concentration of the drug at the site of action is in the range of about 1 nM to about 40 nM, about 20 nM to about 60 nM, about 50 nM to about 70 nM, or about 60 nM to about 90 nM. In yet other embodiments, the desired concentration of drug at the site of action ranges from about 1 nM to about 30 nM, about 10 nM to about 50 nM, about 30 nM to about 70 nM, or about 60 nM to about 100 nM. In some embodiments, the desired concentration of drug at the site of action ranges from about 45 nM to about 55 nM, including 46, 47, 48, 49, 50, 51, 52, 53, and 54 nM. It is understood that other drug ranges bordering, overlapping, or included in the above ranges are also used in certain embodiments.

[0259] <Drugs>

[0260] Therapeutic agents utilized with the drug delivery implant may include one or more of the following drugs, alone or in combination. The drugs utilized may also be one or more prodrugs, equivalents, derivatives, or analogs of the following drugs. Drugs may include, but are not limited to, pharmaceuticals including glaucoma drugs, ophthalmic agents, antimicrobial agents (e.g., antibiotics, antivirals, anthelmintics, antifungals), anti-inflammatory agents (including steroids or nonsteroidal anti-inflammatory drugs), hormones, enzymes or enzyme-related components, antibodies or antibody-related components, oligonucleotides (including DNA, RNA, small interfering RNA, antisense oligonucleotides, etc.), DNA / RNA vectors, viruses (wild-type or genetically modified) or viral vectors, peptides, proteins, enzymes, extracellular matrix components, and biological agents including live cells configured to produce one or more biological components. The use of any particular drug is not limited by its primary effect, or the therapeutic indication or use approved by a regulatory agency. Drugs also include compounds or other materials that reduce or treat one or more side effects of another drug or therapeutic agent. Because many drugs have multiple modes of action, the description of any particular drug within any one therapeutic class below is merely representative of one possible use of the drug and is not intended to limit the scope of its use with the ocular implant system.

[0261] As mentioned above, the therapeutic agent can be combined with any number of excipients known in the art. In addition to the biodegradable polymer excipients mentioned above, other excipients can be used, including, but not limited to, benzyl alcohol, ethyl cellulose, methyl cellulose, hydroxymethyl cellulose, cetyl alcohol, croscarmellose sodium, dextran, dextrose, fructose, gelatin, glycerin, monoglycerides, diglycerides, kaolin, calcium chloride, lactose, lactose monohydrate, maltodextrin, polysorbates, pregelatinized starch, calcium stearate, magnesium stearate, silicon dioxide, corn starch, talc, etc. One or more excipients may comprise only about 1%, 5%, or 10% in total, and in other embodiments, may comprise as much as 50%, 70%, or 90% in total.

[0262] Exemplary drugs include various antisecretory drugs, antimitotic drugs, and other antiproliferative drugs, such as, inter alia, angiogenesis inhibitors, such as angiostatin, anecortave acetate, thrombospondin, VEGF receptor tyrosine kinase inhibitors, and anti-vascular endothelial growth factor (anti-VEGF) drugs, such as ranibizumab (e.g., LUCENTIS®) and bevacizumab (e.g., AVASTIN®), pegaptanib (e.g., MACUGEN®), aflibercept (e.g., E YELEA®), anti-PDGF (e.g., FOVISTA®), latanoprostene bunod (e.g., VESNEO®), netarsudil AR-11324 (e.g., RHOPRESSA®), olopatadine, sunitinib, and sorafenib, as well as any of the various known small molecules and transcription inhibitors that have antiangiogenic activity; various classes of known ophthalmic agents, such as glaucoma agents, e.g., adrenergic antagonists, e.g., beta blockers, e.g., atenolol propranolol, metipranolol, betaxolol, carteolol, levobetaxolol, levobunolol and timolol; adrenergic or sympathomimetic agents, such as epinephrine, dipivefrin, clonidine, apraclonidine and brimonidine; parasympathomimetic or cholinergic agents, such as pilocarpine, carbachol, phosphoryl iodine and physostigmine, salicylate, acetylcholine chloride, eserine, diisopropyl fluorophosphate, demecarium bromide; muscarinic agents; carbonic anhydrase inhibitors, such as topical and / or systemic agents, e.g. These may include, for example, acetozolamide, brinzolamide, dorzolamide and methazolamide, ethoxyzolamide, diamox and diclophenamide; mydriatic-cycloplegic drugs such as atropine, cyclopentolate, succinylcholine, homatropine, phenylephrine, scopolamine and tropicamide; prostaglandins such as prostaglandin F2 alpha, antiprostaglandins, prostaglandin precursors or prostaglandin mimetics such as bimatoprost, latanoprost, travoprost and unoprostone.

[0263] Other examples of drugs include anti-inflammatory agents, such as glucocorticoids and corticosteroids, such as betamethasone, cortisone, dexamethasone, dexamethasone 21-phosphate, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, prednisolone, fluorometholone, loteprednol, medrysone, fluocinolone acetonide, triamcinolone acetonide, triamcinolone, triamcinolone acetonide, bec lometasone, budesonide, flunisolide, fluorometholone, fluticasone, hydrocortisone, hydrocortisone acetate, loteprednol, rimexolone, and nonsteroidal anti-inflammatory drugs such as diclofenac, flurbiprofen, ibuprofen, bromfenac, nepafenac, and ketorolac, salicylates, indomethacin, ibuprofen, naxopren, piroxicam, and nabumetone; anti-infective or anti-bacterial drugs, For example, antibiotics such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, rifampicin, ciprofloxacin, tobramycin, gentamicin, 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, ganciclovir, interferons; antifungals; immunomodulators such as antiallergic drugs such as sodium cromoglycate, antazoline, methapyrilene, chlorpheniramine, cetirizine, pyrilamine, profenpyridamine; antihistamines such as azelastine, emedastine and levocabastine;Immunologic agents (such as vaccines, immunostimulants and / or immunosuppressants); mast cell stabilizers such as cromolyn sodium, ketotifen, lodoxamide, nedocromil, olopatadine and pemirolast; cyclotactic agents such as gentamicin 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, tetrahydrozoline; lipids or antihypertensive lipids; dopamine agonist agonists and / or antagonists, such as quinpirole, fenoldopam, and ibopamine; vasospasm inhibitors; vasodilators; antihypertensives; angiotensin-converting enzyme (ACE) inhibitors; angiotensin-1 receptor antagonists, such as olmesartan; microtubule inhibitors; molecular motor (dynein and / or kinesin) inhibitors; actin cytoskeleton regulators, such as cytochalasin, latrunculin, swinholide A, ethacrynic acid, H-7, and Rho-kinase (ROCK) inhibitors; remodeling inhibitors; extracellular matrix modulators, such as tert-butylhydro-quinolones and AL-3037A; adenosine receptor agonists and / or antagonists, such as N-6-cyclohexyl adenosine and (R)-phenylisopropyl adenosine; serotonergic agents; hormonal agents, such as estrogen, estradiol, progesterone, insulin, calcitonin, parathyroid hormone, peptides and vasopressin hypothalamic releasing factor; growth factor antagonists or growth factors, such as epidermal growth factor, fibroblast growth factor, platelet derived growth factor, Also included may be growth factors or antagonists thereof (e.g., those disclosed in U.S. Pat. No. 7,759,472 or U.S. patent application Ser. Nos. 12 / 465,051, 12 / 564,863 or 12 / 641,270, each of which is incorporated by reference herein in its entirety), transforming growth factor beta, somatotropin, fibronectin, connective tissue growth factor, bone morphogenetic proteins (BMPs); cytokines such as interleukins, CD44, coagulants, and serum amyloids such as serum amyloid A;

[0264] Other therapeutic agents include neuroprotectants, such as lubezole, nimodipine and related compounds, such as blood flow improvers, such as dorzolamide or betaxolol; compounds that promote blood oxygenation, such as erythropoietin; sodium channel blockers; calcium channel blockers, such as nilvadipine or lomerizine; glutamate inhibitors, such as memantine. nitromemantine, riluzole, dextromethorphan or agmatine; acetylcholinesterase inhibitors, e.g. galantamine; hydroxylamine or a derivative thereof, e.g. the water-soluble hydroxylamine derivative OT-440; synaptic modulators, e.g. hydrogen sulfide compounds including flavonoid glycosides and / or terpenoids, e.g. ginkgo biloba; neurotrophic factors, e.g. glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor; cytokines of the IL-6 family of proteins, e.g. ciliary neurotrophic factor or leukemia inhibitory factor; compounds or factors that affect nitric oxide levels, e.g. nitric oxide, nitroglycerin or nitric oxide synthase inhibitors; cannabinoid receptor agonists, e.g. WIN55-212-2; free radical scavengers, e.g. methoxypolyethylene glycol thioester (MPDTE), or methoxypolyethylene glycol thiol coupled with EDTA methyl triester (MPSE DE; antioxidants, such as astaxanthin, dithiolthiones, vitamin E, or metallocorrols (e.g., iron, manganese, or gallium corrols); compounds or factors involved in oxygen homeostasis, such as neuroglobin or cytoglobin; inhibitors or factors affecting mitochondrial division or fission, such as Mdivi-1 (selective inhibitor of dynamin-related protein 1 (Drp1)); kinase inhibitors or modulators, such as the Rho kinase inhibitor H-1152 or the tyrosine kinase inhibitor AG1478; compounds or factors affecting integrin function, such as the beta1-integrin activating antibody HUTS-21; N-acyl-ethanolamines and their precursors, N-acyl-ethanolamine phospholipids; stimulators of the glucagon-like peptide 1 receptor (e.g., glucagon-like peptide 1); polyphenol-containing compounds, such as resveratrol; chelating compounds; apoptosis-related protease inhibitors;These include compounds that inhibit new protein synthesis; radiotherapy drugs; photodynamic therapy drugs; gene therapy drugs; gene regulators; autoimmune modulators that prevent damage to nerves or parts of nerves (e.g., demyelination), such as glatimir; myelin inhibitors, such as anti-NgR blocking protein, NgR(310)ecto-Fc; other immunomodulators, such as FK506 binding proteins (e.g., FKBP51); and dry eye medications, such as cyclosporine, cyclosporine A, demulcents, and sodium hyaluronate;

[0265] Other therapeutic agents that may be used include other beta-blockers, such as acebutolol, atenolol, bisoprolol, carvedilol, esmolol, labetalol, nadolol, penbutolol, and pindolol; other corticosteroids and nonsteroidal anti-inflammatory drugs, such as aspirin, betamethasone, cortisone, diflunisal, etodolac, fenoprofen, fludrocortisone, flurbiprofen, hydrocortisone, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, meloxicam ... cicam, methylprednisolone, nabumetone, naproxen, oxaprozin, prednisolone, piroxicam, salsalate, sulindac and tolmetin; COX-2 inhibitors such as celecoxib, rofecoxib and valdecoxib; other immunomodulators such as aldesleukin, adalimumab (HUMIRA®), azathioprine, basiliximab, daclizumab, etanercept (ENBREL®), hydroxychloroquine, infliximab (REMICADE®), leflunomide, methotrexate other antihistamines such as loratadine, desloratadine, cetirizine, diphenhydramine, chlorpheniramine, dexchlorpheniramine, clemastine, cyproheptadine, fexofenadine, hydroxyzine and promethazine; other antiinfectives such as aminoglycosides such as amikacin and streptomycin; antifungals such as amphotericin B, caspofungin, clotrimazole, fluconazole, itraconazole, ketoconazole, voriconazole, antimalarials such as chloroquine, atovaquone, mefloquine, primaquine, quinidine and quinine; antimycobacterials such as ethambutol, isoniazid, pyrazinamide, rifampin and rifabutin; antiparasitic agents such as albendazole, mebendazole, thiobendazole, metronidazole, pyrantel, atovaquone, iodoquinol, ivermectin, paromycin, praziquantel and trimetrexate;Other antiviral drugs, such as anti-CMV or anti-herpes drugs, such as acyclovir, cidofovir, famciclovir, ganciclovir, 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, ddI, 3TC, d4T, ddC, tenofovir and emtricitabine, delavirdine. other antivirals such as interferons, ribavirin and trifluridiene; other antibacterials such as carbapenems such as ertapenem, imipenem and meropenem; cephalosporins such as cefadroxil, cefazolin, cefdinir, cefditoren, cephalexin, cefaclor, cefepime, cefoperazone, cefotaxime, cefotetan, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, cefoxitin, ftriaxone, cefuroxime and loracarbef; other macrolides and ketolides such as azithromycin, clarithromycin, dirithromycin and telithromycin; penicillins (with and without clavulanic acid) such as amoxicillin, ampicillin, pivampicillin, dicloxacillin, nafcillin, oxacillin, piperacillin, and ticarcillin; tetracyclines such as doxycycline, minocycline and tetracycline; other antibacterial agents such as aztreonam, chloramphenicol, clindamycin, cyclosporine ... damycin, linezolid, nitrofurantoin and vancomycin; alpha blockers such as doxazosin, prazosin and terazosin; calcium-channel blockers such as amlodipine, bepridil, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine and verapamil; other antihypertensive drugs such as clonidine, diazoxide, fenoldopam, hydralazine, minoxidil, nitroprusside, phenoxybenzamine, epoprostenol, tolazoline, treprostinil and nitrates;Anticoagulants, such as heparins and heparinoids, e.g., heparin, dalteparin, enoxaparin, tinzaparin and fondaparinux; other anticoagulants, such as hirudin, aprotinin, argatroban, bivalirudin, desirudin, lepirudin, warfarin and ximelagatran; antiplatelet agents, such as abciximab, clopidogrel, dipyridamole, eptifibatide, ticlopidine and tirofiban; prostaglandin PDE-5 inhibitors and other prostaglandin agents, such as alprostadil, carboprost, sildenafil, tadalafil and vardenafil; thrombin inhibitors; antithrombotic agents; antiplatelet aggregation agents; thrombolytic and / or fibrinolytic agents, such as alteplase, anisidine, thrombin inhibitors, Treplase, Reteplase, Streptokinase, Tenecteplase and Urokinase; Antiproliferative agents such as Sirolimus, Tacrolimus, Everolimus, Zotarolimus, Paclitaxel and Mycophenolic Acid; Hormonal related drugs such as Levothyroxine, Fluoxymestron, Methyltestosterone, Nandrolone, Oxandrolone, Testosterone, Estradiol, Estrone, Etropipate, Clomiphene, Gonadotropins, Hydroxyprogesterone, Levonorgestrel, Medroxyprogesterone, Megestrol, Mifepristone, Norethindrone, Oxytocin, Progesterone, Raloxifene and Tamoxifen; Antineoplastic agents such as Alkylating Agents such as Carmustine. lomustine, melphalan, cisplatin, fluorouracil 3, and procarbazine; antibiotic-like agents such as bleomycin, daunorubicin, doxorubicin, idarubicin, mitomycin, and plicamycin; antiproliferative agents such as 1,3-cis retinoic acid, 5-fluorouracil, taxol, rapamycin, mitomycin C, and cisplatin; antimetabolites such as cytarabine, fludarabine, hydroxyurea, mercaptopurine, and 5-fluorouracil (5-FU); immunomodulatory agents such as aldesleukin, imatinib, rituximab, and tositumomab; mitotic inhibitors docetaxel, etoposide, vinblastine, and vincristine; radioactive agents such as strontium 89; and other antitumor agents such as irinotecan, topotecan, and mitotane.

[0266] The drug carried by the drug delivery implant can be in any form that can be adequately retained within the device, resulting in controlled elution of one or more resident drugs over a period of time lasting up to several years. Some embodiments utilize drugs that are easily soluble in ocular fluids, while other embodiments utilize drugs that are partially or slightly soluble in ocular fluids. It must be reemphasized that "drug" as used herein includes active drugs, their prodrugs and salts, as well as drugs that have been modified to other states for storage, membrane permeability, stability, etc. Drugs stored in the device can include excipients, stabilizers, agents that modify dissolution or dissolution rate, and any other materials or agents that aid in the stability and desired elution of the drug over a period of time.

[0267] For example, the therapeutic agent can be in any form, including, but not limited to, compressed pellets, solids, capsules, multiple particles, liquids, oils, gels, suspensions, slurries, emulsions, and the like. In certain embodiments, the drug particles are in the form of micropellets (e.g., microtablets), fine powders, or slurries, each of which have fluid-like properties and can be reloaded by injection into the inner lumen in the same manner as liquids or oils. In some embodiments, the loading and / or reloading of the device is performed with a syringe / needle that delivers the therapeutic agent. In some embodiments, they are delivered through a needle that is about 23 gauge to about 32 gauge, including 23-25 ​​gauge, 25-27 gauge, 27-29 gauge, 29-30 gauge, 30-32 gauge, and overlapping ranges thereof. In some embodiments, the needle is 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32 gauge.

[0268] When more than one drug is desired for the treatment of a particular condition, or when a second drug is administered to counteract the side effects of a first drug, etc., some embodiments may utilize the same form of the two drugs. In other embodiments, different forms of the drugs may be used. Similarly, when one or more drugs utilize an adjuvant, excipient, or auxiliary compound, for example, to enhance stability or to adjust the elution profile, the compound or compounds may also be in any form that is compatible with the drug and can be adequately retained by the implant.

[0269] In some embodiments, the treatment of a particular condition with a drug released from an implant may not only treat the condition, but may also induce certain undesirable side effects. In some cases, the delivery of certain drugs may treat a pathological condition, but may indirectly increase intraocular pressure. For example, steroids may have such an effect. In some embodiments, a drug delivery implant that delivers steroids to an ocular target tissue may induce an undesirable increase in intraocular pressure. In such embodiments, the drug delivery implant may include a shunt function that reduces undesirable high intraocular pressure by transporting excess aqueous humor from the anterior chamber. Thus, in some embodiments, an implant that functions as both a drug delivery device and a shunt can help deliver a therapeutic agent and at the same time help drain accumulated fluid, thereby reducing the side effects of the drug.

[0270] It is understood that the embodiments described herein may include drugs mixed or compounded with biodegradable materials, excipients, or other agents that alter the release characteristics of the drug. Preferred biodegradable materials include those described above, including poly(lactic-co-glycolic acid), a copolymer of lactic acid and glycolic acid, also known as PLGA. Although some disclosures herein explicitly describe the use of PLGA, those skilled in the art will understand that in such embodiments, other suitable biodegradable materials can be used in place of or in combination with PLGA. It is also understood that in certain embodiments described herein, the drug placed within the lumen of the implant is not compounded or mixed with any other compounds or materials, thereby maximizing the volume of drug placed within the lumen.

[0271] In some embodiments, it may be desirable to define a particular drug release rate from a PLGA copolymer or other polymeric material. The drug release rate from a polymer correlates with the degradation rate of that polymer, so controlling the degradation rate is a means to control the drug delivery rate. The average molecular weight of the polymer or copolymer chains that make up the PLGA copolymer or other polymer can be used to control the degradation rate of the copolymer, thereby obtaining a desired duration or alternative release profile of therapeutic agent delivery to the eye. In certain other embodiments employing copolymers, the biodegradation rate of the copolymer can be controlled by changing the ratio of monomers or oligomers in the copolymer. Yet other embodiments use a combination of changing the average molecular weight of the copolymer components and changing the composition of the copolymer to obtain a desired biodegradation rate. EXAMPLES

[0272] In many configurations of the bioabsorbable implants disclosed herein, the protein drug concentration within the device will gradually decrease during use. Since the elution rate is proportional to the concentration gradient inside and outside the device, the elution rate will also gradually decrease. Taking this into account, in some embodiments, the elution features and initial protein drug concentrations are selected such that a therapeutic elution rate is still delivered for an extended period of time (e.g., 3, 6, 9 months or more).

[0273] 21A and 21B show predicted elution data associated with elution from an implant according to some embodiments, where the initial protein concentration in the device is 300 mg / mL, the initial loading of protein is 300 μg, the total elution feature area and wall thickness are sized such that the initial elution rate through the elution features is 14 μg / week, and the elution feature dimensions are fixed. Under these assumptions, the concentration of drug protein in the device will decrease by about 9-fold over 6 months as the drug elutes through the elution features (FIG. 21A), and the rate will decrease over time (FIG. 21B).

[0274] The rate of erosion can be determined by selecting the chemical structure of the bioabsorbable material. The bioabsorbable material can be determined to be absorbable over days, weeks, or months. The chemical bonds within the bioabsorbable material can be hydrodegradable (polymers, copolymers, and oligomers of glycolide, dl-lactide, l-lactide, dioxanone, esters, carbonates, and trimethylene carbonate); or enzymatically degradable (peptides, amides, polyetheramides, etc.); or poly(hydroxy acids), poly(orthocarbonates), poly(anhydrides) (poly(anydride)), poly(lactones), poly(amino acids), poly(carbonates), and poly(phosphonates), or any combination of the above.

[0275] Figures 22A and 22B show drug elution data according to some embodiments herein. Figure 21A shows the drug elution rate over time from an implant, where the tubing is a approximately 1 inch long segment of LDPE, 0.040 inch (1 mm) ID, the hydrogel plugs were polymerized from 5% acrylamide and 0.14% methylene bisacrylamide, the hydrogel plugs were cut to approximately 1-3 mm lengths, the protein solution was initially 150 mg / ml bovine serum albumin (e.g., a surrogate for ranibizumab), and approximately 1 cm of each tubing was filled with a loading amount of approximately 1200 μg of BSA solution.

[0276] FIG. 22B shows the time course of drug elution rate from the implants, where the tubing was approximately 1 inch long segments of 350×500 micron PLG8523, the hydrogel plugs were polymerized from 7.5% acrylamide and 0.21% methylenebisacrylamide, the hydrogel plugs were cut to approximately 1-3 mm lengths, the protein solution was initially 200 mg / ml 40 kD FITC-dextran (e.g., a surrogate for ranibizumab), and approximately 1.5 cm of each tubing was filled with a loading amount of approximately 300 μg of FITC-dextran solution.

[0277] Although certain embodiments of the present disclosure have been described, these embodiments are presented by way of example only and are not intended to limit the scope of the present disclosure. Indeed, the novel methods, systems, and devices described herein may be embodied in a variety of alternative forms. For example, one illustrated or described implant embodiment may be combined with another illustrated or described shunt embodiment. Furthermore, the implant may be utilized for other purposes. For example, the implant may be used to drain fluid from the anterior chamber to the eye or elsewhere outside the eye. Moreover, various omissions, substitutions, and changes may be made in the form of the methods, systems, and devices described herein without departing from the spirit of the present disclosure.

[0278] One or more of the features shown in the drawings and / or described herein may be rearranged and / or combined into a single component or embodied as several components. Additional components may also be added. While certain exemplary embodiments have been described and illustrated in the accompanying drawings, it is to be understood that such embodiments are merely illustrative and not limiting. Thus, the invention is not limited to the specific constructions and arrangements shown and described, since various other modifications may occur to those skilled in the art based on this disclosure.

[0279] The various operations of the methods described above may be performed by any suitable means capable of performing an operation, such as various hardware and / or software components, circuits, and / or modules. In general, any operation illustrated in the figures may be performed by a corresponding functional means capable of performing the operation.

[0280] The methods disclosed herein include one or more steps or actions for performing the described method. Method steps and / or actions may be interchanged with one another without departing from the scope of the claims. In other words, unless a specific order of steps or actions is specified, the order and / or use of specific steps and / or actions may be modified without departing from the scope of the claims. Method steps and / or actions disclosed herein may be performed in conjunction with one another, and steps and / or actions may be further divided into additional steps and / or actions.

[0281] It is to be understood that the claims are not limited to the precise configuration and components illustrated above. Various modifications, changes and variations can be made in the arrangement, operation and details of the methods and apparatus described above.

Claims

1. 1. An ocular implant configured for implantation into an eye of a subject, comprising: an elongated shell comprising a bioerodible material and shaped to define a single continuous internal lumen extending from a proximal end to a distal end; a plug and drug mixture located within the internal lumen, the mixture including a drug at least partially dispersed or mixed within the internal plug, the plug and drug mixture filling the entire internal lumen; a first orifice and a second orifice located substantially opposite the first orifice; Including, the drug is configured to pass through the inner plug, which controls elution of the drug through at least one of the orifices; The ocular implant is disposed within the vitreous cavity.

2. 2. The ocular implant of claim 1, wherein the one or more orifices are located near a distal end of the outer shell, the orifices configured to control the elution of the drug through the inner plug and out of the implant.

3. 3. The ocular implant of claim 1 or 2, further comprising a coating surrounding at least a portion of the outer shell.

4. The ocular implant of any one of claims 1 to 3, wherein the proximal end comprises a cap.

5. 5. The ocular implant of claim 1, wherein the outer shell is configured to begin to bioerode after all or substantially all of the drug has eluted from the interior lumen of the implant.

6. 5. The ocular implant of claim 1, wherein the outer shell is configured to begin to bioerode while at least a portion of the drug that elutes from the internal lumen of the implant remains in the internal lumen.

7. The ocular implant of any one of claims 1 to 6, wherein the implant is configured for implantation into the eye of a subject.

8. The ocular implant of any one of claims 1 to 7, wherein the implant is located within the lumen of a 23-25 ​​gauge needle or cannula of a delivery device.

9. 9. The ocular implant of claim 1, wherein the one or more orifices are disposed near a proximal end of the shell, the orifices being configured to control the elution of the drug out of the implant.

10. The ocular implant of any one of claims 1 to 9, wherein the implant is in a capsule shape.

11. The ocular implant of any one of claims 1 to 10, wherein the proximal and distal ends are each rounded.

12. The ocular implant of any one of claims 1 to 11, wherein the drug comprises at least 50% of the inner plug and drug mixture.

13. The ocular implant of any one of claims 1 to 12, wherein the inner plug and drug mixture is preformed.

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