Implant piece having feature of controlled drug delivery and method using the same

Abstract

To provide a drug delivery device and method for treating an eye disease that requires targeted and controlled dosage of drug to the inside of an eye in order to alleviate or prevent a symptom of disorder.SOLUTION: The device has a structure that can perform controlled discharge of one or more drugs and enables treatment of intraocular pressure elevation by allowing aqueous humor to flow out from an anterior chamber through the device.SELECTED DRAWING: Figure 18S

Description

[Technical field]

[0001] <Related Items>

[0002] This application claims the benefit of U.S. Provisional Application No. 61 / 788,731, filed March 15, 2013, the disclosure of which is incorporated herein by reference in its entirety.

[0003] <Field>

[0004] 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 some embodiments, the present disclosure relates to the treatment of elevated intraocular pressure by draining aqueous humor from the anterior chamber via a surgical implant route. In some embodiments, the present disclosure also relates to the treatment of ocular diseases with drug delivery devices secured to the eye, particularly fibrous tissue within the eye. [Background technology]

[0005] The mammalian eye is a specialized sensory organ that can receive light and visual images. The retina of the eye consists of photoreceptors, which are sensitive to different levels of light, and interneurons that relay signals from the photoreceptors to retinal ganglion cells, which transmit light-induced signals to the brain. The iris is the inner lining of the eye responsible for controlling the amount of light that reaches the retina. The iris consists of two layers (arranged from front to back): pigmented vascular connective tissue known as the stroma, and pigmented epithelial cells. The stroma connects a sphincter muscle (sphincter pupillae), which constricts the pupil, and a pair of dilator muscles (dilator pupillae), which dilate the pupil. The pigmented epithelial cells block light from passing through the iris, thereby limiting light passage into the pupil.

[0006] A number of conditions, 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 provides 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 others.

[0007] Other conditions such as abnormal intraocular pressure may also affect vision. Aqueous humor is a clear liquid that fills at least the area in the front of the eye between the cornea and the lens, creating pressure in the orbit. Normal intraocular pressure is maintained by drainage of aqueous humor from the anterior chamber by the trabecular meshwork in the anterior chamber angle between the iris and the cornea, or by the "uveoscleral pathway," a space or passageway by which aqueous humor leaves the eye, passing through the ciliary muscle bundles in the anterior chamber angle and into the tissue plane between the choroid and sclera that extends posterior to the optic nerve. 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, which, if untreated, can lead to blindness. Elevated intraocular pressure is the only risk factor associated with glaucoma that can be treated, therefore lowering intraocular pressure is the primary treatment goal in all cases of glaucoma, which can be accomplished by medical therapy, surgery, or a combination thereof.

[0008] 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. In many cases, absorption and processing of the active drug components of a therapeutic agent occurs before the drug reaches the ocular target site. Due to this metabolism, systemic administration may require harmfully high concentrations of the drug to reach therapeutic levels at the ocular target site. This may not only be impractical or expensive, but may also increase the incidence of side effects. Local administration may be limited by limited diffusion through the cornea or dilution of locally administered drugs 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 addresses the limitations of other delivery routes. Summary of the Invention [Means for solving the problem]

[0009] Some embodiments disclosed herein provide a drug delivery ocular implant including an outer shell having a proximal end, a distal end, the outer shell shaped to define an internal lumen, at least one first active drug disposed within the internal lumen, a cap configured to reversibly interact with the proximal end of the outer shell, a membrane disposed between the cap and the proximal end of the outer shell, and a retention protrusion on the distal end of the outer shell configured to secure the ocular implant to a target tissue site.

[0010] In some embodiments, the cap includes at least one opening. In some embodiments, a plurality of openings are provided. The total surface area of ​​the one or more openings can be selected, in one particular embodiment, based on the desired elution rate of the first active drug from the implant.

[0011] In some embodiments, a cap can be placed on the proximal end of the shell to 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 active 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 active drug occurs only through the membrane (e.g., compressing the membrane with the cap serves to seal release into other unintended drug pathways). In some embodiments, a distally placed seal is located within the lumen to limit fluid communication between the internal lumen and the ocular cavity only through the membrane. In some embodiments, the selected combination of dimensions (e.g., surface area) of the membrane and opening(s) is tailored to a particular desired elution rate of the first active agent.

[0012] In some embodiments, the membrane has a thickness of about 50 to about 100 μm. In such embodiments, such thickness provides drug elution from the implant for a period of about 12 to about 24 months. In some embodiments, the membrane has a thickness of about 90 to about 200 μm. In such embodiments, such thickness provides drug elution from the implant for a period of about 24 to about 48 months.

[0013] In some embodiments, the shell further comprises at least one fluid inflow pathway and one fluid outflow pathway, the at least one fluid inflow pathway and one fluid outflow pathway being configured to deliver ocular fluid to a physiological outflow pathway. Thus, in some embodiments, the implant is configured to provide not only medical therapy but also physical therapy (e.g., drainage). In some embodiments, the physiological outflow pathway is Schlemm's canal. In some embodiments, the at least one first active drug comprises a prostaglandin, a prostaglandin analog, a prostaglandin inhibitor, and / or combinations thereof. Additionally, in some embodiments, a second drug may be optionally provided. In some embodiments, the second (or third, etc.) drug provides a synergistic effect when combined with the first drug. In another embodiment, the second drug reduces one or more side effects associated with the first drug.

[0014] Further, in some embodiments, a drug delivery ocular implant is provided that includes an elongated shell having a proximal end, a distal end, the shell shaped to define an internal lumen, at least one first active drug disposed within the internal lumen, at least one fluid flow path extending from a proximal region of the shell to a more distal region of the shell, and a valve disposed at the distal-most end of the shell that can be reversibly opened and closed to allow passage of the at least one first active drug from the internal lumen to a target site outside the implant.

[0015] In some embodiments, the at least one fluid flow path is configured to direct ocular fluid to a physiological outflow pathway (e.g., to supplement the pharmacological effect of the active agent). In some embodiments, the first active agent comprises a plurality of drug pellets and the implant includes at least a second active agent. In some embodiments, the second active agent is contained within a polymer configured to polymerize at physiological temperatures to become a solid or semi-solid.

[0016] In some embodiments, the second active agent is contained within a micellar or vesicular structure configured to release the second active agent at a known rate. In some embodiments, the second active agent is contained within a micellar or vesicular structure configured to release the second active agent at a known rate, and the micellar or vesicular structure is mixed with a polymer configured to polymerize to a solid or semi-solid at physiological temperatures. Thus, in some such embodiments, upon delivery of the second agent to an ocular target tissue, exposure to the normal body temperature of the intraocular environment causes the polymer to polymerize, inhibiting migration of the second agent away from the target site (thereby improving its therapeutic effect).

[0017] In some further embodiments, a drug delivery ocular implant is provided that includes an elongated shell having a proximal end, a distal end, the shell being shaped to define an internal lumen with at least one first active drug disposed within the internal lumen, the shell having a first thickness, and the shell including one or more regions of drug release.

[0018] In some embodiments, the elongated shell is formed by extrusion. In some embodiments, the elongated shell comprises a biodegradable polymer. In some embodiments, the shell is permeable or semi-permeable to the first active drug, such that at least about 5% of the total elution of the first active drug can occur through the portion of the shell having the first thickness.

[0019] In some embodiments, the shell comprises a polyurethane, hi some embodiments, the polyurethane comprises a polysiloxane-containing polyurethane elastomer.

[0020] In some embodiments, the drug release region is configured to allow a drug elution rate different from elution through the outer shell. In some embodiments, the total elution rate of the first active drug from the implant is greater in the distal region of the implant. In some embodiments, the amount of the first active drug in the distal half of the implant is greater than the proximal half of the implant. In some other embodiments, the total elution rate of the first active drug from the implant is greater in the proximal region of the implant. In some embodiments, the amount of the first active drug in the proximal half of the implant is greater than the distal half of the implant. In some such embodiments, the implant is thus configured to treat the anterior segment of the subject's eye, and in some embodiments, drains ocular fluid to the outflow tract.

[0021] In some embodiments, the one or more regions of drug release comprise one or more regions of thin shell material, one or more orifices through the shell, or a combination thereof, hi certain embodiments, the one or more regions of drug release comprise an orifice, the orifice being disposed along the longitudinal axis of the implant shell.

[0022] In some embodiments, the implant further comprises one or more coatings that alter the elution rate of the first active agent from the implant.

[0023] In some embodiments, at least the distal most about 5 mm to about 10 mm of the inner lumen contains the drug.

[0024] In some embodiments, elution of the first active drug from the implant continues for at least one year.

[0025] In some embodiments, the first active drug is present as one or more micro-tablets. The micro-tablets have 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 active 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 internal diameter of about 23 to 25 gauge.

[0026] In some embodiments, the micro-tablets are formed by utilizing one or more processes selected from the group consisting of tabletting, freeze-drying, granulation (wet or dry), flaking, direct compression, molding, and extrusion. In some embodiments, the micro-tablets are configured to equilibrate the osmotic pressure between the internal lumen and the ocular environment outside the implant after implantation. In further embodiments, the micro-tablets are optionally coated with a coating that modulates the release of the first active drug from the micro-tablet. In some embodiments, the coating is a polymer coating.

[0027] In some embodiments, the first active drug is an angiogenesis inhibitor. In some embodiments, the first active drug is selected from the group consisting of angiostatin, anecortave acetate, thrombospondin, VEGF receptor tyrosine kinase inhibitors and anti-vascular endothelial growth factor (anti-VEGF) drugs. In some embodiments, the anti-VEGF drug is selected from the group consisting of ranibizumab, bevacizumab, pegaptanib, sunitinib and sorafenib. In some embodiments, the first active drug is bevacizumab.

[0028] In some embodiments, the first active 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, levobetaxolol, and combinations thereof. In some embodiments, the non-selective beta-adrenergic antagonist is selected from the group consisting of timolol, levobunolol, certeolol, metipranolol, and combinations thereof. In some embodiments, at least one active drug is used, and in some embodiments, the at least one first active drug is timolol.

[0029] 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.

[0030] Also provided herein is a method of treating an ocular condition or disorder in an intraocular target tissue, comprising connecting an opening in the temporal region of the 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, positioning the implant such that at least one of one or more drug release regions is adjacent to an intraocular target, 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 at least one year.

[0031] In some embodiments, the intraocular target is in the posterior chamber of the eye. 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 of the eye.

[0032] In some embodiments, inserting the drug delivery ocular implant into the 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, and Schlemm's canal, hi some embodiments, the drug delivery ocular implant is delivered to the lacrimal punctum.

[0033] Accordingly, some embodiments provide an implant for insertion into a 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 a punctum of the subject's eye, at least one first active drug disposed within the internal lumen, at least one region of drug release at a proximal portion of the outer shell, and a distal closure member of the internal lumen that prevents elution of the first active drug from the distal end of the implant.

[0034] In some such embodiments, the first active drug is eluted from the lumen into the tear film of the subject's eye 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 disposed in the lacrimal duct. In some embodiments, the implant is dimensioned to be implanted with the distal end of the shell disposed in the lacrimal sac. In some embodiments, the implant is dimensioned to be implanted with the distal end of the shell disposed in the nasolacrimal duct.

[0035] In some embodiments, the at least one region of drug release comprises at least one opening, and 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.

[0036] In some embodiments, the at least one region of drug release comprises a plurality of openings arranged randomly or in a pattern 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 described above.

[0037] In some embodiments, the implant further comprises a cap configured to reversibly interact with the proximal end of the shell, the cap comprising at least one opening. In some embodiments, the implant further comprises a membrane disposed between the proximal end of the shell and the cap, the membrane closing the at least one opening and 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.

[0038] Advantageously, in some embodiments, the at least one membrane is dimensioned based on the permeability of the membrane to the at least one first active drug and the desired elution time period of the first active drug, thereby tailoring the elution profile. For example, in some embodiments, the membrane has a thickness of about 50 to about 100 μm. In some such embodiments, the at least one first active drug elutes from the ocular implant for a period of about 12 to about 24 months. In some embodiments, the membrane has a thickness of about 90 to about 200 μm. In some such embodiments, the at least one first active drug elutes from the ocular implant for a period of about 24 to about 48 months.

[0039] In some embodiments, the distal closure member includes a plug. In yet another embodiment, the distal closure member includes a one-way valve that allows fluid flow from the internal lumen to the distal end of the device. In some such embodiments, the one-way valve is configured to remain closed until exposed to high fluid pressure. For example, in some embodiments, the one-way valve is configured to open in response to infusion fluid to allow flushing from the internal lumen to the nasolacrimal duct. This may occur, for example, if the concentration or type of drug eluting from the implant changes or when the implant is reloaded.

[0040] In some embodiments, the implants configured for insertion into the punctum are about 0.5 to about 2.5 mm in length. For example, in some embodiments, the implants are about 1.4 to about 1.6 mm in length. In some embodiments, the implants are about 0.2 to about 1.5 mm in diameter. For example, in some embodiments, the implants are about 0.2 to about 1.5 mm in diameter. In some embodiments, the implants are about 0.2 to about 0.6 mm in diameter. Advantageously, the length and diameter of any of the implants disclosed herein can be adjusted to fit the dimensions of the physiological space in which the implant is to be placed. In some embodiments, this ensures that the implant is placed and remains in the desired location.

[0041] In some embodiments, the first active drug is disposed proximal to the lumen of the implant so as to be disposed at the tear punctum. In some embodiments, the first active drug is for treating dry eye. For example, in some embodiments, the first active drug is cyclosporine, cyclosporine A, moxifloxacin, or a combination of these drugs (or any of the other drugs disclosed herein). In some embodiments, the first active drug is a drug for treating glaucoma. In some embodiments, the first active drug is a steroid. In some embodiments, the first active drug promotes tear production.

[0042] Also provided is a composition for treating ophthalmic disease comprising a therapeutic agent having anti-vascular endothelial growth factor (VEGF) activity. The anti-VEGF agent is formed into at least one micro-tablet. In some embodiments, the anti-VEGF agent is freeze-dried prior to forming the micro-tablet. In some embodiments, the anti-VEGF agent comprises at least 70% by weight of the total weight of each micro-tablet, and in some embodiments, each micro-tablet has a density of about 0.7 g / cc to about 1.6 g / cc. In yet another embodiment, each micro-tablet has 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, each micro-tablet has an aspect ratio of length to diameter of about 2.8 to 3.6.

[0043] Also provided is a system for administering a therapeutic agent to an injured or diseased eye. The system includes an ocular implant delivery device including a cannula having a proximal end, a distal end, and an inner diameter of about 23 to 25 gauge; an ocular implant including an elongated shell having a proximal end, a distal end, the shell being shaped to define an internal lumen suitable for receiving one or more micro-tablets, the shell having at least a first thickness, and including one or more drug release regions; and a therapeutic agent having anti-vascular endothelial growth factor (VEGF) activity formed into at least one micro-tablet. In some embodiments, the anti-VEGF agent is lyophilized prior to micro-tablet formation. In some embodiments, the anti-VEGF agent comprises at least 70% by weight of the total weight of each micro-tablet. In some embodiments, each micro-tablet has a density of about 0.7 g / cc to about 1.6 g / cc. In yet another embodiment, the micro-tablet has an aspect ratio of length to diameter of about 2.8 to 3.6.

[0044] Also provided herein is a method for intravitreal injection of a drug for treating an ocular disease, comprising advancing a delivery device comprising a proximal end, a distal end, and a cannula of about 23 to 25 gauge inner diameter containing a therapeutic agent having anti-vascular endothelial growth factor (VEGF) activity, one or more micro-tablets containing an activating agent operable to expel the contents of the cannula from the device through the proximal end, to the scleral surface of the eye, piercing the scleral surface to perforate the sclera, advancing the delivery device further through the hole such that the proximal end is within the vitreous cavity of the eye, activating the activating agent to expel the anti-VEGF micro-tablets, and withdrawing the device from the eye, thereby delivering the anti-VEGF micro-tablets to treat the disease.

[0045] In some embodiments, the micro-tablets have a minor axis of about 0.28 to 0.31 mm and a major axis of about 0.8 to 1.1 mm, hi some embodiments, the density of the micro-tablets is about 0.7 g / cc to about 1.6 g / cc.

[0046] In some embodiments, the scleral perforation is performed with an instrument having a sharp proximal end, hi some embodiments, the hole in the sclera is small enough to self-heal.

[0047] According to some embodiments, a drug delivery ocular implant is provided, comprising an elongated shell having a proximal end and a distal end, the shell being shaped to define an internal lumen, and at least a first drug disposed within the internal lumen. In some embodiments, the shell has a substantially uniform first thickness, the shell is permeable or semi-permeable to the drug, such that at least about 5% of the total elution of the drug can occur through the portion of the shell having the first thickness, and the shell comprises one or more drug release regions. In some embodiments, the one or more drug release regions comprise regions of greater or higher elution or drug permeability than the portion of the shell having the first thickness. Such regions of higher permeability can include one or more shells of a smaller thickness, one or more orifices, a material different from the remainder of the shell, and / or other means of increasing the permeability or elution of the drug. In other embodiments, the entire elution of the drug is through the shell, which may be considered a drug release region in its entirety or one or more portions thereof.

[0048] In some embodiments, a drug delivery ocular implant is provided that includes an elongated shell having a proximal end, a distal end, the shell being shaped to define an internal lumen, and at least a first drug disposed within the internal lumen. The shell preferably has a substantially uniform first thickness such that about 5 to 15% of the total elution of the drug may occur through the shell having the first thickness. The shell may include one or more drug release regions, the drug release regions configured to permit different drug elution rates from one another. In some embodiments, the total elution rate of the drug from the implant may vary along the length of the implant, in some cases.

[0049] In some embodiments, an implant is provided having regions of drug release, with one or more regions that allow for a higher drug elution rate than elution through another region of the shell that is configured to allow for a higher drug elution rate than elution through another region of the shell. In some embodiments, the regions of higher drug release include one or more regions of thin shell material, one or more orifices through the shell, or a combination thereof. In some embodiments, the shell can optionally include silicone and / or have one or more orifices through the shell. In such embodiments, the orifices can be located along the long axis of the implant shell or elsewhere. In other embodiments, the shell can optionally include siliconized urethane and / or include regions of reduced thickness, with or without any orifices through the shell.

[0050] In some embodiments disclosed herein, a drug delivery ocular implant is provided that includes an outer shell having a proximal end, a distal end, and a shape that defines an inner lumen, the outer shell having a substantially uniform first thickness and one or more regions of a second thinner shell thickness compared to the first thickness, and a drug disposed within the inner lumen. The thickness of the outer shell is inversely proportional to the drug elution rate through the shell. In some embodiments, the outer shell of the first thickness is substantially impermeable to the drug. Release of the drug from the inner lumen is at least partially controlled by the permeability of the outer shell to the drug, with regions of thinner shell thickness having a higher release rate.

[0051] Also provided is a drug delivery ocular implant comprising an outer shell having a proximal end, a distal end, and a shape defining an internal lumen, the outer shell having one or more partitions located within the inner lumen thereby forming two or more minor lumens, with a drug disposed within each minor lumen, in some embodiments, at least a portion of the outer shell is substantially drug impermeable, and the outer shell also includes one or more regions that are more permeable to the drug than the remainder of the shell, and release of the drug from the inner lumen is controlled at least in part by the permeability of the more permeable outer shell regions.

[0052] In some embodiments, a drug delivery ocular implant is also provided that includes an outer shell having a proximal end, a distal end and a shape defining an internal lumen, and a drug disposed within the internal lumen, wherein at least a portion of the outer shell is substantially impermeable to the drug, and the outer shell includes one or more regions that are more permeable to the drug than the remainder of the shell.

[0053] In some embodiments disclosed herein, a drug delivery ocular implant is provided that includes an outer shell shaped to define an inner lumen, a drug disposed within the inner lumen, the outer shell including a permeable material capable of transporting both a solvent and the drug through the shell, and release of the drug from the inner lumen is initiated by exposing the shell to a suitable solvent such that the solvent transports through the permeable material to contact the drug, and after the solvent contacts the drug, the drug transports through the permeable material and out of the shell, and transport of the drug is controlled at least in part by the permeability of the permeable material. The outer shell may also include one or more regions of substantially impermeable material.

[0054] In some embodiments, a medical device is provided for delivering a therapeutic agent to a patient, the medical device comprising a device dimensioned for placement in an area of ​​the patient's body and a therapeutic agent disposed on or within at least a portion of the device, where at least a portion of the device provides a physical effect that is useful in mitigating an undesirable side effect of the therapeutic agent.

[0055] In some embodiments, a drug delivery ocular implant is provided that includes an outer shell having one or more orifices therein and shaped to define an internal lumen, a drug disposed within the internal lumen, and one or more coatings disposed on an inner surface of the shell, an outer surface of the shell, and / or partially or entirely covering the drug disposed within the internal lumen. Embodiments may further include any one or more of the following features: the outer shell includes a material that is substantially impermeable to ocular fluid; the outer shell is substantially impermeable to the drug; at least one of the coatings defines, at least in part, a drug release rate; and the implant is dimensioned such that a distal end of the implant is disposed in the suprachoroidal space and a proximal end of the implant is disposed entirely within the eye.

[0056] In some embodiments, a drug delivery ocular implant is provided that includes an outer shell, optionally substantially impermeable to ocular fluids and having one or more orifices therein, shaped to define an internal lumen, a drug disposed within the internal lumen, and one or more coatings disposed on an inner surface of the shell, an outer surface of the shell, and / or partially or completely covering the drug disposed within the internal lumen, the implant being dimensioned such that the drug is released to a desired intraocular target following implantation.

[0057] In some embodiments, a drug delivery ocular implant is provided that includes a flexible material mixed with or coated with at least one drug, a flexible tether, the flexible material can be rolled or folded to form a tubular shape, the tubular shape is sized to be placed within a delivery device, the delivery device deploys the drug delivery ocular implant into intraocular tissue, and the tubular shape is released upon withdrawal of the delivery device, whereby the flexible material, which can be in the form of a sheet or disk, substantially returns to its original shape or configuration.

[0058] In some embodiments, a drug delivery ocular implant is provided that includes an outer shell shaped to define an internal lumen or space having an open end, a cap dimensioned to be fitted in or over the open end and having one or more orifices therein, and a drug disposed within the internal lumen. One or more coatings are optionally positioned between the cap inner surface, the cap outer surface, and / or layers of drug disposed within the internal lumen.

[0059] Any of the embodiments disclosed herein may optionally further include a lumen, opening, or shunt configured to transport ocular fluid from a first undesirable location to one or more other locations, thereby reducing intraocular pressure.

[0060] The implants described herein optionally exhibit differential elution along the length of the implant, and in some such embodiments, the elution rate is greater in the distal portion of the implant than in the more proximal region of the implant. In other embodiments, the elution rate of the implant is greater in the proximal portion of the implant than in the more distal region of the implant. Additionally, the implants may optionally further include one or more coatings on the interior and / or exterior of the device and / or on the drug contained therein that alter the rate of drug elution from the implant. The coatings may optionally cover different portions of the implant.

[0061] In some embodiments, the inner lumen contains the drug in the distal most 5 mm to about 10 mm. In some embodiments, the shell is about 10 mm to about 20 mm in length, has an outer diameter of about 150 μm to about 500 μm, and an inner lumen diameter of about 75 μm to about 475 μm.

[0062] In some embodiments described herein, the drug elutes from the implant with zero order or pseudo-zero order kinetics.

[0063] Also described herein is a method of treating or preventing an ocular condition at an intraocular target tissue, comprising making an incision in a strategic location (e.g., temporal, nasal, superior, inferior, etc.) on the cornea or limbus of an eye, advancing a delivery device coupled to a drug delivery implant according to some of the embodiments disclosed herein through the cornea of ​​the eye and across the anterior chamber, inserting at least a portion of the drug delivery implant into the suprachoroidal space of the eye, positioning the implant such that one or more regions of drug release are positioned sufficiently near the intraocular target to allow substantially all of the drug released from the implant to reach the intraocular target, and withdrawing the delivery device from the eye.

[0064] 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.

[0065] 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 micrograms, the steroid is released from the implant at a rate of about 0.05 to about 10 micrograms per 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 a first location to a remote second location (e.g., from the anterior chamber to an existing physiological outflow pathway, such as Schlemm's canal or uveoscleral pathway). However, the optional shunt is also used in other embodiments where the side effects associated with the active drug do not include fluid accumulation. For example, some embodiments relate to the treatment of an area with a therapeutic agent in combination with a drainage technique (even in the absence of an increase in ocular fluid production induced by the therapeutic agent).

[0066] Various embodiments of the implants disclosed herein can include one or more of the following optional features: a drug disposed near the distal end of the shell, a drug disposed near the proximal end of the shell, one or more obstructions disposed within the internal lumen that limit the forward (or, in some embodiments, rearward) elution of the drug, and / or an obstruction including a one-way valve disposed to allow fluid to pass in a proximal to distal direction through the implant. In some embodiments having one or more obstructions disposed within the internal lumen, the one or more obstructions facilitate the simultaneous (or over time) elution of one or more drugs into the anterior and / or posterior chambers for a desired effect.

[0067] In some embodiments disclosed herein, a coating, preferably a polymeric coating, is formed that is biodegradable. In some embodiments, two or more polymeric coatings are disposed 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), covers a different portion of the shell, including covering one or more optional orifices in the shell, and / or allows ocular fluid to contact the drug in the internal lumen by passing through an increasing number of open orifices in the shell over time that are formed by the degradation of the coating material. In some embodiments, the coating is optionally disposed on the outer surface of the shell, disposed between the drug and the inner surface of the shell, and / or disposed to encase the drug in the internal lumen. The drug can be in the form of one or more pellets, beads or tablets, oils, gels, emulsions, and the like.

[0068] In some embodiments, biodegradation of the barrier or coating is induced by an externally derived stimulus, such as intraocular injection of a fluid that initiates biodegradation of the barrier, application of heat, ultrasound, radio frequency, etc. In some embodiments, the barrier and / or coating degrades faster than the drug, in other embodiments the drug degrades faster, or in yet other embodiments the degradation rates are unique to each other.

[0069] Any of the embodiments disclosed herein may optionally further include one or more anchoring structures, one or more excipients mixed with the drug, one or more orifices or openings in the proximal portion of the device that can drain ocular fluid from the anterior chamber, and / or one or more wicks through any outer shell of the implant.

[0070] Some embodiments optionally include retention protrusions configured to secure the implant to ocular tissue. Such retention protrusions optionally include one or more of ridges, tabs, 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.

[0071] The implants described herein are optionally fixed (e.g., any mechanism or element that allows the implant to be permanently or transiently anchored, secured, or attached to an appropriate target intraocular tissue) to intraocular tissue 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. In certain embodiments involving implants fixed within the lens capsule, such implants are preferably implanted simultaneously with or following removal of the natural lens (e.g., by cataract surgery).

[0072] In some embodiments, the device includes one or more regions that are permeable to a drug or that are more permeable to a drug than another region of the device. The increased permeability can be achieved by any means, including but not limited to the use of a thinner or reduced thickness of a material that has some drug permeability (reduced thickness increases the rate of drug diffusion or transport), orifices or holes that can be of any suitable size or shape to allow release of the drug and / or entry of ocular fluids, the use of a second material with increased drug permeability, the use of a coating that enhances transport of the drug from the inside to the outside of the device, and any combination of the above.

[0073] Additionally, any of the implant embodiments described herein can include a lumen or passageway that can drain ocular fluid from a first location to a second location, for example, from the anterior chamber to a physiological outflow pathway.

[0074] In any of the embodiments disclosed herein, the drug is preferably released from the implant to act on the diseased or damaged target tissue to exert a therapeutic effect, in some embodiments the drug further produces side effects associated with the accumulation of physiological fluids, and in such embodiments the implant further includes a stent or passageway to transport the accumulated fluids from the first location to a remote second location.

[0075] According to the present disclosure, any of the described implants can include a shell of metal or polymeric material. Polymeric materials include homopolymers, polymer blends, and copolymers, such as random copolymers, block copolymers, etc. In some embodiments, the polymeric material includes ethyl vinyl acetate, polyethylene, Elasthane®, silicone, polyurethane, polyethersulfone, and / or polyamide. In other embodiments, the polymeric material includes poly(carbonate urethane), poly(ether urethane), silicone poly(carbonate urethane), silicone poly(ether urethane), PurSil®, CarboSil®, or Bionate®.

[0076] In embodiments having regions of reduced shell thickness, such regions may be formed by any suitable means, including one or more of ablation, stretching, etching, polishing, and molding. The regions may be in any pattern on or around the implant, including spiral patterns, patches, rings, and / or bands.

[0077] Regions characterized by increased drug delivery rates, whether by reduced shell thickness, orifices, permeable materials, or any other means or combination of means described herein, may be present in or on any portion or combination of portions of the device. Preferably, the regions are positioned to direct the drug to the ocular tissue targeted for treatment with the drug. In some embodiments, such regions (or a single such region) are preferably concentrated toward the distal end of the elongate device to direct drug delivery to tissues distal to the posterior chamber. In some embodiments, such regions (or a single such region) are preferably concentrated toward the proximal end of the elongate device to direct drug delivery to tissues in the anterior chamber.

[0078] The implants described herein can optionally be configured to interact with a recharging device to recharge the implant with additional or replacement doses of drug. Such rechargeable implants optionally include a reversible connection between a proximal end of the implant and a clamping sleeve of the recharging device. In certain embodiments, the clamping sleeve contains a flexible clamping grip that creates a stable connection between the implant and the recharging device. The stable connection can optionally allow the recharging device to deliver the drug to the lumen of the implant using a flexible pusher or loading tube contained within the recharging device. In some embodiments, the stable connection between the implant and the recharging device can allow the drug to be delivered to the lumen of the implant using a flexible spring-loaded pusher tube contained within the recharging device. In some embodiments, a one-way passage is provided that allows the drug to be deposited in the lumen of the implant but prevents the drug from flowing out of the lumen through the passage after removal of the recharging device.

[0079] In some embodiments, the implant further includes at least one partition within the internal lumen, thereby forming at least two sub-lumens. In some embodiments having two or more sub-lumens, each sub-lumen optionally contains a different drug than the other sub-lumens, or a different concentration of the same drug, and optionally releases the drug to a different portion of the eye. In some embodiments in which the implant contains multiple drugs, one drug is therapeutically effective against an ocular disorder and another drug mitigates side effects of administration of the first drug.

[0080] In addition to the sub-lumens, some embodiments are provided in which the implant further includes a distal region of the shell that is more permeable to drug than the more proximal region, a proximal region of the shell that is more permeable to drug than the more distal region, a partition disposed perpendicular to the longitudinal axis of the shell, the partition being semi-permeable to drug disposed within the sub-lumen, and wherein drug release from the sub-lumens occurs first from the most distal sub-lumen and last from the most proximal sub-lumen, and / or wherein drug release from the sub-lumens occurs first from the most proximal sub-lumen and last from the most distal sub-lumen.

[0081] In some such embodiments, the partition optionally alters drug permeability within the minor lumens such that the overall elution profile includes a period of reduced or no drug release.

[0082] Any of the embodiments disclosed herein that include lumens, pathways, or shunts in addition to drug elution in the implant can optionally drain fluid to any existing physiological outflow pathways, including the suprachoroidal space, trabecular meshwork, or Schlemm's canal, and optionally can direct drug delivery to the anterior chamber, posterior chamber, both the anterior and posterior chambers, and / or specifically target the macula, retina, optic nerve, ciliary body, and / or intraocular vasculature.

[0083] In some such embodiments, the implant comprises a substantially straight, rigid, generally cylindrical shell or body. In some embodiments, the implant, when implanted, extends at its proximal end into the anterior chamber and at its distal end into the suprachoroidal space. For example, the body can be 7 mm or less in length, preferably about 5 mm or less, more preferably about 4 mm or less and about 2 mm or more in length. In some embodiments, the body has a tip that tapers toward the distal end of the implant. In yet other embodiments, the body comprises a substantially flexible, generally cylindrical shell or body that can be about 25 mm in length, including about 15 to about 18 mm, about 18 to about 21 mm, about 21 to about 23 mm, about 23 to about 25 mm, about 25 mm to about 27 mm, about 27 to about 30 mm, and overlapping ranges thereof.

[0084] In some embodiments, at least one opening located at or near the proximal end of the implant communicates with at least one internal lumen. The proximal opening can be located at the proximal end of the implant and can be substantially perpendicular to the long axis of the implant. In some embodiments, a first active drug is disposed within the internal lumen. Once implanted, the drug can be eluted into the anterior chamber of the subject's eye through the proximal opening. Depending on the embodiment, the drug elution into the anterior chamber can be controlled, for example, by placing a membrane over or around the proximal opening with a known drug permeability. In some embodiments, the membrane is also permeable to aqueous humor or aqueous components of aqueous humor (e.g., the membrane allows bidirectional flow, i.e., aqueous humor or aqueous components of aqueous humor into the device and drug out of the device).

[0085] In embodiments including a shunt, the internal lumen terminates in one or more openings located at or near the distal end of the implant, In such embodiments, aqueous humor from the anterior chamber flows into the implant through the proximal opening and out the distal opening into the suprachoroidal space, reducing intraocular pressure in the anterior chamber.

[0086] Any of the embodiments disclosed herein may deliver a drug and / or exhibit a therapeutic effect for several days, 1 to 2 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, and / or at least 5 years.

[0087] Any of the embodiments disclosed herein can be configured to target diseased or damaged target tissue characterized by a limited ability to swell without loss or impairment of physiological function.

[0088] In some embodiments, a method of treating or preventing an ocular condition is provided that includes making an incision in an eye, inserting at least a portion of a drug delivery implant according to some embodiments disclosed herein into the suprachoroidal space of the eye, and withdrawing the delivery device from the eye.

[0089] In some embodiments, the implant is positioned such that the area of ​​the implant from which the drug is released is located sufficiently close to the intraocular target that substantially all of the drug released from the implant can reach the intraocular target.

[0090] In some embodiments, the methods disclosed herein optionally include one or more of making an incision in a strategic location on the cornea or limbus of the eye (e.g., temporal, nasal, superior, inferior, etc.) and advancing a delivery device through the cornea of ​​the eye to the implantation site.

[0091] In some embodiments, a method of delivering an ocular implant is provided that includes a stent according to some embodiments disclosed herein. The stent treats an ocular condition while simultaneously reducing side effects associated with the treatment, particularly side effects associated with increased fluid accumulation in the eye and / or elevated intraocular pressure. In some embodiments, the shunted ocular implant serves to reduce intraocular pressure in conjunction with the elution of a first drug from the ocular implant by providing an open outflow pathway through which aqueous humor can drain.

[0092] Another embodiment optionally includes creating a peripheral iridotomy adjacent to the implanted drug delivery device, and optionally holding the peripheral iridotomy open with a stent.

[0093] 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 and not limiting of 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]

[0094] [Figure 1] FIG. 1 is a schematic cross-sectional view of an eye. [Diagram 2] FIG. 1 illustrates a drug delivery device according to an embodiment disclosed herein. [Diagram 3] FIG. 1 illustrates a drug delivery device according to an embodiment disclosed herein. [Figure 4] FIG. 1 illustrates a drug delivery device according to an embodiment disclosed herein. [Diagram 5] FIG. 1 illustrates a drug delivery device according to an embodiment disclosed herein. [Figure 6] 1A-1D illustrate various aspects of a drug delivery device according to embodiments disclosed herein. [Figure 7] 1 is a cross-sectional view of a drug delivery implant according to an embodiment disclosed herein. [Figure 8] FIG. 2 illustrates a distal portion of a drug delivery implant according to an embodiment disclosed herein. [Figure 9] FIG. 13 illustrates a distal portion of another drug delivery implant according to embodiments disclosed herein. [Figure 10A] FIG. 1 illustrates another drug delivery implant according to embodiments disclosed herein. [Figure 10B] FIG. 1 illustrates another drug delivery implant according to embodiments disclosed herein. [Figure 10C] FIG. 1 illustrates another drug delivery implant according to embodiments disclosed herein. [Figure 10D] FIG. 1 illustrates another drug delivery implant according to embodiments disclosed herein. [Figure 10E] FIG. 1 illustrates another drug delivery implant according to embodiments disclosed herein. [Figure 10F] FIG. 1 illustrates another drug delivery implant according to embodiments disclosed herein. [Figure 10G] FIG. 1 illustrates another drug delivery implant according to embodiments disclosed herein. [Figure 11] FIG. 1 illustrates various embodiments of the implants disclosed herein that contain one or more drug-containing pellets within the implant. [Figure 12A] FIG. 1 illustrates another drug delivery implant incorporating a shunt according to embodiments disclosed herein. [Figure 12B] FIG. 13 illustrates yet another drug delivery implant incorporating a shunt according to embodiments disclosed herein. [Figure 12C] 1 is a cross-sectional view of one embodiment of a retention feature on a drug delivery implant according to embodiments disclosed herein. [Figure 13] FIG. 1 illustrates a drug delivery implant according to embodiments disclosed herein. [Figure 14] FIG. 1 illustrates a drug delivery implant according to embodiments disclosed herein. [Figure 15] 1 shows an illustrative embodiment of a drug delivery implant and retention protrusions. [Figure 16] FIG. 1 illustrates one embodiment of a drug delivery implant according to embodiments disclosed herein. [Figure 17] FIG. 1 illustrates another embodiment of a drug delivery implant according to embodiments disclosed herein. [Figure 18A] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 18B] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 18C] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 18D] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 18E] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 18F] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 18G] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 18H] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 18I] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 18J] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 18K] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 18L] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 18M] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 18N] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 18O] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 18P] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 18Q] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 18R] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 18S]1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 18T] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 18U] 1A-1D illustrate various drug delivery devices according to embodiments disclosed herein. [Figure 19A] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19B] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19C] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19D] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19E] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19F] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19G] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19H] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19I] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19J] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19K] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19L] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19M] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19N] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19O] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19P] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19Q] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19R] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19S] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19T] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19U] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19V] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19W] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Fig. 19X] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 19Y] 1A-1C illustrate various fixation elements that may be used in some embodiments disclosed herein. [Figure 20A] FIG. 1 illustrates a rechargeable drug delivery device according to an embodiment disclosed herein. [Figure 20B] FIG. 1 illustrates a rechargeable drug delivery device according to an embodiment disclosed herein. [Figure 20C] FIG. 1 illustrates a rechargeable drug delivery device according to an embodiment disclosed herein. [Figure 20D]1A-1C illustrate various features of an elongate delivery device according to some embodiments disclosed herein. [Figure 20E] 1A-1C illustrate various features of an elongate delivery device according to some embodiments disclosed herein. [Figure 20F] FIG. 1 illustrates one embodiment of a delivery device according to embodiments disclosed herein. [Figure 20G] 1A-1D illustrate various implantation configurations of a drug delivery device according to embodiments disclosed herein. [Figure 20H] 1A-1D illustrate various implantation configurations of a drug delivery device according to embodiments disclosed herein. [Figure 20I] 1A-1D illustrate various implantation configurations of a drug delivery device according to embodiments disclosed herein. [Figure 20J] 13A-13D illustrate additional features of the distal portion of certain drug delivery devices according to embodiments disclosed herein. [Figure 21] FIG. 1 illustrates an apparatus for implanting a drug delivery device according to embodiments disclosed herein. [Figure 22] FIG. 1 illustrates another apparatus for implanting a drug delivery device according to embodiments disclosed herein. [Diagram 23] 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 24] 1 illustrates another implantation procedure according to some embodiments disclosed herein, with the size of the implant exaggerated for illustrative purposes. [Diagram 25] 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 26] 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 27A] 1A-1D are cross-sectional views of an eye during steps of one embodiment of a method of implanting a drug delivery device disclosed herein. [Figure 27B] 1A-1D are cross-sectional views of an eye during steps of one embodiment of a method of implanting a drug delivery device disclosed herein. [Figure 27C] 1A-1D are cross-sectional views of an eye during steps of one embodiment of a method of implanting a drug delivery device disclosed herein. [Figure 27D] 1A-1D are cross-sectional views of an eye during steps of one embodiment of a method of implanting a drug delivery device disclosed herein. [Figure 28] 1 is a schematic cross-sectional view of an eye with a delivery device advanced across the eyeball to target the iris adjacent the anterior chamber angle, the size of the shunt exaggerated for illustrative purposes. [Figure 29] 1 is a schematic cross-sectional view of an eye with another embodiment of a delivery device targeted to the iris adjacent the anterior chamber angle, the size of the shunt exaggerated for illustrative purposes. [Diagram 30] FIG. 1 is a schematic cross-sectional view of an eye with an implant fixed to the iris. [Diagram 31] FIG. 1 is a schematic cross-sectional view of an eye with an implant implanted in the anterior chamber angle. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0095] Achieving localized ocular administration of drugs may involve not only direct injection or application, but may also involve the use of drug-eluting implants. A portion of the drug-eluting implant may be placed in close proximity to the target site of action within the eye or within the eye 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 for a period of time. Furthermore, other conditions may require periods of no release (e.g., "drug holiday"). Additionally, the implant may perform additional functions after drug delivery is complete. The implant may maintain the patency of a fluid passageway within the orbit, may act as a reservoir for future administration of the same or a different therapeutic agent, or may function to maintain the patency of a fluid flow path or passageway from a first location to a second location, for example, functioning as a stent. Conversely, if the drug is only needed acutely, the implant may be completely biodegradable.

[0096] The implants according to the embodiments disclosed herein preferably do not require an osmotic or ionic gradient for the release of the drug(s) and may be implanted with a device that reduces ocular morbidity by minimizing trauma to healthy tissues of the eye and / or may be used to deliver one or more drugs in a targeted and controlled release manner to treat multiple ocular conditions or a single condition and its symptoms. However, in some embodiments, an osmotic or ionic gradient is used to initiate, control (in whole or in part) or regulate the release of the drug(s) from the implant. In some embodiments, the osmotic pressure is balanced between the interior(s) of the implant and the ocular fluid and does not produce an 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.

[0097] 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 biologics, including but not limited to proteins, nucleic acids, antibodies, etc., whether such drugs are natural, synthetic, or recombinant. Drug may refer to the drug alone or in combination with the above excipients. Drug may also refer to the active drug itself, or a prodrug or salt of the active drug.

[0098] 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 ​​for individual parameters are given along with lists of values. It should be noted that in these cases, such disclosure includes not only the values ​​in the list, but also the range of values, including integer and fractional values, between any two of the values ​​in the list.

[0099] 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 in some embodiments is generally uniform in thickness, except for areas of reduced thickness where the drug is more likely to pass from the internal lumen to the target tissue. In other words, drug release regions can be formed by reducing the thickness. In some other embodiments, the shell of the implant includes one or more regions of increased drug permeability (e.g., based on different properties of each part of the shell, such as materials, orifices, etc.), thereby forming distinct regions where the drug is preferentially released. In another embodiment, the entire outer shell can be a drug release region if the material of the outer shell is substantially permeable to the drug. In yet another embodiment, the portion of the outer shell that surrounds the location of the drug in the internal lumen or void of the device can be considered a drug release region. For example, if the drug is loaded toward or in the distal end of the device (e.g., in the distal half or distal two-thirds of the device), the drug may preferentially elute through the portion of the shell proximal to the drug, such that the distal portion of the device becomes the region of drug release. Thus, as used herein, the term "region of drug release" shall have its ordinary meaning and shall include the embodiments disclosed in this paragraph, including any of these features in conjunction with a region of drug permeability or increased drug permeability based on the properties of the material and / or thickness of the material, one or more orifices or other passageways through the implant (as also shown below), a region of the device proximal to the drug, and / or one or more additional layers of material used to control drug release from the implant. Depending on the context, these terms and phrases may be used interchangeably or explicitly throughout this disclosure.

[0100] In some embodiments, the shell includes one or more orifices such that ocular fluid contacts the drug within the lumen(s) of the implant resulting in drug release. In some embodiments, the rate of drug release from the implant can be controlled by using single or multiple layers of permeable or semi-permeable material to cover (wholly or partially) the implant and (wholly or partially) the orifice(s), as discussed in more detail below. Additionally, in some embodiments, a combination of one or more orifices, single or multiple layers covering one or more orifices, and areas of reduced thickness are used to tailor the rate of drug release from the implant.

[0101] In yet another embodiment, a combination of materials can be used to construct the implant (eg, polymeric portions of a shell bonded, connected, joined or attached to a shell comprising a different material).

[0102] In yet another embodiment, the drug to be delivered is not included in the shell. In some embodiments, the drug is formulated as a compressed pellet (or other form) that is exposed to the environment in which the implant is deployed. For example, a compressed pellet of the drug is coupled to the implant body, which is then inserted into the ocular cavity (see, e.g., FIG. 19T). In some embodiments, the implant body includes a fluid flow path. In some embodiments, the implant optionally includes a retention feature. In some embodiments, the drug is encapsulated, coated, or covered in a biodegradable coating, and the timing of initial drug release is controlled by the biodegradation rate of the coating. In some embodiments, such implants are advantageous because they can introduce different amounts of drug depending on the type and duration of therapy to be administered (e.g., not limited by the dimensions of the implant shell). In some embodiments that have a shunt function, the shunt function works in conjunction with a drug to treat one or more symptoms of a patient's disease or condition. For example, in some embodiments, the shunt removes fluid from the anterior chamber while the drug reduces ocular fluid production. In another embodiment, as discussed herein, the shunt counteracts one or more side effects of administration of a particular drug (e.g., the shunt drains ocular fluid produced by the action of the drug).

[0103] In some embodiments, the biocompatible drug delivery implant comprises a flexible sheet or disk optionally flexibly coupled (e.g., tethered) to retention protrusions (e.g., fixation elements, grippers, claws, or other mechanisms that permanently or transiently secure the sheet or disk to intraocular tissue). In certain such embodiments, a therapeutic agent is mixed with and / or applied to the sheet or disk. In some embodiments, the flexible sheet or disk implant is sized so that it can be rolled or folded for placement within the lumen of a delivery device, such as a small diameter hollow needle.

[0104] After implantation at a desired site within the eye, the drug is released from the implant in a targeted and controlled manner, preferably over 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 requiring drug administration to specific tissues within the eye, such as the posterior chamber, anterior chamber, or the macula, ciliary body, or other ocular target tissues.

[0105] 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 the suprachoroidal space, which is located between the choroid 28 and the sclera 11. The eye also includes a posterior region 30 of the eye, which includes the macula 32.

[0106] <General>

[0107] In some embodiments functioning as a sole drug delivery device, the implant is configured to deliver one or more drugs to an anterior region of the eye in a controlled manner, while in other embodiments, the implant is configured to deliver one or more drugs to a posterior region of the eye in a controlled manner. In yet other embodiments, the implant is configured to simultaneously deliver drugs to both 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 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, choroid, suprachoroidal space, retinal artery and vein, optic disc, central retinal vein, optic nerve, macula, fovea, and / or retina. In yet other embodiments, delivery of drugs from the implant is directed to the general chamber of the eye. It should be understood that each of the embodiments described herein can target one or more of these regions and may be combined in some cases with shunt function (described below).

[0108] In some embodiments, the implant comprises an outer shell. In some embodiments, the outer shell is tubular and / or elongated, while other embodiments use other shapes (e.g., circular, elliptical, cylindrical, etc.). In some embodiments, the outer shell is not biodegradable, while in other embodiments, the shell is optionally biodegradable. In some embodiments, the shell is formed with at least a first inner lumen. In some embodiments, the first inner lumen is located at or near the distal end of the device. In other embodiments, the lumen can run the entire length of the outer shell. In some embodiments, the lumen is subdivided. In some embodiments, the first inner lumen is located at or near the proximal end of the device. In embodiments that also function as a shunt, the shell can have one or more additional lumens within the portion of the device that functions as a shunt.

[0109] In some embodiments, the drug(s) are located within the internal lumen(s) of the implant shell. In some embodiments, the drug is preferentially located within the more distal portion of the lumen. In some embodiments, the distal most 15 mm of the implant lumen(s) contain the drug(s) 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(s) contain the drug to be released. In some embodiments, the drug is preferentially located within the more proximal portion of the lumen.

[0110] 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(s) 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(s) 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 the drug 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 amount.

[0111] In some embodiments, the implant shell has one or more regions of increased drug permeability through which the drug is released in a controlled manner to the target ocular tissue.

[0112] In some embodiments, the drug(s) are disposed within the internal lumen(s) of the implant. The implant shell includes one or more orifices to allow ocular fluid to contact the drug(s) and induce drug release. In some embodiments, the implant includes a polymer coating on the exterior surface of the shell. In other embodiments, the implant includes a polymer coating on the interior surface of the shell. In yet other embodiments, the polymer coating is on both the interior and exterior surfaces. In yet other embodiments, 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, single or multiple layers over one or more orifices, and areas of reduced thickness to tailor the rate of drug release from the implant.

[0113] In some embodiments, the internal lumen containing the drug(s) is separated from the proximal portion of the implant by a proximal obstruction in the internal lumen that prevents elution of the drug(s) into the anterior segment of the eye. In some embodiments, the internal lumen(s) containing the drug(s) 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 segment of the eye but allows ocular fluid from the anterior segment of the eye to reach the internal lumen(s) containing the drug(s).

[0114] 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.

[0115] In some embodiments including a shunt, the shunt portion drains fluid from the ocular chamber to the 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 outlet of the implant drains ocular fluid to a remote area and / or to the physiological outflow pathway.

[0116] 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 function, 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 those 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.

[0117] In yet another embodiment, the combined drug delivery-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 together 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 or swelling. In some embodiments, the shunt function reduces the side effects of the delivered agent. It is understood that the dimensions and features 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.

[0118] 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 shunt function, 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.

[0119] A delivery device, described in more detail below, can be used to facilitate delivery and / or implantation of a drug delivery implant to a desired location in the eye. The delivery device can be used to position the implant at a desired location, such as the lower portion of the iris, the suprachoroidal space near the macula, a location from the anterior chamber to the suprachoroidal space, or other intraocular regions, by applying a continuous implantation force, by tapping the implant into position with a distal portion of 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, or use as a guidewire. As used herein, the term "incision" shall have its ordinary meaning and may refer to a cut, opening, slit, notch, puncture, and the like.

[0120] In some embodiments, the drug delivery implant can include one or more drugs that may or may not be mixed with a bioerodible polymer or a bioerodible polymer and at least one additional agent. In yet other embodiments, the drug delivery implant is used to deliver multiple drugs sequentially. Additionally, some embodiments are constructed with different shell materials and / or materials of different permeability to create a customized drug elution profile. Some embodiments are constructed with different numbers, sizes and / or locations of orifices in the implant shell to create a customized drug elution profile. Some embodiments are constructed with different polymer coatings and coating locations on the implant to create a customized drug elution profile. Some embodiments elute the drug at a constant rate, while other embodiments create a zero-order release profile. Still other embodiments create a diverse elution profile. Still other embodiments are designed to stop elution completely or nearly completely for a predetermined period of time (e.g., a "drug holiday") and then resume elution at the same or different elution rates or concentrations. Some such embodiments elute the same therapeutic agent before and after the drug holiday, while other embodiments elute different therapeutic agents before and after the drug holiday.

[0121] <Drug delivery implants>

[0122] The present disclosure relates to ocular drug delivery implants that, after implantation at an implantation site, controllably release one or more drugs to a desired target area within the eye, and over an extended period of time. Various embodiments of the implants are shown in Figures 2-20 and are referenced herein.

[0123] FIG. 2 is a schematic cross-sectional view of one embodiment of an implant according to the present disclosure. The implant includes an outer shell 54 made of one or more biocompatible materials. The outer shell of the implant is manufactured by extrusion, drawing, injection molding, sintering, micromachining, laser machining, and / or electrochemical discharge machining, or any combination thereof. Other suitable manufacturing and assembly methods known in the art may also be used. In some embodiments, the outer shell is tubular and includes at least one internal lumen 58. In some embodiments, the internal lumen is defined by the outer shell and a partition 64. 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 or drugs. In some other embodiments, a different shell shape is used that also forms at least one internal lumen. In some embodiments, the outer shell 54 of the implant is manufactured such that the implant has a distal portion 50 and a proximal portion 52. In some embodiments, the thickness of the outer shell 54 is generally uniform. In other embodiments, the thickness varies in certain regions of the shell. Depending on the desired implantation site within the eye, thicker regions of the outer shell 54 are located where necessary to maintain the structural integrity of the implant.

[0124] In some embodiments, the implant is made of a flexible material. In other embodiments, a portion of the implant is made of a flexible material and another portion of the implant is made of a rigid material. In some embodiments, the implant includes one or more curves (e.g., hinges). In some embodiments, the drug delivery implant is pre-curved but flexible enough to fit into a straight lumen of a delivery device.

[0125] In another embodiment, at least a portion of the implant (e.g., the internal protrusions or fasteners) is made of a material capable of shape memory. The material capable of shape memory can be compressed and upon release can expand axially, radially, or both axially and radially to assume a particular shape. In some embodiments, at least a portion of the implant has a preformed shape. In another embodiment, at least a portion of the implant is made of a superelastic material. In some embodiments, at least a portion of the implant is made of Nitinol. In another embodiment, at least a portion of the implant is made of a deformable material.

[0126] In some embodiments, the majority of the surface of the outer shell of the implant is substantially impermeable to ocular fluids. In some embodiments, the majority of the surface of the outer shell of the implant is also substantially impermeable to a drug 62 contained within the interior lumen of the implant (discussed below). In other embodiments, the shell is semi-permeable to the drug and / or ocular fluids, with certain regions of the implant being made less or more permeable by coatings, layers or impermeable (or low-permeability) materials disposed within or on the shell.

[0127] In some embodiments, the shell also has one or more regions of drug release 56. In some embodiments, the regions of drug release are thinner than the adjacent and surrounding thickness of the shell. In some embodiments, the regions of reduced thickness 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 regions of drug release are formed with a different thickness (e.g., thinner in some embodiments and thicker in others) than the surrounding shell, but with a higher permeability to the drug 62 and / or ocular fluid. In yet other embodiments, the shell is constructed with materials that are uniform or nearly uniform in thickness, but with different permeabilities to intraluminal ocular fluid and drugs. Thus, these embodiments have distinct regions of drug release from the implant.

[0128] The drug release region can be any shape necessary to adequately deliver the drug to a particular target tissue of the eye. For example, in FIG. 2, the region 56 is shown as a distinct area of ​​thinner material. FIG. 3A shows a drug release region used in another embodiment, a thin spiral shape 56. In some embodiments, the spiral is located substantially at the distal end of the implant, while in other embodiments, the spiral can be the length of the internal lumen. In yet another embodiment, the spiral region of drug release is located on the proximal portion of the implant. In some embodiments, the spiral is on the inner surface of the implant shell (i.e., the shell is cut with a spiral groove; see FIG. 3A). In other embodiments, the spiral is on the outer surface of the shell (see FIG. 3B). In other embodiments, the drug release region is formed as a circumferential band around the implant shell.

[0129] FIG. 4 illustrates another embodiment in which the drug release region is located at the most distal portion of the implant. Certain such embodiments are used when treating more posterior regions of the eye. Alternatively, or in conjunction with the embodiment of FIG. 4, the proximal portion of the implant can have a drug release region at or near the most proximal portion. In another embodiment, the drug release region is uniformly or nearly uniformly distributed along the distal and / or proximal portions of the implant. In some embodiments, the drug release region is located at or near the distal end of the implant, and in other embodiments, at or near the proximal end of the implant (or in yet other embodiments, at or near both the proximal and distal ends). In certain embodiments, the implants (based on regions of drug release (based on thickness / permeability, orifices, layers, etc.) are strategically positioned to provide different patterns of drug elution from the implant depending on the target tissue to be treated after implantation. In some embodiments, the regions of drug release are configured to preferentially elute the drug from the distal end of the implant. In some such embodiments, the regions of drug release are strategically located at or near target tissue in more posterior regions of the eye after the implantation procedure is completed. In some embodiments, the regions of drug release are configured to preferentially elute the drug from the proximal end of the implant. In some such embodiments, the regions of drug release are configured to preferentially elute the drug from the proximal end of the implant. Strategically located at or near the target tissue in the anterior chamber after completion of the implantation procedure. As discussed in more detail below, in some embodiments, the drug release region includes one (or more) orifices that allow communication between the internal lumen of the implant and the environment in which the implant is implanted. It should also be understood from this disclosure that in some embodiments, combinations of drug release regions (described above) can be combined with one or more orifices and / or coatings (described below) to tailor the drug release profile. Similarly, the above embodiments shown in Figures 2-4 can be adapted for implantation into the punctum of a subject, as described in more detail below in paragraphs

[0221] -

[0227] .

[0130] The implant in some embodiments includes a distal portion located at the distal end of the implant. In some embodiments, the distal portion is sufficiently sharp to pierce ocular tissue near the scleral promontory of the eye. The distal portion can be sufficiently rounded so as not to substantially penetrate the scleral tissue of the eye. In some embodiments, the implant is generally sharp 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. The sharp leading end can be, for example, conical or tapered. The taper angle of the sharp end is, for example, about 30 degrees ± 15 degrees in some embodiments. In some embodiments, the radius of the distal tip is about 70 μm to about 200 μm. In embodiments including a shunt as further discussed herein, the outlet opening is formed at the distal end of the shunt, and the distal portion gradually increases in cross-sectional size proximally, preferably at a substantially constant decreasing rate or radius or parabolically.

[0131] In some embodiments, the body of the implant includes at least one irregular surface. The irregular surface can include, for example, ridges, grooves, elevations, holes, or annular grooves. The discontinuous or irregular surface can also include barbs or other projections that extend from the implant outer surface and can prevent the implant from moving from its implanted position. In some embodiments, the projections include an external framework that prevents displacement of the implant. The irregular surface in some embodiments interacts with the tissue of the inner wall of the sclera and / or with the tissue of the ciliary body attachment tissue. In some embodiments, the implant is secured by a mechanical interlock between the tissue and the irregular surface and / or by a friction fit. In some embodiments, as discussed in more detail herein, the irregular surface functions to prevent host tissue growth (e.g., fibrous growth) into or onto the implant, which may reduce drug elution efficiency in some embodiments.

[0132] In some embodiments, the implant incorporates fixation features such as flexible radial (i.e., outwardly extending) extensions. The extensions can be separate pieces attached to the implant, can be integrally formed with the implant, or can be formed by slitting the implant wall and thermally forming or mechanically deforming the extensions radially outward. If the extensions are separate pieces, they can be constructed of a flexible material such as Nitinol or polyimide. The extensions can be located at the proximal or distal ends of the implant, or both, to prevent the implant from extruding from its intended location. In some embodiments, the extensions are longitudinally positioned along the implant. The spacing between the extensions can be regular or irregular. The flexibility of the fixation features facilitates entry through the corneal incision and through the ciliary muscle attachment tissue.

[0133] In some embodiments, the implant has a cap or tip on one or both ends. The distal cap can include a tissue piercing end. In some embodiments, the cap has a cone-shaped tip. In another embodiment, the cap can have a tapered tip. The tip can be sharp enough to pierce ocular tissue near the scleral promontory of the eye. The tip can also be sufficiently rounded so as not to substantially penetrate the scleral tissue of the eye. In some embodiments, the cone-shaped tip facilitates delivery of the shunt to a desired location. In embodiments that include a shunt, the distal cap has one or more outlet openings through which fluid flows. Each of the one or more outlet openings can be in communication with at least one of the one or more lumens.

[0134] In some embodiments, the implant has a proximal end cap. For example, an O-ring cap with a drug release region (discussed in more detail herein with reference to Figures 18K and 18M) can be placed on the proximal end of the implant to allow drug elution into the anterior chamber. In another embodiment, a crimp cap including a drug release region (discussed in more detail herein with reference to Figures 18L and 18N) is placed on the proximal end of the implant. The region of the crimp cap can be compressible so that the cap can be securely placed and sealed onto the implant body. In some embodiments, the cap includes one or more orifices or layers instead of or in addition to the drug release region, based on the thickness and / or permeability of the cap material. In some embodiments, a coating is placed within the cap to encase the orifice therein. The coating can include a membrane or layer of a semipermeable polymer. In some embodiments, the coating has a well-defined thickness and therefore a well-defined known permeability to various drugs and ocular fluids. In some embodiments, the coating is disposed in another location, including on the outside of the cap, within the orifice, or a combination thereof. In some embodiments, the above embodiments are adapted to implant the implant into the punctum of a subject, as described in more detail below in paragraphs

[0221] -

[0227] .

[0135] 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, 19 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 that decreases or increases in cross-sectional size (e.g., diameter) along its length. In some embodiments, the distal end of the implace has a taper, or a portion that continuously decreases in radial dimension relative to the luminal axis along the length of the shaft. The taper preferably terminates in a smaller radial dimension at the distal end in some embodiments. During implantation, the taper can be manipulated to shape, expand and / or increase the size of the incision or puncture formed in the tissue. The diameter of the taper can be from about 30 gauge to about 23 gauge, preferably about 25 gauge.

[0136] In some embodiments, lumens are present in both the proximal and distal portions of the implant (see FIG. 5; 58a and 58, respectively). In such embodiments, both the proximal 52 and distal 50 portions of the implant have one or more drug release regions. In some such embodiments, the proximal and distal portions of the implant contain two drugs 62a (proximal) and 62 (distal) in the lumen. See FIG. 5. In other embodiments, the proximal and distal portions of the implant can contain the same drug, or different concentrations of the same drug, or the same drug in combination with another excipient. It will be appreciated that the placement of the drug release region, whether within the proximal portion, the distal portion, or both portions of the implant, is useful for specifically targeting certain intraocular tissues. For example, placing a drug release region at the most distal portion of the implant is useful in some embodiments for specifically directing drug release to a particular intraocular region, such as the macula. In another embodiment, the drug release region is positioned to specifically release the drug to another target tissue, such as the ciliary body, retina, ocular vasculature, or any of the ocular targets discussed above or known in the art. In some embodiments, the specific placement of the drug release region to specifically target a tissue reduces the amount of drug required to achieve a therapeutic effect. In some embodiments, the specific placement of the drug release region to specifically target a tissue reduces non-specific side effects of the eluted drug. In some embodiments, the specific placement of the drug release region to specifically target a tissue increases the overall duration of drug delivery from the implant.

[0137] A drug release region is a distinct, known area, regardless of its shape and location(s) on the outer shell of the implant. Distinct areas aid in calculating drug elution rates from the implant (discussed below). Drug release regions are formed in some embodiments by reducing the thickness of the shell in a distinct area and / or by controlling the permeability of specific areas of the shell. Figures 6A-I show specific embodiments of drug release regions. Figures 6A and B show overlapping areas of thicker and thinner sections 54 and 54a of the outer shell material. The result is an effectively thinner area of ​​material, i.e., drug release region 56. Figures 6C and 6D show joining of thicker and thinner sections 54 and 54a of the outer shell material. The resulting thinner area of ​​material is drug release region 56. It should be understood that joining of the thicker and thinner regions can be achieved, for example, by butt welding, gluing with an adhesive or biocompatible adhesive, casting the shell as a single unit of varying thickness, heat welding, heat fusing, compression fusing, or fusing the regions with a combination of heat and pressure. Other suitable linking methods known in the art may also be used.

[0138] 6E shows a thick sleeve of outer shell material at least partially overlapping with a thin shell material. The thin non-overlapping areas 56 are the drug release regions. It should be understood that the degree of overlap of materials can be controlled such that the non-overlapping shell regions are of a desired area for a desired elution profile.

[0139] FIG. 6F shows the shell material having thinned areas 56 formed by one or more of ablation, stretching, etching, grinding, molding, and other similar techniques that remove material from the shell.

[0140] Figure 6G shows a "tube within a tube" design in which a tube 54 of a first thickness is encased within a second tube 54a of a second thickness. The first tube has one or more slits or gaps in its shell and an overlying thinner shell 54a covers the slits or gaps, thereby forming regions of drug release. In the embodiment shown in Figure 6G, and in certain other embodiments, the slits or gaps in the shell 54 having the first thickness are not in direct communication with the external environment.

[0141] FIG. 6H illustrates an embodiment in which the drug release regions are in contact with both an outer shell 54 and a substantially impermeable matrix material 55 having communicating particulate matter 57 dispersed in the impermeable matrix. In some embodiments, the communicating particulate matter is mixed with the impermeable matrix material during implant manufacture. The implant can then be contacted with a solvent. The solvent is then transported through the communicating particulate matter to reach the drug contained within the lumen of the implant. Preferred solvents include water, saline, or ocular fluid, or biocompatible solvents that are not expected to affect the structure or permeability properties of the impermeable matrix.

[0142] When the drug in the lumen dissolves in the solvent, the drug migrates from the lumen of the implant through the communicating particulate matter to the ocular target tissue. In some embodiments, the implant is contacted with the solvent prior to implantation in the eye, such that the drug is susceptible to immediate release during or immediately after implantation. In other embodiments, the implant is contacted only with ocular fluid, such that there is a short period of time during which there is no drug release from the implant while ocular fluid migrates through the communicating particulate matter to the lumen of the implant.

[0143] In some such embodiments, the communicating particulate matter comprises hydrogel particles, such as polyacrylamide, cross-linked polymers, poly(2-hydroxyethylmethacrylate) (HEMA), polyethylene oxide, polyAMPS, and polyvinylpyrrolidone, or naturally occurring hydrogels such as agarose, methylcellulose, hyaluronan, etc. Other hydrogels known in the art may also be used. In some embodiments, the impermeable material is silicone. In other embodiments, the impermeable material may be Teflon, flexible graphite, silicone rubber, glass-reinforced silicone rubber, neoprene, glass fiber, cloth-filled rubber, vinyl, nitrile, butyl, natural rubber, urethane, carbon fiber, fluoroelastomers, and / or other such impermeable or substantially impermeable materials known in the art. In this embodiment and other embodiments disclosed herein, terms such as "substantially impermeable" or "impermeable" should be interpreted as referring to the relative impermeability of the material to the drug of interest. This is because the permeability of a material to a particular drug depends on the properties of the material (eg, crystallinity, hydrophilicity, hydrophobicity, water content, porosity) as well as the properties of the drug.

[0144] FIG. 6I shows another embodiment in which the drug release regions are in contact with both the outer shell 54 and an impermeable matrix material 55, such as silicone, with communicating particulate matter 57 dispersed in the impermeable matrix. In another embodiment, the impermeable material can be Teflon, flexible graphite, polydimethylsiloxane and other silicone elastomers, neoprene, fiberglass, cloth filled rubber, vinyl, nitrile, butyl, natural rubber, urethane, carbon fiber, fluoroelastomers, and / or other such impermeable or substantially impermeable materials known in the art. In some embodiments, the communicating particulate matter is mixed with the impermeable matrix material during implant manufacture. The resulting matrix is ​​impermeable until placed in a solvent that dissolves the communicating particulate matter. In some embodiments, the communicating particles are salt crystals (e.g., sodium bicarbonate crystals or sodium chloride crystals). In another embodiment, another soluble and biocompatible material can be used as the communicating particulate matter. Preferred communicating particulate matter is soluble in solvents such as water, saline, ocular fluid, or other biocompatible solvents that would not affect the structure or permeability properties of the impermeable matrix. It is understood that in certain embodiments, the impermeable matrix material mixed with the communicating particulate matter has sufficient structural integrity to form the outer shell of the implant (i.e., no additional shell material is required).

[0145] In some embodiments, the communicating particles are extracted with a solvent prior to implantation. Thus, upon extraction of the communicating particles, communicating passages are formed within the impermeable material. Pores (or other passages) in the impermeable material allow ocular fluid to enter the particles, which then deliver fluid to the lumen of the implant. Similarly, the particles deliver drugs from the lumen of the implant to the target ocular tissue.

[0146] Embodiments such as those shown in Figures 6H and 6I deliver drugs from the lumen of the implant to the ocular tissue through communicating particles or through spaces in the impermeable matrix obtained after dissolution of the particles, as opposed to traditional pores or orifices (described in more detail below). Thus, these embodiments create an indirect pathway (i.e., a circuitous or tortuous path of pathway) from the lumen of the implant to the eye. Thus, the rate and kinetics of drug release can be further controlled by deliberately designing the particulate material, the rate at which the particulate material delivers fluid, or the rate at which the particulate material dissolves in the solvent. In some embodiments, drug release regions are used on implants adapted for implantation into the punctum of a subject, as described in more detail below in paragraphs

[0221] -

[0227] . For example, in some implant embodiments configured for treating glaucoma, the punctal implant has drug release regions located along the proximal portion of the implant rather than at the proximal end. This advantageously allows release of the therapeutic agent from the implant but prevents the drug from being washed down into the nasolacrimal duct by tear drainage, see also Figures 7-9.

[0147] In some embodiments, the drug release regions include one or more orifices. It is understood that certain embodiments utilize non-orifice drug release regions alone or in combination with one or more orifices to obtain a controlled and targeted drug release profile appropriate for the envisioned therapy. FIG. 7 is a schematic cross-sectional view of one embodiment of an implant according to the present disclosure. As described above, the implant includes a distal portion 50, a proximal portion 52, an outer shell 54 made of one or more biocompatible materials, and one or more orifices 56a passing through the shell. In some embodiments, the outer shell of the implant is substantially impermeable to ocular fluids. In some embodiments, the implant contains a drug 62 within the inner lumen 58 of the implant.

[0148] As discussed in more detail below, in some embodiments, the drug includes a drug therapeutically effective for a particular ocular condition and any additional compounds necessary to prepare a therapeutic agent in a form compatible with the drug. In some embodiments, the therapeutic agent is in the form of a drug-containing pellet. Some embodiments of the therapeutic agent include a drug mixed with a polymer formulation. In some embodiments, the polymer formulation includes poly(lactic-co-glycolic acid), i.e., PLGA copolymer, or other biodegradable or bioerodible polymer. The drug is shown disposed within lumen 58 in FIG. 7, but is omitted in some other figures to clarify other features of the embodiment. However, it should be understood that all embodiments herein may optionally include one or more drugs.

[0149] In some embodiments, the implant further includes a coating 60 that can be disposed in various locations in or on the implant, as described below. In some embodiments, the coating 60 is a polymer coating. FIG. 8 illustrates an implant in which the coating 60 is disposed on the inside of the implant, but encases the therapeutic agent contained within the lumen, while FIG. 9 illustrates the coating 60 on the exterior surface of the shell 54. Some alternative embodiments can include implants having a non-polymer coating instead of or in addition to a polymer coating. The coating is optionally biodegradable. Some alternative embodiments can include implants made entirely of biodegradable materials, 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. Similarly, in some embodiments where the coating is disposed on the inside of the implant, the coating covers the entire inner surface of the lumen, while in other embodiments, only a portion of the inner surface is covered. It should be understood that the implants according to some embodiments disclosed herein combine regions of drug release with one or more coatings in addition to the regions of drug release described above to control the drug release profile.

[0150] 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 internal lumen 58 of the implant (FIGS. 7-9). 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 can be of any shape, such as spherical, cubic, ellipsoidal, etc. The number, location, size, and shape of the orifices formed in a given implant determine the ratio of orifice to implant surface area. This ratio can vary depending on the desired release profile of the drug delivered by a particular embodiment of the implant, as described below. In some embodiments, the orifice to implant surface area ratio 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.

[0151] In another embodiment, the shell can include one or more orifices 56b at the distal tip of the implant, as shown in Figures 10A and 10B. In another embodiment, the shell can include one or more orifices at the proximal tip of the implant, for example, drug elution and / or fluid inflow (e.g., for dissolution of a drug contained within the implant and / or for shunting fluid to a fluid outflow path). The shape and size of the orifice(s) can be selected based on the desired elution profile. Yet another embodiment includes a combination of a distal orifice and multiple orifices located more proximally on the shell. Yet another embodiment includes a combination of distal orifices, proximal orifices and / or drug release regions (and possibly one or more coatings) on the shell. Yet another embodiment has a closed distal end. In such an embodiment, the drug release regions (based on shell thickness / permeability, orifices, coatings, drug placement, etc.) are 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 that occurs in some embodiments of the implantation procedures disclosed herein.

[0152] In some embodiments, the distal orifice comprises a biodegradable or bioerodible plug 61 having multiple orifices 56b that maintains drug elution from the implant when one or more of the orifices become blocked by tissue during insertion / implantation. In another embodiment, the orifice(s) 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 orifices, on the inside of the shell and cover the orifices, 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 for embodiments in which the outer shell orifices are elongated. The arrows in FIG. 10B indicate the flow of drug from the implant.

[0153] In some embodiments, additional structure(s) within the lumen provide some control over the elution of the drug from the implant. In some embodiments, a proximal obstruction 64a is located near the drug 62 (FIGS. 7 and 10C). An optional shunt feature may also be included, including an outflow opening 66 in communication with a proximal inflow lumen 68 in the proximal region 52 of the implant. Single or multiple layers of permeable or semi-permeable materials may be used to contain the drug as discussed above, and FIG. 10C shows an internal plug 210 that in some embodiments is between the drug 62 and the various orifices 56a and 56b. In such embodiments, the internal plug need not completely surround the drug. In some embodiments, the material of the internal plug 210 is different from the shell 54, and in some embodiments, the material of the internal plug 210 is the same material as the shell 54. Suitable materials for the internal plug include, but are not limited to, agarose or hydrogels, such as polyacrylamide, polymethylmethacrylate, or HEMA (hydroxyethyl methacrylate). Additionally, any of the materials disclosed herein used for the shell or other portions of the implant may be suitable for the internal plug in certain embodiments.

[0154] In embodiments where the materials are the same, the physical properties of the material used to construct 210 may differ from shell 54. For example, the size, density, porosity, or permeability of the material of 210 may differ from shell 54. In some embodiments, the internal plug is formed in place (i.e., within the internal lumen of the implant), for example, by in situ polymerization, molding, or solidification of a dispensed liquid, powder, or gel. In other embodiments, the internal plug is preformed outside the shell and placed within the shell prior to implantation. In such embodiments, the selection of the preformed internal plug can be optimized based on the individual drug, patient, implant, or disease being treated, to construct a customized implant. In some embodiments, the internal plug is biodegradable or bioerodible, and in some other embodiments, the internal plug is durable (e.g., neither biodegradable nor bioerodible).

[0155] In some embodiments, the internal plug may be attached or bonded adjacent to the inner wall of the shell. In such embodiments, the internal 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 internal 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 in this case 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 region, the size and location of the internal plug relative to both the drug and the orifice and / or drug release region, and the permeability of the internal plug to the drug and bodily fluids. Additionally, in some embodiments, the internal plug increases the path length between the drug and the orifice and / or drug release region, thereby providing an additional point of control for the drug release rate.

[0156] In some alternative embodiments, the internal plug 210 can be more loosely attached to the internal lumen of the shell, thereby allowing the drug to flow or transport around the plug. See FIG. 10D. In yet other embodiments, the internal plug can include two or more pieces or segments. See FIG. 10E. In such embodiments including a looser attached or segmented plug, the drug can elute from the implant by passing through the gap between the internal plug and the inner wall of the shell. The drug can also elute from the implant by passing through the gap between the pieces or segments of the internal plug. The drug can also elute from the implant by passing through a permeable internal plug. Similarly, bodily fluids can enter the implant from outside the implant and reach the drug by any of these or other routes. It is understood that elution of the drug can occur as a result of any combination of these passageways or permeation routes.

[0157] 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. See FIG. 10F. 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 of FIG. 10G that can exhibit, for example, specific permeability.

[0158] As with the internal plugs and drug release regions described above, 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 internal plugs 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.

[0159] In some embodiments, multiple pellets 62 of a single or multiple drugs are placed end-to-end within the internal lumen of the implant (FIG. 11A). In some such embodiments, the orifice 56a (or drug release region) is placed at a more distal location on the implant shell. In other such embodiments, the orifice 56a (or drug release region) is placed at a more proximal location on the implant shell depending on the target ocular tissue. In some other embodiments, a partition 64 is used to seal the therapeutic agents separately when they are contained within the same implant internal lumen. In some embodiments, the partition 64 is bioerodible at a specific rate. In some embodiments, the partition 64 is incorporated into the drug pellet and provides a seal against the internal dimensions of the implant shell 54 to prevent the drug from eluting in an undesired direction. In some embodiments that further include a shunt, the partition can be placed distal to the shunt exit hole, which is described in more detail below.

[0160] In certain alternative embodiments, the orifices or drug release regions can be located along a portion or substantially the entire length of the shell surrounding the inner lumen, and the drugs to be delivered can be separated by one or more partitions.

[0161] Additional non-limiting yet another embodiment of the drug pellet-containing implant is shown in FIG. 11B (cross section). In certain embodiments, the pellets are micropellets 62' (e.g., microtablets) having characteristics described in more detail below. In some embodiments, one or more such micropellets are contained within a polymer tube 54' having a wall of a desired thickness. In some embodiments, the polymer tube is extruded, possibly having a circular cross section. In other embodiments, it forms another shape (e.g., oval, rectangular, octagonal, etc.). In some embodiments, the polymer is a biodegradable polymer, such as those discussed in more detail below. Regardless of the material or shape, some embodiments of the implant are sized for implantation into a subject's eye (e.g., sized to pass through a 21 gauge, 23 gauge, 25 gauge, 27 gauge, or smaller needle).

[0162] Within that context, the dimensions of some embodiments of such devices can be altered to provide a desired release time for the therapeutic agent in the micropellets. For example, the wall thickness of the polymer tube can be adjusted to alter the permeability of the polymer tube to the therapeutic agent. Additionally, in the case of biodegradable polymers, the wall thickness can also be altered to control the overall degradation rate of the device. In combination with other variables described in more detail herein, such as the polymer chemistry and molecular weight of the polymer used, the elution of the therapeutic agent from the implant can be highly controlled.

[0163] As generally shown in FIG. 11B, the micropellets 62' can be contained within compartments defined by end pieces or partitions 64'. In some embodiments, the end pieces 64' that define each lumen or compartment are thermoformed from the same material as the tube 54'. In other embodiments, they can be formed from pieces of polymer filament. In yet other embodiments, the end pieces are formed inside the tube by injecting or applying a small amount of a thermosetting polymer, adhesive, a solution of a polymer in a volatile solvent, or the like. Alternatively, the end pieces can be machined from a hard polymer, metal, or another material, and can be placed and held within the tube by solvent or adhesive bonding. In embodiments where the end pieces are polymeric, some embodiments employ biodegradable polymers that can be designed to degrade before, during, or after release of the micropellet therapeutic agent. Additionally, the polymer end pieces can include the same polymer as the extruded polymer tube 54', or can be a different polymer.

[0164] 11B is shown sized to hold a single micro-tablet of therapeutic agent 62', it should be understood that in some embodiments, lumen 58 can be sized to hold multiple micro-tablets containing the same or different therapeutic agents. Advantageously, such embodiments can use an extrusion shell to release the therapeutic agent from the implant in a controlled manner with one or more micro-pellets without exposing the therapeutic agent to the high temperatures often required for extrusion. Rather, the shell can be extruded first and then filled with micro-pellets after the temperature has returned to ambient.

[0165] As discussed in more detail herein, each tablet contains a therapeutic agent (also referred to herein as an active pharmaceutical ingredient (API)), optionally in combination with one or more excipients. The excipients may include, among other things, small molecules (e.g., salts) that are freely soluble in water to create an osmotic pressure gradient across the wall of the tube 54'. In some embodiments, such a gradient increases the stress on the wall and shortens the drug release time.

[0166] The in vivo environment in which some embodiments of the implants disclosed herein are placed can consist of an aqueous solution (such as aqueous humor, blood plasma, etc.) or a gel (such as vitreous humor, etc.). Water from the surrounding in vivo environment diffuses through the semi-permeable or perforated stent wall, in some embodiments, into the drug reservoir (e.g., one or more internal lumens, depending on the embodiment). Water that collects in the drug-containing internal lumen then begins to dissolve small amounts of the tablet or drug-excipient powder. The dissolution process continues until a solution is formed in the lumen that is in osmotic equilibrium with the in vivo environment.

[0167] In yet another embodiment, an osmotic agent such as a sugar or salt is added to the drug to facilitate water influx and the formation of an isotonic solution. With relatively insoluble drugs, such as corticosteroids, in some embodiments, the isotonic solution can be saturated with respect to the drug. In certain such embodiments, saturation can be maintained until the drug supply is nearly depleted. In some embodiments, maintaining a saturated state is particularly advantageous since the dissolution rate tends to be essentially constant according to Fick's law.

[0168] Implants such as those generally shown in FIG. 11B can be implanted singly (e.g., a single implant) or, in some cases, as multiple devices. In some embodiments, multiple implants can be joined (e.g., end-to-end) to form a single larger implant. As discussed above and in more detail below, implants with different drug release times can be created, for example, by varying the degradability over time of the extruded tube 54'. Implantation of multiple, diverse devices with different release times, and desired overall drug release profile, can be obtained based on sequential (or simultaneous) drug release from multiple implants for a given period of time. For example, the release time can be designed such that a first period of drug release occurs, followed by a "drug holiday" before a second period of drug release.

[0169] 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 and has its usual 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 may be configured to be a fluid flow path that drains aqueous humor from the anterior chamber to an outflow pathway to reduce intraocular pressure, as generally shown in FIG. 12A. In another embodiment, the shunt may be configured to be a fluid flow path that drains aqueous humor to an outflow pathway. Yet another embodiment may be configured to drain ocular or interstitial fluid from an area of ​​the eye and an area around the eye to a remote location. Yet another combined drug delivery-shunt implant may be configured to drain physiological fluid from a first physiological site to a second site (which may be a physiological site or external to the patient). In yet another embodiment, the shunt may also (or alternatively) function to provide a bulk fluid environment that facilitates dilution and / or elution of the drug.

[0170] The shunt portion of the implant can have an inflow portion 68 and one or more outflow portions 66. As mentioned above, the outflow portion can be located at or near the proximal end 52 of the implant. Although not shown, in some embodiments, the shunt outflow portion can be located at or near the distal end of the implant, and the inflow portion can be located at a different location or locations on the implant. In some embodiments, when the implant is deployed, the inflow portion can be sized and configured to reside in the anterior chamber, and the outflow portion can be sized and configured to reside in the supraciliary or suprachoroidal space. In some embodiments, the outflow portion can be sized and configured to reside in the supraciliary region of the uveoscleral pathway, the suprachoroidal space, another portion of the eye, or another physiological space susceptible to fluid deposition.

[0171] 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 a luminal axis from the inflow end to the outflow end. In some embodiments, the lumen extends substantially through the longitudinal center of the shunt. In other embodiments, the lumen may be offset from the longitudinal center of the shunt.

[0172] In implants that further include a shunt at the proximal portion of the device, the first (most proximal) outflow orifice of the implant is located 1-10 mm from the anterior chamber of the subject. In some embodiments that further include a shunt at the proximal portion of the device, the first (most proximal) outflow orifice of the implant is preferably located 2-5 mm from the anterior chamber of the subject. Additional outflow orifices can be located at more distal locations, i.e., up to or beyond the beginning of the internal lumen that contains the drug or therapeutic agent.

[0173] In some embodiments including a shunt, the shunt inflow is preferably located at or near the proximal end of the implant and the shunt outflow is preferably located at or near the distal end of the shunt. When implanted, in some embodiments, the shunt inflow is sized and configured to reside in the anterior chamber and the shunt outflow is sized and configured to reside in the uveoscleral pathway. In some embodiments, the shunt outflow is sized and configured to reside in the supraciliary region of the iveoscleral outflow pathway or in the suprachoroidal space. Depending on the embodiment, multiple outflow points can be used on a single device.

[0174] In some embodiments, the flow path through the implant is configured to regulate the flow rate to reduce the possibility of hypotony. In some embodiments, the intraocular pressure is maintained at about 8 mmHg. In other embodiments, the intraocular pressure is maintained at a pressure below about 8 mmHg, for example, the intraocular pressure can be maintained between about 6 mmHg and about 8 mmHg. In other embodiments, the intraocular pressure is maintained at a pressure above about 8 mmHg. For example, the intraocular pressure can be maintained between about 8 mmHg and about 18 mmHg, more preferably between 8 mmHg and 16 mmHg, and most preferably at or below 12 mmHg. In some embodiments, the flow rate can be limited to about 2.5 μL / min or less. In some embodiments, the flow rate can be limited to about 1.9 μL / min to about 3.1 μL / min.

[0175] For example, according to the Hagen-Poiseuille equation, a 4 mm long shunt with a flow rate of 2.5 μL / min should have an internal diameter of 52 micrometers to provide a pressure gradient of 5 mmHg above the pressure in the suprachoroidal space.

[0176] FIG. 12B illustrates another embodiment of a drug-eluting implant 430 that includes a shunt that can serve to drain fluid from the anterior chamber to the uveoscleral pathway (e.g., the suprachoroidal space). The drug-eluting implant 430 can include at least one internal lumen 436 extending therethrough, in which at least one first active drug can be disposed. The internal lumen 436 of the implant 430 can communicate with an inflow portion 432 and an outflow portion 434. When implanted, the inflow portion 432 is sized and configured to reside in the anterior chamber, and the outflow portion 434 is sized and configured to reside in the uveoscleral pathway. The first active drug can elute from the inflow portion 432 into the anterior chamber to treat the target ocular tissue. As the first active drug elutes from the internal lumen 436 into the anterior chamber, fluid can be directed through the internal lumen 436 of the implant.

[0177] The implant 430 preferably has an outer diameter that allows the implant 430 to be fitted into a 21 or 23 gauge needle or hollow instrument during implantation. However, larger or smaller gauge instruments 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.

[0178] 12C, 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.

[0179] The outflow portion 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. 12B, the outflow portion 434 has a tapered portion 444, but can have another shape (e.g., hemispherical, paraboloidal, hyperboloidal) in which the radial dimension decreases continuously relative to the lumen axis 442 along the length of the axis 442. The tapered portion 444 preferably terminates in a smaller radial dimension at the outflow end 440. During implantation, the tapered portion 444 can be manipulated to create, expand, and / or increase the size of an incision or puncture formed in tissue. For example, the distal end 440 can function as a trocar to puncture or make an incision in tissue. After the distal end 440 of the implant 430 has been advanced, the tapered portion 444 can be advanced through the puncture or incision. As tapered portion 444 advances through tissue, it serves to widen or expand the tissue surrounding the puncture or incision to accommodate the increasing size of tapered portion 444 .

[0180] 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 be advanced 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 is advanced 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.

[0181] Once the implant 430 is in place, with the inflow 432 in the anterior chamber and the outflow 434 in the uveoscleral pathway, the first active drug elutes from the lumen 436 of the implant 430 into the anterior chamber, and aqueous humor can flow from the anterior chamber through the lumen 436 of the implant 430 into the uveoscleral pathway. Fluid flow is preferably restricted by the size of the lumen 436, which creates capillary action that limits fluid flow for a given pressure. The capillary action of the lumen allows the shunt to restrict flow and regulate fluid flow without a valve. Fluid flow through the implant 430 is preferably configured to limit the flow rate to reduce the chance of hypotony. For example, in some embodiments, the flow rate can be limited to about 2.5 μL / min or less. In some embodiments, the flow rate can be limited to about 1.9 μL / min to about 3.1 μL / min. In another application, multiple implants 430 can be used in a single eye to elute at least a first drug into the anterior chamber and direct fluid from the anterior chamber to the uveoscleral pathway. In such applications, the cumulative flow rate through the implants preferably ranges from about 1.9 μL / min to about 3.1 μL / min, although the flow rate of each of the implants can be significantly less than about 2.5 μL / min. For example, if an application requires the implantation of five implants, each implant 430 can be configured to provide a flow rate of about 0.5 μL / min.

[0182] While the lumen 436 shown in FIG. 4 extends substantially through the longitudinal center of the implant 430, in some embodiments the lumen may be offset from the longitudinal center of the shunt. For example, the implant 430 shown in FIG. 4 has a tapered portion 444 that terminates substantially where the tapered portion 444 meets the lumen 436, but the lumen 436 may be offset from the center of the implant 430 such that it opens along one of the sides of the tapered portion 444. Thus, the tapered portion 444 may terminate at a location offset from the lumen axis 442 and may extend beyond the point where the inner lumen 436 meets the outer tapered portion 444. Additionally, the lumen 436 may change direction along its length.

[0183] In some embodiments, the implant includes one or more lumens or sub-lumens, as further described herein. In some embodiments, at least one first active drug is disposed in at least one sub-lumen. The sub-lumen can have a closed distal end or can have an outlet at or near the distal end to allow fluid to flow from the anterior chamber to the uveoscleral pathway. In some embodiments, at least one sub-lumen does not contain an active drug and is configured solely to allow fluid to flow from the anterior chamber to the uveoscleral pathway.

[0184] The implant 430 preferably comprises any of the materials described herein. The implant 430 can be manufactured by conventional micromachining techniques or by procedures commonly used to manufacture optical fibers. For example, in some embodiments, the implant 430 is drawn and has holes or lumens extending therethrough. In some embodiments, the tapered portion 444 of the outflow section 434 can be made by shearing the end tubular body. This can create a tapered portion 444 that can be used to puncture or incise tissue during implantation and expand the puncture or incise during advancement of the implant 430. Other materials can be used for the implant 430 of FIG. 4 and other methods of manufacturing the implant 430 can be used. For example, the implant 430 can be made of metal or plastic and the implant can be machined and drilled as described above.

[0185] The implant 430 of FIG. 4 is an implant having a configuration that allows for the opportunity to vary the size of the implant 430 or lumen 436. The implant 430 need not have a single configuration, i.e., be formed from the same piece of material. For example, the proximal portion of the implant can be formed from glass that is drawn to have at least one small diameter lumen. The distal portion of the implant can be a cap made of a different material. The cap can include a tissue piercing end and one or more outlet openings. Each of the one or more outlet openings communicates with at least one of the one or more lumens of the proximal portion. In one preferred form, the cap has a cone-shaped tip with multiple outlet openings located proximal to the distal end of the tip.

[0186] In some embodiments, the implant has a proximal end cap. For example, an O-ring cap with a drug release region (discussed in more detail herein with reference to Figures 18K and 18M) can be placed on the proximal end of the implant to allow drug elution into the anterior chamber. In another embodiment, a crimp cap including a drug release region (discussed in more detail herein with reference to Figures 18L and 18N) is placed on the proximal end of the implant. The region of the crimp cap can be compressible so that the cap is securely placed and sealed onto the implant body. The drug release region can be further permeable to aqueous humor to allow aqueous humor to drain from the anterior chamber through the lumen of the implant. In some embodiments, the cap includes one or more orifices or layers instead of or in addition to the drug release region, depending on the thickness and / or permeability of the cap material. The one or more orifices or layers can be permeable to aqueous humor to allow drainage from the anterior chamber. In some embodiments, a coating is placed within the cap to encase the orifice therein. The coating can include a semi-permeable polymeric film or layer. In some embodiments, the coating has a well-defined thickness and therefore a well-defined, known permeability to various drugs and ocular fluids. In some embodiments, the coating is disposed at another location, including on the outside of the cap, within the orifice, or a combination thereof.

[0187] In some embodiments, one or more splits are longitudinally positioned within the outer shell to form an implant with multiple additional sub-lumens formed within the interior lumen of the shell. The split(s) can be any shape (e.g., rectangular, cylindrical) or size that is mounted within the implant to form two or more sub-lumens and can be made of the same or different material as the outer shell, including one or more polymers, copolymers, metals, or combinations thereof. In one embodiment, the splits are made of a biodegradable or bioerodible material. The multiple sub-lumens can be in any configuration relative to each other. In some embodiments, a single split can be used to form two sub-lumens within the implant shell. See, for example, FIG. 13A. In some embodiments, the two sub-lumens are the same size. In other embodiments, a split can be used to form sub-lumens of different sizes. In yet other embodiments, multiple splits can be used to form two or more sub-lumens within the shell. In some embodiments, the lumens can be the same size. See, for example, Figure 13B. Alternatively, the divisions can be arranged so that the sub-lumens have different sizes.

[0188] In some embodiments, one or more of the sub-lumens formed by the divisions may traverse the entire length of the implant. In some embodiments, one or more of the sub-lumens may be defined or blocked by laterally or diagonally disposed divisions or partitions. Blocked sub-lumens may be formed with any size necessary to accommodate a particular dose or concentration of drug.

[0189] In some embodiments including a shunt, one or more lumens extend through the shunt to form at least a portion of the flow path. Preferably, there is at least one lumen that serves to direct fluid through the shunt. Each lumen preferably extends along a lumen axis from the inflow end to the outflow end. In some embodiments, the lumen extends substantially through the longitudinal center of the shunt. In other embodiments, the lumen may be offset from the longitudinal center of the shunt.

[0190] In another embodiment, the implant is formed as a combination of one or more tubular shell structures 54 that are substantially impermeable to ocular fluid, nested together to form a "tube within a tube" design, as shown in FIG. 13C. In another embodiment, cylindrical dividers are used to partition the interior of the implant into nested "tubes." In such an embodiment, a coating 60, which may be optionally polymeric, may be located in or on the tubular implant. In such an embodiment, at least a first interior lumen 58 and an ocular fluid flow lumen 70 are formed. In some embodiments, the ocular fluid flow lumen 70 is centrally located. In another embodiment, the ocular fluid flow lumen 70 may be offset to be located closer to the implant shell. In yet another embodiment, additional shell structures are added to form additional lumens within the implant. A drug 62 may be disposed within one or more of the formed lumens. Orifices or drug release regions may be located as needed to allow ocular fluid to contact the therapeutic agent. In some embodiments, a coating is located on the exterior surface of the outer shell. In some embodiments, two or more biodegradable coatings are used on a single implant, with each coating covering a separate portion of the implant or covering overlapping portions. In embodiments using biodegradable coatings, each coating optionally has a unique rate of biodegradation in ocular fluid.

[0191] In some embodiments, the implant includes a core 82 (FIG. 14). The core can take any form that aids in transporting ocular fluid from the exterior of the device to the interior lumen more quickly than the orifices of the drug release regions alone can. While FIG. 14 shows the core passing through the orifices, it is understood that the core can also be used in implants that only have drug release regions. In such embodiments, the core can be placed through the outer shell during the manufacture of the implant so that it does not form an orifice. In some embodiments, fibers are placed in the orifices or through the outer shell so that a portion of the core is adjacent to the drug in the lumen of the implant. In another embodiment, the drug is formed around the core to deliver ocular fluid directly to the interior of the drug. In yet another embodiment, one or more cores are used as described above to dissolve the drug from the exterior and interior of the drug pellets or chunks.

[0192] FIG. 15 is a schematic cross-sectional view of one embodiment of an implant according to the present disclosure further comprising a retention protrusion 359 for securing the implant to an ocular tissue. Although FIG. 15 and other figures show a distal portion at the implant end and a proximal portion at the retention protrusion 359 end, in some embodiments, the distal and proximal portions may be reversed relative to the orientation of FIG. 15 depending on the site and orientation of the implant. Additionally, while the illustrated implant shows the presence of an orifice through the outer shell, it should be understood that embodiments of the implant including regions of drug release based on the thickness and / or permeability of the shell material may also incorporate retention features. Additionally, implants including a combination of one or more orifices, one or more layers of permeable and / or semi-permeable material, and one or more zones of drug release based on the thickness and / or permeability of the shell material are used in some embodiments.

[0193] In some embodiments, the implant includes a sheet 400 and retention protrusions 359. See FIG. 16. In some embodiments, the sheet is not connected to the retention protrusions. The sheet can be made of any biocompatible material, including but not limited to polymers, fibers, or composites. In some embodiments, the sheet is mixed with one or more therapeutic agents. In some embodiments, the sheet is coated with a material mixed with one or more therapeutic agents. In another embodiment, the sheet mixed with a first therapeutic agent is coated with a material mixed with a second therapeutic agent, a different concentration of the first therapeutic agent, or with an auxiliary agent. In some embodiments, the sheet is biodegradable, while in other embodiments it is not. In another embodiment, a disk 402 (FIG. 17) is used instead of the sheet. In some embodiments, the sheet or disk is flexible.

[0194] To deliver some embodiments of the sheet or disc implant, the sheet or disc is sized to be rolled, folded, or packed into a delivery device. In some embodiments, the entire implant is flexible. In some embodiments, the implant is pre-curved or pre-bent, yet still flexible enough to be placed into a non-curved lumen of a delivery device. In some embodiments, the thickness of the flexible sheet or disc is about 0.01 mm to about 1.0 mm. Preferably, the delivery device has a cross-section small enough that the insertion site self-seals without sutures when the device is withdrawn from the eye. For example, the outer dimensions are preferably about 18 gauge or less, and about 27 or 30 gauge or more. In such embodiments, the rolled or folded sheet or disc can be attached to ocular tissue and can substantially return to its original dimensions after withdrawal of the delivery device. In some embodiments, a thickness of about 25 to 250 μm is used, including about 50 to 200 μm, about 100 to 150 μm, about 25 to 100 μm, and about 100 to 250 μm.

[0195] In some embodiments, the implant is affixed (e.g., tethered) to the iris and dimensioned to float in the aqueous humor. The term "floating" in this context does not refer to the buoyancy of the implant, but rather to the ability of the sheet surface of the implant to move within the ocular fluid of the anterior chamber to the extent permitted by the retention protrusions. In some embodiments, such implants are not tethered to intraocular tissue and float within the eye. In some embodiments, the implant can be adhesively secured to the iris using a biocompatible adhesive. In some embodiments, the biocompatible adhesive can be pre-activated, and in other embodiments, the adhesive can be activated by contact with ocular fluid. Yet other embodiments can include activation of the adhesive by an external stimulus after placement of the implant and prior to withdrawal of the delivery device. Examples of external stimuli include, but are not limited to, heat, ultrasound, and radio frequency or laser energy. In some embodiments, it is preferable to affix the implant to the iris due to the large surface area of ​​the iris. In other embodiments, the implant is flexible with respect to the retention protrusions affixed to the iris, but does not float. The embodiments disclosed herein are affixed to the iris to allow ordinary light to pass through the pupil.

[0196] As mentioned above, some embodiments disclosed herein employ materials with different permeabilities to control the drug release rate from the implant. FIGS. 18A-18Q show another implant embodiment employing materials with different permeabilities to control the drug release rate from the implant. FIG. 18A is a top view of the implant body 53 shown in FIG. 18B. The implant body 53 includes an outer shell 54 and a retention protrusion 359. Although not explicitly shown, it should be understood that in some embodiments, the implant including the body and cap may be constructed without a retention protrusion. FIG. 18C shows an implant cap 53a made of the same material as the outer shell 54 in some embodiments. In another embodiment, the cap 53 is made of a different material than the outer shell. The drug release region 56 is formed in the cap using a material having a different permeability than the shell 54. It is also understood that the implant, including the body and cap (and optional retention protrusions), can be constructed with orifices through the body or cap, can be constructed with layers or coatings of permeable or semi-permeable material covering all or a portion of any orifice, and can be constructed with regions of drug release based on the thickness and / or permeability of the shell material and combinations of the above. See 18E-18F.

[0197] 18G-18J show an assembled implant according to some embodiments disclosed herein. The implant body 53 is coupled with the implant cap 53a to form a lumen 58 that is filled with a drug 62. In some embodiments, the material of the implant body 54 is different from the cap 54a. Thus, the combination of the cap and body of different materials forms a region of drug release 56.

[0198] Another non-limiting embodiment of the cap is shown in Figures 18K and 18L. In Figure 18K, a cross section of an O-ring cap 53a with a drug release region 56 is shown. In another embodiment, one or more drug release regions can be present in the cap. An O-ring 99 (or another sealing mechanism) is placed around the cap so that a fluid impermeable seal is provided between the cap and the body of the implant upon assembly. A crimped cap is shown in Figure 18L. The outer shell of the cap includes a compressible region 98 to ensure that the cap is securely placed and sealed to the implant body. As mentioned above, some embodiments employ orifices and layers instead of or in addition to drug release regions based on the thickness and / or permeability of the shell material. Figure 18M shows a cross section of an O-ring cap 53a. A coating 60 is placed within the outer shell 54 of the cap, covering the orifice 56a. In another embodiment, one or more orifices can be present in the cap. In some embodiments, the coating 60 includes a semi-permeable polymeric membrane or layer. In some embodiments, the coating 60 has a well-defined thickness and therefore a well-defined, known permeability to various drugs and ocular fluids. Figure 18N shows a crimp cap including an orifice and a coating. Although the coating is shown disposed within the cap, it should be understood that other locations are used in some embodiments, including the exterior surface of the cap, within the orifice, or a combination thereof (see Figure 18O).

[0199] Further, as shown in Figures 18P and 18Q, in some embodiments, coatings are used within the drug material to form layers. Coatings can separate different drugs 62a, 62b, 62c, 62d within the lumen (Figure 18P). In some embodiments, coatings are used to separate different concentrations of the same drug (Figure 18Q). It should be understood that such internal layers are also useful in embodiments that include drug release regions (alone or in combination with other drug release elements disclosed herein, e.g., orifices). In some embodiments, the layers create a particularly desirable drug elution profile. For example, a slow eroding layer is used to provide a period of low drug release, or "drug holiday". Alternatively, the layers can be formulated to be zero order (or another kinetic profile), as discussed in more detail below.

[0200] In each of the illustrated and alternative embodiments, the coating or outer layer of shell material may be applied by spraying, dipping, or by some other equivalent means known in the art. Thus, in some embodiments, the permeability (and therefore elution rate) of the layer(s) covering the drug release region or orifice is limited, at least in part, by the materials used to manufacture the implant, the coating (if any) of the implant, and the effective thickness of the implant outer shell.

[0201] Moreover, in some 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 ready for insertion into a target site. For example, as shown in FIG. 18R, 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 (although of course sized to allow interaction between the parts). As shown in FIG. 18R, cap 54a includes a central opening, thereby forming a drug release region 56. In some embodiments, assembly of certain such embodiments takes advantage of the elastic or semi-elastic properties of membrane 60 through which the drug(s) 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 in place by pressure exerted against 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(s), but also functions as a gasket that seals the interior of the implant from the outside environment, thus limiting fluid communication between the interior and the outside only through the membrane 60. As discussed in more detail below with respect to possible materials from which the outer shell may be constructed, the membrane 60 may be constructed of similar materials or combinations thereof (depending on the embodiment).For example, membrane 60 in one embodiment comprises ethyelene 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 selection of the membrane material and its dimensions (e.g., its thickness) will be guided at least in part by the therapeutic agent of choice.

[0202] 18S is an exploded view of one embodiment of an implant disclosed herein. The implant 53 includes, for example, retention protrusions 459 at one end to anchor the implant in the target tissue. The implant 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 target therapeutic agent(s).

[0203] In various embodiments, the thickness of membrane 60 (together with the particular therapeutic agent(s) of choice) ranges from about 30 to about 200 μm, 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 membrane 60 also at least partially limits the elution rate of the desired drug(s).

[0204] As discussed herein, the drug elution rate is controlled to allow drug release over a desired time frame depending on the embodiment, for example, in some embodiments, the period of drug release ranges from several months to several years, e.g., from about 6 to about 12 months, from about 12 to about 18 months, from about 18 to about 24 months, from about 24 to about 30 months, from about 30 to about 36 months, etc. depending on the embodiment.

[0205] FIG. 18T illustrates another embodiment in which the implant 53 further includes at least one inflow pathway 38k and at least one fluid outflow pathway 56k. Alternative fluid inflow / outflow configurations are also detailed elsewhere herein (see, for example, FIGS. 19R-19Y). As shown in FIG. 18T, the retention protrusions 359 secure the implant to ocular tissue, allowing the implant to rest at or near the trabecular meshwork 23, and the fluid outflow pathways 56k to direct ocular fluid through the implant (via the fluid inflow pathway 38k) and into a physiological outflow space, shown here as Schlemm's canal 22. As with the above embodiment, there is a drug release region 56 that can elute a drug to the desired target tissue(s). It should be understood that any of the various fluid inflow / outflow configurations can be easily adapted for use with any of the various implant bodies disclosed herein. Similarly, any of the retention protrusions can be easily adapted for use with any of the implant shells, depending on the target tissue, the drug to be delivered, the desired drug delivery period, etc. For example, although the implant shown in FIG. 18T is shown as having spike-like or barbed retention protrusions, the implant can also be configured with a threaded region, for example, as shown in FIG. 19C.

[0206] FIG. 18U is a cross-sectional view of an embodiment of an implant having a fluid inflow pathway 38K and a fluid outflow pathway 56k. As shown, the implant includes a lumen 58 containing a drug that is delivered to the target tissue by elution through the membrane 60 and is delivered from the implant via the drug release region 56. An embodiment of a cap structure 53a incorporating the membrane 60 is shown. To ensure that ocular fluid only enters the implant through the membrane 60 (ensuring controlled release) to dissolve the drug (and drug outflow from the implant), the cap 53 includes a seal 99. Similarly, an additional lower seal 99a is located distal to the drug-containing lumen 58 to prevent ocular fluid from entering the implant from adjacent the inflow pathway 38k. In some embodiments, various features that allow for controlled release of a therapeutic agent(s) from the implant can be used and adapted to be implanted into the punctum of a subject, as described in more detail in paragraphs

[0221] -

[0227] below.

[0207] During the manufacture of an implant of an embodiment, one or more internal lumens 58 are formed within the outer shell of the implant. In some embodiments, the internal lumen is localized at the proximal portion of the implant, while in other embodiments, the internal lumen spans the entire length or any intermediate length of the implant. Some embodiments consist of a single internal lumen, while other embodiments include two or more internal lumens. In some embodiments, one or more of the internal lumens can communicate with an ocular chamber or region, such as the anterior chamber. In some embodiments, the implant is dimensioned to communicate with more than one ocular chamber or region. In some embodiments, both the proximal and distal ends of the implant are disposed within a single ocular chamber or region, while in other embodiments, both ends of the implant are disposed in different ocular chambers or regions.

[0208] The drug 62 is contained within the internal lumen 58 of the implant. The drug 62 includes an agent therapeutically effective against a particular ocular condition and any additional compounds in a drug-compatible form that are necessary to prepare the drug. In some embodiments, one or more of the internal lumens can contain different drugs or different concentrations of drugs, which can be delivered simultaneously (combination therapy) or separately. In some preferred embodiments, the internal lumen is sized in proportion to the desired amount of drug to be placed within the implant. The final dimensions of the internal lumen of a given embodiment depend on the type, amount, and desired release profile of the drug(s) to be delivered, as well as the composition of the drug(s).

[0209] In some embodiments, the drug is in the form of a drug-containing pellet, while in other embodiments, the drug is a liquid, slurry, micropellets (e.g., microtablets), or powder. In certain such embodiments, the form of the drug allows the implant to be flexible. In some embodiments, the drug is mixed with a polymer formulation. In some embodiments, the drug disposed in the lumen is pure drug. In certain embodiments, the polymer formulation comprises poly(lactic-co-glycolic acid), i.e., PLGA copolymer, or other biodegradable or bioerodible polymers. In yet other embodiments, the inner lumen contains only drug.

[0210] In some embodiments, multiple pellets 62 of a single or multiple drugs are placed within the internal lumen of the implant. In some embodiments, an impermeable partition 64 is used to seal the drug(s) within the lumen such that the only exit path from the implant is through the drug release region. In some embodiments, the impermeable partition 64 can bioerode at a specific rate. In some embodiments, the impermeable partition 64 is incorporated into the drug pellet and forms a seal against the internal dimensions of the implant shell 54. In other embodiments, more than one impermeable partition is used within the lumen to form a sub-lumen. The sub-lumens can contain different drugs, different concentrations of the same drug, the same or different drugs mixed with various excipients, etc. In such embodiments, sequential drug release can occur, or release of two agents that are inactive within the implant but become active when mixed outside of their respective sub-lumens can occur.

[0211] In some embodiments, the therapeutic agent is formulated as micropellets or microtablets. Furthermore, in some embodiments, microtablets allow a higher amount of therapeutic agent to be used in the implant because, in some embodiments, tableting provides a higher density than can be achieved by filling the device with pellets. Increasing the amount of drug in a given volume can also be achieved by reducing the amount of excipients used as a weight percentage of the total tablet. The inventors have found this to be possible when forming tablets of extremely small size while retaining the integrity of the tablet. In some embodiments, the percentage (by weight) of active therapeutic agent is about 70% or more. As discussed herein, the therapeutic agent can be combined with excipients or binders known in the art. In some embodiments, the percentage of therapeutic agent is in the range of about 70% to about 95%, about 75 to 85%, about 75 to 90%, about 70 to 75%, about 75% to about 80%, about 80% to about 85%, about 85% to about 90%, about 90% to about 95%, about 95% to about 99%, about 99% to about 99.9%, and overlapping ranges thereof. In some embodiments, the percentage of therapeutic agent is in the range of about 80% to about 85%, including 81, 82, 83, and 84% by weight.

[0212] In some embodiments, micro-tablets provide advantages in terms of the amount of drug that can be loaded, packed, or placed into the implants disclosed herein. The resulting implants containing micro-tablets, in some embodiments, therefore contain a higher density of therapeutic agent than can be obtained using non-micro-tablets. For example, in some embodiments, the density of the micro-pellet dosage form of the drug within the implant ranges from about 0.7 g / cc to about 1.6 g / cc. In some embodiments, the densities used for the implants range from about 0.7 g / cc to about 0.9 g / cc, about 0.9 g / cc to about 1.1 g / cc, about 1.1 g / cc to about 1.3 g / cc, about 1.1 g / cc to about 1.5 g / cc, about 1.3 g / cc to about 1.5 g / cc, about 1.5 g / cc to about 1.6 g / cc, and overlapping ranges thereof. In some embodiments, therapeutic agent densities greater than 1.6 g / cc are used.

[0213] As described herein, some embodiments of the devices disclosed herein are rechargeable, and therefore the size of the micro-tablets is advantageous. In some embodiments, loading and / or recharging of the device is performed using a syringe / needle that delivers the therapeutic agent. In some embodiments, the micro-tablets are delivered through a needle that is about 23 gauge to about 32 gauge, including 23-25 ​​gauge, 25 to 27 gauge, 27-29 gauge, 29-30 gauge, 30-32 gauge, and overlapping ranges thereof. In some embodiments, the needle is 23, 25, 27, 30, or 32 gauge. In some embodiments, the micro-tablets can be introduced directly into the eye, such as into the vitreous cavity, using a syringe or cannula.

[0214] In one embodiment, micro-tablets of the above characteristics, or any combination thereof, are manufactured by techniques known in the art, including tabletting, lyophilization, granulation (wet or dry), flaking, direct compression, molding, extrusion, etc. Furthermore, as discussed below, variations in the characteristics discussed above can be used to tailor the release profile of the micro-tablet therapeutic from the implant.

[0215] In some embodiments, lyophilization of the therapeutic agent is used prior to the micropelleting process. In some embodiments, lyophilization improves the stability of the therapeutic agent incorporated into the microtablets. In some embodiments, lyophilization allows a higher concentration of the therapeutic agent to be obtained prior to micropelleting, thereby enhancing the ability to obtain a higher percentage of the active therapeutic agent, which is desirable in some embodiments. For example, many commercially available therapeutic agents that are useful for treating ocular diseases have been developed as first-line drugs for other diseases. Thus, their original formulations may not be suitable or ideal for micropelleting or for administration to ocular targets via ocular implants such as those disclosed herein. For example, some anti-VEGF compounds are supplied as sterile liquids in single-use vials for intravenous administration (e.g., bevacizumab). As a result, such liquid agents are less favorable for forming micropellets than solid agents. However, liquid therapeutic agents may be used in some embodiments in some cases. To obtain a higher percentage of the therapeutic agent, such liquid agents may be frozen (e.g., stored at temperatures of -20 to -80°C for 16 to 24 hours or more) and then lyophilized to dryness. Alternatively, air nebulization, crystallization or other means may optionally be used to dry the therapeutic agent.

[0216] After drying, the purity of the lyophilized (or dried) therapeutic agent is optionally tested. In some embodiments, a solvent can be added to the liquid (or solid) agent to dissolve and remove (by evaporation) non-therapeutic components (e.g., excipients or inactive binders). In some embodiments, the therapeutic agent is purified by conventional methods (e.g., antibody-based chromatography, HPLC, etc.) prior to lyophilization. In such embodiments, lyophilization often serves to increase the concentration of the therapeutic agent in the recovered purified sample.

[0217] In some embodiments, the dried therapeutic agent (optionally dried in bulk for efficiency purposes) is ground, sieved, macerated, freeze-fractured, or otherwise aliquoted into known amounts and then micropelletized.

[0218] After lyophilization and / or comminuted, the therapeutic agent is sent to a micropelletization process. In some embodiments, standard techniques (e.g., compression, extrusion, molding, or other means) are used. However, in some embodiments employing a high percentage of active therapeutic agent, more specialized techniques are used.

[0219] In some embodiments, the therapeutic agent is a protein, and in such embodiments, drying and / or tabletting should be completed under conditions (e.g., temperature, acid / base, etc.) that do not adversely affect the biological activity of the therapeutic agent. To help maintain the biological activity of the micropellet therapeutic agent, in some embodiments, the protein therapeutic agent is formulated with a stabilizer (e.g., mannitol, trehalose, starch, or other polyhydroxypolymers) to maintain the structure (and therefore activity) of the therapeutic protein.

[0220] <Punctal graft>

[0221] In some embodiments, the implant is specifically configured for use (e.g., implanted) in the puncta of the subject's eye (e.g., the upper and / or lower puncta of the upper and / or lower canaliculi, respectively). The puncta function to collect tears released by the lacrimal gland to the surface of the eye. However, in some individuals, tear production is reduced, blocked, reduced, or insufficient to maintain an adequate level of moisture in the eye(s). If eye moisture remains reduced, the corneal surface of the eye may be damaged. When functioning normally (e.g., in patients with normal tear production), the puncta deliver tears to the lacrimal sac, which can then drain it through the nasolacrimal duct into the internal nose. One treatment for dry eye or similar syndromes is the implantation of a plug in time. When implanted, the plug functions to block tear drainage and increase tear retention in the eye. However, some of the implant embodiments disclosed herein can advantageously deliver one or more therapeutic agents to the eye to treat one or more aspects of reduced tear production to compensate for the physical blockage of tear drainage. Thus, in some embodiments, one or more therapeutic agents are disposed in the implant to increase tear production and / or treat symptoms of dry eye, including but not limited to swelling, reduced irritation, and / or reduced inflammation of the eye and surrounding tissues. Additional symptoms that may be reduced, ameliorated, and in some cases eliminated include stinging or inflammation of the eye, a rough or gritty feeling as if something is in the eye, the onset of excess tears after periods of extreme dry eye, mucus secretion from the eye, eye pain and redness, temporary or long-term onset of blurred vision, heavy eyelids, reduced ability to cry, discomfort when wearing contact lenses, reduced tolerance to reading, computer work, any activity requiring sustained visual attention, and eye strain.

[0222] In some embodiments, the implant advantageously does not require additional topical medications (e.g., ointments, artificial tears, etc.). However, in some embodiments, the implant is configured to work synergistically with one or more such medications (e.g., have a particular drug release profile). For example, in some embodiments, the implant is configured to deliver a dose of a therapeutic agent over a period of time to treat an injured or diseased eye. A subject with the implant in place can also use, for example, artificial tears, to further enhance the efficacy of the medication delivered from the implant.

[0223] In some embodiments, the agent delivered from the implant is used to treat another eye condition, such as glaucoma, ocular hypertension, and / or elevated intraocular pressure.

[0224] Advantageously, as discussed herein, some embodiments of implants configured for timed deployment can deliver a metered amount, i.e., at a constant rate, of one or more therapeutic agents, thereby reducing the peaks and valleys in therapeutic agent concentration that occur with local administration (e.g., via eye drops).

[0225] Any of the relevant features disclosed herein may be applied to embodiments configured for a punctum. For example, the implant dimensions, its shape, its drug release characteristics, etc. may be tailored for a punctum. In some embodiments, the plug may be tailored to the punctum dimensions of a particular subject. Additionally, the plug may be configured to be removable or, in some embodiments, permanent (e.g., rechargeable). In some embodiments, the punctal implant includes at least a first active agent preferentially loaded, at least in part, in a proximal region of the implant (e.g., such that the agent is released into the subject's tear film), and a distal region of the implant is disposed within the tear duct. In some such embodiments, the implant is specifically adapted to prevent unintentional release of the active agent(s) from the distal portion of the implant. In some such embodiments, the plug (e.g., an impermeable closure member), membrane (e.g., a membrane with little or no permeability to the active agent(s)), and / or valve (e.g., a one-way valve) prevent elution in the distal region of the device.

[0226] In some embodiments, the use of a valve or plug allows the implant to be flushed. For example, if a therapeutic agent needs to be replaced (e.g., with a different agent or a different dose of the same agent), it may be beneficial to substantially remove residual agent within the implant. In such cases, the plug can be removed and the implant flushed in a proximal to distal direction to flush any remaining therapeutic agent from the implant down into the nasolacrimal duct. The implant can then be refilled with another dose, another agent, etc. Similarly, a valve can be placed in a distal region of the implant to flush the implant. The valve opens under pressure applied during the flushing procedure, preventing flushed agent from flowing back into the implant.

[0227] In some embodiments, an implant and method for treating an eye with latanoprost or another therapeutic agent(s) are provided. The method includes inserting a distal end of the implant into at least one punctum of the eye, and positioning the implant such that a proximal portion of the implant delivers latanoprost or another therapeutic agent(s) to the tear fluid near the eye. In some embodiments, delivery of latanoprost or another therapeutic agent(s) is inhibited distal to the proximal end.

[0228] 19A-19W show various embodiments of the retention protrusion drug. As used herein, retention protrusion shall have its ordinary meaning and may refer to any mechanism or fixation element that permanently or transiently secures, fixes or attaches the implant to the appropriate target intraocular tissue (generally shown at 15 in FIGS. 19A-19G). For example, a portion of the implant that includes a biocompatible adhesive may be considered a retention protrusion, as may barbs, barbs with holes, thread-like elements, jagged elements, and the like. In some embodiments, the implant is sutured to the target tissue. For example, in some embodiments, the implant is sutured to the iris, preferably the lower portion. It should be understood that any retention means may be used with any of the illustrated (and / or described) implants (even if not explicitly illustrated or described as such). In some embodiments, the implants described herein are wedged or captured (permanently or transiently) based on their shape and / or size in a particular desired ocular cavity. For example, in some embodiments, the implant (e.g., a suprachoroidal stent) is wedged into the ocular space (e.g., the suprachoroidal space) based on the outer dimensions of the implant that creates a sufficient amount of friction against the ocular tissue to hold the implant in place.

[0229] Intraocular targets for anchoring the implant include, but are not limited to, fibrous tissues of the eye. In some embodiments, the implant is anchored to the ciliary muscle and / or tendon (or fibrous band). In some embodiments, the implant is anchored to Schlemm's canal, trabecular meshwork, episcleral vein, iris, iris root, lens cortex, lens epithelium, lens capsule, sclera, scleral promontory, choroid, suprachoroidal space, anterior chamber wall, or is located within the anterior chamber angle. As used herein, the term "suprachoroidal space" shall have its ordinary meaning. It should be understood that there are other potential ocular spaces in various regions of the eye that may be encompassed by the term "suprachoroidal space." For example, the suprachoroidal space in the anterior region of the eye is also known as the supraciliary space, and thus, in certain contexts herein, the use of "suprachoroidal space" shall be meant to encompass the supraciliary space.

[0230] The retention protrusions can be formulated from the same biocompatible material as the outer shell. In some embodiments, biodegradable retention protrusions are used. In other embodiments, one or more of the retention protrusions can be formed from a different material than the outer shell. Different types of retention protrusions may be included in a single device.

[0231] In some embodiments, see for example FIG. 19A, the retention protrusion 359 can include a raised pin 126, which includes a ridge 128 or a series of ridges formed on the surface of the base 130. Such ridges can be formed in any direction on the surface of the implant, such as, but not limited to, offset from the long axis of the implant, spiraling around the implant, or encircling the implant (see, for example, FIG. 19B). Similarly, the ridges can be spaced apart or in contact with each other. Other fixation elements can also be used, such as raised nubs, cylinders, deep threads 134 as shown in FIG. 19C, ribs 140 as shown in FIG. 19D, a rivet-shaped base 146 as shown in FIG. 19E, a biocompatible adhesive 150 that surrounds the retention element 359 and penetrates the eye tissue as shown in FIG. 19F, and barbs 170 as shown in FIG. 19G. In some embodiments, the retention protrusions are placed within an existing intraocular cavity or lumen, generally designated as 20. For example, as shown in FIG. 19H, an elongated blade 34 is attached to a base 130 that resides within Schlemm's canal 22 and across the trabecular meshwork 21. In another embodiment, as shown in FIG. 19I, a shorter base 130a is used and attached to the elongated blade 34 that resides within Schlemm's canal 22, based on the dimensions of the intraocular lumen as is known in the art.

[0232] In certain embodiments, an expandable material 100 is used in conjunction with or in place of the physical retention protrusions. For example, in Fig. 19J, certain areas of the base 130 are covered with an expandable material 100. When this material comes into contact with a suitable solvent containing ocular fluid, it expands (as indicated by the arrows) and thus exerts pressure on the surrounding tissue, e.g., the trabecular meshwork 21 and the base of Schlemm's canal 22 in Fig. 19J.

[0233] In some embodiments, an external stimulus is used to expand the expandable material 100. As shown in FIG. 19K, certain areas of the base 130 are covered with the expandable material 100. When stimulated by an external stimulus hv, the material expands (as indicated by the arrows), thus exerting pressure on the surrounding tissue, e.g., the trabecular meshwork 21 and the base of Schlemm's canal 22 in FIG. 19K. Suitable external stimuli include, but are not limited to, light energy, electromagnetic energy, heat, ultrasound, radio frequency, or laser energy.

[0234] In some alternative embodiments, the expandable material 100 is coated or layered onto the shell 54 and expands upon contact with a solvent. See Figures 19L-19Q. In some embodiments, the expandable material swells, coagulates or gels, or expands upon contact with bodily fluids once the implant is generally positioned within the desired intraocular cavity. (See dimensions D and D in Figures 19L-19Q.) 1 (Compare ). The expanded material then exerts pressure on the surrounding ocular tissue to secure the implant in place. In some embodiments, such an expandable material (or another retention mechanism) is used on an implant adapted for implantation into the subject's punctum, as described in more detail above in paragraphs

[0221] -

[0227] .

[0235] In some embodiments, the expandable material fills the void between the implant shell and the surrounding intraocular tissue, and in some such embodiments, the expanded material blocks a portion of the implant from filling or seals off the volume around the implant shell, preventing fluid from flowing around the implant and forcing it to flow through the implant.

[0236] In other embodiments, such as those shown diagrammatically in Figures 19P and 19Q, an expandable material 100 is placed over selected areas of the implant shell 54. The expanded material then exerts pressure on the surrounding ocular tissue as well as forming zones of fluid flow 102 around the implant shell and the expandable material to maintain patency of the natural ocular fluid passageways. In yet other embodiments, the expandable material can be placed within the lumen of the implant such that the expansion of the material helps or causes the lumen to remain open.

[0237] The expandable material may be disposed on the implant by dipping, molding, coating, spraying, or other suitable process known in the art.

[0238] In some embodiments, the expandable material is a hydrogel or similar material. A hydrogel is a three-dimensional network of cross-linked hydrophilic polymer chains. Due to the hydrophilic nature of the polymer chains, the hydrogel swells in the presence of a sufficient amount of fluid. In another embodiment, the expandable material is a foam, collagen, or any other similar biocompatible material that swells, solidifies, gels, or expands. In some embodiments, the expandable material begins to expand immediately upon contact with a suitable solvent. In another embodiment, the expansion occurs after a short period of time, and the implant can be entirely placed at the desired target site before the material expands. Preferred solvents for inducing expansion include water, saline, ocular fluid, aqueous humor, or other biocompatible solvents that are not expected to affect the structure or permeability properties of the outer shell.

[0239] The expansion of the expandable material varies in some embodiments. In some embodiments, the material is placed on the outer shell of the implant, as described above, such that the expanded material exerts pressure on the surrounding ocular tissue to secure the implant in place. In other embodiments, the expandable material can be placed adjacent to, around, or under another fixation element (such as those described above), and expansion of the expandable material causes the fixation element to transition from a first retracted state to a second expanded state, securing the implant to the ocular structures in the expanded state. In some embodiments, the expandable material is designed to expand only in two dimensions, while in other embodiments, the material expands in three dimensions.

[0240] 19L and 19M show the expandable material as a rectangular cross section, it is understood that the cross-sectional shape may vary in some embodiments and may include circular, elliptical, irregular, and other shapes. In some embodiments, the relative expansion of the material (dimension D to D 1 In one embodiment, the change from D to D 1 The change from D to D is greater than in other embodiments, and in some embodiments is smaller. 1 The change to is caused by the expansion of the material.

[0241] 19P and 19Q are side views of an implant having expandable fixation elements 100 that include protrusions extending radially outward from the implant body. In some such embodiments, the fixation elements are individually connected to the implant body, while in other embodiments, they are interconnected by a sheath region provided on the implant body.

[0242] In selected embodiments, the implant and / or the retention protrusion further includes a shunt feature. The term "shunt" as used herein is a broad term having its usual 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 an implant that defines one or more flow paths for transporting fluid from a first, often undesirable location to one or more other locations. The term "stent" may also be used to refer to a shunt. In some embodiments, the shunt may be configured to be a fluid flow path that drains aqueous humor from the anterior chamber to an outflow pathway to reduce intraocular pressure, as shown, for example, in Figures 19R-19T. In yet other embodiments, the shunt feature of the implant may be located at any physiological location that requires simultaneous drug delivery and fluid transport from a first physiological location to a second location (which may be a physiological location or external to the patient).

[0243] The shunt portion of the implant can have an inflow portion 38k and one or more outflow portions 56k. In some embodiments, the inflow and outflow portions are located at various locations on the implant depending on the physiological space to be placed. As shown in FIG. 19R, the outflow portion can be located at or near the proximal end 52 of the implant. When the implant is deployed, the inflow portion can be sized and configured to reside in the anterior chamber and the outflow portion can be sized and configured to reside in the trabecular meshwork 23 or Schlemm's canal 22. In other embodiments, the outflow portion can be sized and configured to reside in the supraciliary region of the uveoscleral pathway, the suprachoroidal space, another portion of the eye, or another physiological space prone to fluid deposition.

[0244] At least one lumen can extend 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 a luminal axis from the inflow end to the outflow end. In some embodiments, the lumen extends substantially through the longitudinal center of the shunt. In other embodiments, the lumen may be offset from the longitudinal center of the shunt.

[0245] As mentioned above, in some embodiments, the unshelled compressed pellets 62 of drug are attached or coupled to an implant that includes a shunt and retention feature. As shown in FIG. 19T, the shunt portion of the implant includes one or more inflows 38k and one or more outflows 56k. In some embodiments, the inflows are located in a different physiological space than the outflows. In some embodiments, such a location allows for fluid transport from a first location to a second location. For example, in some embodiments, when deployed in the eye, the inflows are located in the anterior chamber and the outflows are located in Schlemm's canal 22. In this manner, ocular fluid that accumulates in the anterior chamber is drained from the anterior chamber into Schlemm's canal, thereby reducing the fluid pressure in the anterior chamber. In other embodiments, the outflows can be sized and configured to be in the supraciliary region of the uveoscleral pathway, the suprachoroidal space, another portion of the eye, or another physiological space that is prone to fluid deposition.

[0246] Yet another embodiment including a shunt can be used to drain ocular fluid from a first location to a different location. As shown in FIG. 19U, the shunt 30p directs aqueous humor from the anterior chamber 20 directly into the collection channel 29 and drains into the aqueous vein. The shunt 30p has a distal end 160 that is placed in the posterior wall of Schlemm's canal. A removable alignment pin 158 is utilized to align the shunt lumen 42p with the collection channel 29. In use, the pin 158 extends through the implant lumen and the shunt lumen 42p, protrudes from the base 160, and extends into the collection channel 29 to center and / or align the shunt 30p with the collection channel 29. The shunt 30p is then firmly pressed against the posterior wall 92 of Schlemm's canal 22. A permanent bioadhesive 162 is used between the shunt base and the posterior wall 92 of Schlemm's canal 22 to mount and securely hold the shunt 30p in place. Once placed, the pin 158 is withdrawn from the shunt and implant lumen 42p, allowing aqueous humor to flow from the anterior chamber 20, through the implant, the shunt, and into the collection canal 29. The collection canal is nominally 20 to 100 micrometers in diameter and is visualized by appropriate microscopy (such as ultrasound biomicroscopy (UBM)) or laser imaging to guide placement of the shunt 30p. In another embodiment, the pin 158 is biodegradable in ocular fluids and does not require manual removal from the implant.

[0247] In some embodiments, the shunt 30p is inserted through an incision previously made in the trabecular meshwork 23. In other embodiments, the shunt 30p can be formed in a blade shape to impart self-trephine capability. In these cases, the incision in the trabecular meshwork 23 is made by a self-trephine shunt device having a blade at or adjacent to its base.

[0248] As shown in FIG. 19V, a shunt extending from the anterior chamber 20 through the trabecular meshwork 23 to Schlemm's canal 22 of the eye can be configured to be axially symmetrical with respect to the flow of aqueous humor therethrough. For example, as shown in FIG. 19V, a shunt 229A includes an inlet end 230 configured to be disposed in the anterior chamber 20 and coupled to a drug delivery implant according to an embodiment disclosed herein. The implant is not shown so that the shunt function can be more clearly seen. A second end 231 of the shunt 229A is configured to be disposed in Schlemm's canal 22. At least one lumen 239 extends through the shunt 229A between the inlet and outlet ends 230, 232. The lumen 239 defines an opening 232 at the inlet end 230 and an outlet 233 at the outlet end 231.

[0249] In the illustrated embodiment, the outer surface 238 of the shunt 229A is conical. Thus, the circumference of the outer surface 238 adjacent the inlet end 230 is less than the circumference of the outer surface 238 at the outlet end 231.

[0250] With the shunt 229A extending through the trabecular meshwork 23, the tissue of the trabecular meshwork 23 provides additional anchoring force that holds the inlet end 230 of the shunt 229A in the anterior chamber and its outlet end 231 in Schlemm's canal. For example, it is believed that the trabecular meshwork 23 will naturally tend to close the opening occupied by the shunt 229A. Thus, the trabecular meshwork 23 should be prone to compress the shunt 229A. Because the outer surface 238 is conical, the compressive force exerted by the trabecular meshwork 23 should tend to draw the shunt 229A towards Schlemm's canal 22. In the illustrated embodiment, the shunt 229A is sized such that a portion 234 of the shunt 229 adjacent the inlet end 230 remains in the anterior chamber 20 and a portion 235 of the shunt 229 adjacent the outlet end 231 remains in Schlemm's canal 22.

[0251] In the illustrated embodiment, the outer surface 238 of the shunt 229A is smooth. Alternatively, the outer surface 238 can have other contours, such as, but not limited to, curved, stepped, etc. In one embodiment, the outer surface 238 can be concavely curved to form a trumpet shape. Alternatively, the outer surface 238 can be convex.

[0252] In one embodiment, the shunt 229A preferably includes one or more posts or legs 236 configured to maintain a space between the outlet opening 233 and the wall of Schlemm's canal 22. The legs 236 thus prevent the wall of Schlemm's canal from completely blocking the outlet opening 233 of the shunt 229A. In the illustrated embodiment, the legs 236 are coupled to the distal-most surface of the shunt 229A and are approximately parallel to the implant axis that extends through the shunt 229A between the anterior chamber 20 and Schlemm's canal 22.

[0253] The arrangement of legs 236 and outlet 233 imparts axisymmetric flow characteristics to shunt 229A. For example, aqueous humor can flow in any direction from outlet 233. Thus, shunt 229A can be implanted in Schlemm's canal at any angular position relative to its implant axis. Thus, the angular orientation of shunt 229A does not need to be determined prior to implantation, nor does it need to maintain a particular orientation during the implantation procedure.

[0254] 19W illustrates a variation of shunt 229A, generally designated by reference numeral 229B. In this embodiment, shunt 229B includes a flange 237 extending radially from portion 234. Preferably, flange 237 is configured to retain first portion 234 within the anterior chamber 20. Generally, aqueous humor flows from the anterior chamber 20 toward Schlemm's canal 22, although it will be understood that shunts 229A, 229B, or any of the shunts described above, as well as others described below, may allow aqueous humor to flow in any direction.

[0255] 19X illustrates another variation of shunt 229A, generally designated by reference numeral 229C. In this embodiment, outer surface 238C is not conical. Instead, outer surface 238C is cylindrical. Shunt 229C includes flange 240, which may be the same size and shape as flange 237. Leg 236C extends from flange 240.

[0256] When constructed in this manner, the tissue of the trabecular meshwork 21 tends to naturally close the hole in which the shunt 229C is placed, helping to secure the shunt 229C in place. Additionally, the pedicle 236C helps prevent the walls of Schlemm's canal from completely occluding the outlet 233C of the lumen 239C.

[0257] Referring to FIG. 19Y, another embodiment of an axisymmetric trabecular shunt device is shown and generally designated by the reference numeral 229F.

[0258] The shunt 229F includes an inlet (proximal) section having a first flange 240F, an outlet (distal) section having a second flange 237F, and an intermediate section 284 connecting the inlet and outlet sections. The lumen 239F of the device 229F is configured to transport aqueous humor, fluid, or therapeutic agent between the inlet and outlet sections.

[0259] The inlet section of the shunt 229F has at least one inlet opening 286 and the outlet section includes at least one outlet opening 287. In some embodiments, the inlet opening 286 is directly coupled to the proximal end of the implant, such that ocular fluid flowing through the lumen of the implant flows into the lumen 239F of the shunt. In other embodiments, the inlet opening 286 connects or couples the shunt to the implant such that the ocular fluid receives directly from the orbit without first passing through the implant. In yet other embodiments, the shunt conveys fluid from both sources (e.g., from the eye and the implant lumen).

[0260] A further advantage of such an embodiment is that the outlet section 237F includes at least one opening 287, 288 appropriately positioned to drain aqueous humor, fluid or therapeutic agent in a substantially axially symmetric manner, the opening 287, 288 being in fluid communication with the lumen 285 of the device 281. In the illustrated embodiment, the opening 288 extends radially from the lumen 285 and opens at an outwardly facing surface around the periphery of the outlet flange 237F.

[0261] It should be understood that all such fixation elements and retention protrusions can also be flexible. It should also be understood that other suitable shapes can be used and that the list here is not limiting. Additionally, it should also be understood that while some of the illustrated devices may not appear to be flexible, the devices can be flexible. In embodiments including rechargeable devices, the retention protrusions not only help to secure the implant, but also make it less likely to move so that the implant is more positionally stable within the eye during recharging.

[0262] For ease of understanding, only a few of the possible implant embodiments having various retention protrusions are shown, and it should be understood that any implant embodiment can be readily combined with any of the retention protrusions disclosed herein, and vice versa.

[0263] Additionally, while several embodiments described above are shown, in some cases, as being secured in or to particular intraocular tissues, it should be understood that each embodiment can be readily adapted to be secured or deployed in or on any of the target intraocular tissues disclosed herein, or to other ocular tissues known in the art.

[0264] Additionally, while both the above and below embodiments include discussion of retention protrusions, it should also be understood that some embodiments of the implants disclosed herein need not include specific retention protrusions. Such embodiments can be used to deliver drugs to ocular targets that do not require specific fixation points and simply deploy the implant in the desired intraocular space. Such targets include the vitreous humor, ciliary muscle, ciliary tendon, ciliary fibrous band, Schlemm's canal, trabecular meshwork, episcleral vein, anterior chamber and anterior chamber angle, lens cortex, lens epithelium, and lens capsule, ciliary process, posterior chamber, choroid, and suprachoroidal space. For example, in some embodiments, implants according to some embodiments described herein are injected (via a needle or another penetrating delivery device) through the sclera at a specific anatomical site (e.g., pars plana) into the vitreous humor. It should also be understood that such embodiments need not be constructed with retention protrusions, and thus, in some embodiments, the use of retention protrusions is optional for a particular target tissue.

[0265] 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. Upon completion of the implantation procedure, in some embodiments, the proximal end of the device can be located at or near the anterior chamber. The distal end of the implant can be located anywhere within the suprachoroidal space. In some embodiments, the distal end of the implant is near the limbus. In other embodiments, the distal end of the implant is 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. 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 synonymously with "at" herein, 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.

[0266] 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 typically fibrous or porous and is relatively easy to puncture, 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.

[0267] In some embodiments, the total length of the implant is 1 to 30 mm in length. In some embodiments, the length of the implant is 2 to 25 mm, 6 to 25 mm, 8 to 25 mm, 10 to 30 mm, 15 to 25 mm, or 15 to 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 to 600 μm. In some embodiments, the diameter of the implant is about 150 to 500 μm, about 125 to 550 μm, or about 175 to 475 μm. 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 μm. In some embodiments, the inner diameter of the implant is about 50-500 μm. In some embodiments, the inner diameter is about 100-450 μm, 150-500 μm, or 75-475 μm. 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 μm. In some embodiments, including but not limited to those in which the device is disk or wafer shaped, the thickness is about 25 to 250 μm, including about 50 to 200 μm, about 100 to 150 μm, about 25 to 100 μm, and about 100 to 250 μm. In some embodiments configured for implantation into the punctum, the implant ranges from about 0.5 to about 2.5 mm in length (e.g., from proximal to distal end).The length of the implant, in some embodiments, is in the range of about 0.5 mm to about 0.7 mm, about 0.7 mm to about 0.9 mm, about 0.9 mm to about 1.0 mm, about 1.0 mm to about 1.1 mm, about 1.1 mm to about 1.2 mm, about 1.2 mm to about 1.3 mm, about 1.3 mm to about 1.35 mm, about 1.35 mm to about 1.4 mm, about 1.4 mm to about 1.45 mm, about 1.45 mm to about 1.5 mm, about 1.5 mm to about 1.55 mm, about 1.55 mm to about 1.6 mm, about 1.6 mm to about 1.65 mm, about 1.65 mm to about 1.7 mm, about 1.7 mm to about 1.9 mm, about 1.9 mm to about 2.1 mm, about 2.1 mm to about 2.3 mm, about 2.3 mm to about 2.5 mm, or any length between these ranges. In some embodiments, the diameter of an implant configured for implantation into a punctum is about 0.2 mm to about 0.3 mm, about 0.3 mm to about 0.4 mm, about 0.4 mm to about 0.5 mm, about 0.5 mm to about 0.6 mm, about 0.5 mm to about 0.6 mm, about 0.6 mm to about 0.7 mm, about 0.7 mm to about 0.8 mm, about 0.8 mm to about 0.9 mm, about 0.9 mm to about 1.0 mm, about 1.0 mm from about 0.2 mm to about 2.0 mm, including diameters between these ranges.

[0268] In further embodiments, any or all of the internal lumens formed during manufacture of the implant may be coated with a layer of hydrophilic material, thereby increasing the rate of contact between ocular fluid and therapeutic agent(s) disposed within the lumen. In one embodiment, the hydrophilic material is permeable to ocular fluid and / or drugs. Conversely, any or all of the internal lumens may be coated with a layer of hydrophobic material, cooperatively inhibiting contact between ocular fluid and therapeutic agent(s) disposed within the lumen. In one embodiment, the hydrophobic material is permeable to ocular fluid and / or drugs.

[0269] Selected embodiments of the drug delivery implants described herein allow for recharging of the implant, i.e., reloading the implant with additional (same or different) therapeutic agent. In the embodiment shown in Figures 20A-20C, the proximal end 52 of the implant is open and interacts with a recharging device 80. The recharging device 80 includes a clamping sleeve 72 that houses a flexible clamping gripper 74 that interacts with the proximal end 52 of the implant. A flexible pusher tube 76 that can be spring loaded includes a small internal recess 78 that accommodates a new therapeutic agent 62 to be delivered to the implant lumen 58. In Figure 20A, a new dose of drug, coated with a shell and capped with a proximal obstruction, is inserted into the implant lumen. Figures 20B and 20C show the reloading of the implant with multiple drug pellets. In such an embodiment, a one-way passage 70 allows for the insertion of a recharging device that carries the drug pellets into the implant lumen, but upon removal of the recharging device, the passage closes to prevent the drug from leaking out of the lumen. In addition to providing the ability to renew the dose of drug in the implant, reloading the implant with multiple pellets may provide one or more other advantages. In some embodiments, the pellets are sized to increase the surface area of ​​the drug in contact with ocular fluid (compared to implants loaded with a solid drug core). Since contact with ocular fluid is a variable in the overall drug elution rate, in such embodiments, the size of the pellets can be adjusted as needed to obtain a particular desired release rate. Furthermore, in some embodiments, even when the drug loading is sufficient, the size of the multiple pellets can be adjusted to increase the rate or capacity at which fluid flows through the lumen of the implant. Furthermore, one or more of the multiple pellets are coated in some embodiments to control the dissolution or elution of the drug. As discussed above with respect to the implant itself, it is understood that the pellets can be coated with coatings with or without apertures of various thicknesses, compositions, etc., to control the drug release rate from the pellets themselves. In some embodiments, coated pellets are used in uncoated devices, and in other embodiments, a combination of coated and uncoated pellets is used in coated devices.For example, if an ocular condition is known to require drug therapy in addition to the removal / diversion of ocular fluid, the pellets can be sized to deliver a sufficient amount of drug to provide a therapeutic effect while allowing ocular fluid to flow through the lumen of the implant from a first location to a second location. Furthermore, the presence of multiple pellets or particles, as opposed to a single solid core of drug, can provide flexibility to the implant in certain embodiments. In such embodiments, the implant can be connected as needed to be attached within or adjacent to a desired physiological space, and the shape of the pellets can be designed to provide space around the pellets so that this joint is not hindered by pellet-to-pellet contact. It is understood that in such embodiments, the pellets may contact each other to some extent and still allow the implant to be loaded with drug with a high degree of efficiency. It is also understood that in certain embodiments where flexibility of the implant is unnecessary or undesirable, the pellets can be shaped to be in closer contact with each other to compensate for the rigidity of the implant.

[0270] As shown diagrammatically in Figures 20D and 20E, an elongated implant can include multiple features as disclosed herein. For example, Figure 20D shows an elongated 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 20D and 20E 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., Schlemm's canal).

[0271] 20G illustrates a schematic of an eye in which an embodiment of an elongated implant has been positioned in accordance with some embodiments disclosed herein. As shown, the proximal end 52 of the implant is near the anterior portion of the eye and the 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 the 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.

[0272] FIG. 20H illustrates additional configurations that may be used in some embodiments. For example, in one embodiment, the implant is placed in the eye (e.g., using a custom inserter 1000) with the distal end 50 at the posterior portion of the eye and the proximal end 52 at a more anterior region. The illustrated implant, described in more detail herein, includes multiple drug release regions, shown as 56 and 56a in FIG. 20H, and multiple types of therapeutic agents, i.e., 58 and 58a. Some embodiments of such implants may be used, for example, when the addition or bolus of a therapeutic agent (58a) is beneficial for an acute or relatively short-term effect (perhaps to reduce inflammation or risk of infection, for example). A longer-term formulation of therapeutic agent (e.g., pellets, 58) then provides a controlled release of the drug for a period beyond the acute effect. In some embodiments, such configurations may reduce complications associated with the insertion of the device and shorten the time from insertion to relief of one or more symptoms associated with the disease or disorder being treated.

[0273] FIG. 20I illustrates yet another embodiment of an elongate device with a different drug elution strategy. Again, the implant has a distal portion 50 positioned in the posterior region of the eye. In the illustrated embodiment, drug release regions 56 and 56a are positioned at or near the very distal end of the implant. The distal end is configured to allow pellets of therapeutic agent 58, and / or a different formulation (e.g., micropellets, vesicles, gel) of therapeutic agent, or a different therapeutic agent (e.g., one that reduces or prevents side effects due to the first therapeutic agent) to be flushed out of the distal end of the implant. A schematic diagram of such an implant is shown in FIG. 20J. The distal end 50 of the implant includes a drug release region 56 formed by a one-way valve 70. In some embodiments, the valve includes two or more flaps 70 that are open at the proximal end and reversibly closed at the distal end. Pressure on the proximal portion of the flap opens the flap, allowing the drugs 58 and 58a to be expelled (partially or completely) from the implant. In some embodiments, the flap returns to its closed (or substantially closed) position such that a seal is formed that prevents ocular fluid (which may include expelled therapeutic agent) from flowing back into the implant. However, in other embodiments, a fluid-tight seal is not formed. Depending on the embodiment, different flaps or sealing mechanisms are used.

[0274] Such an embodiment is used during the initial implantation procedure in some embodiments. In such a case, washing out the therapeutic agent 58 may expose the therapeutic agent 58 sufficiently to the intraocular environment to hasten the therapeutic effect of the therapeutic agent. Furthermore, once the initial therapeutic agent 58 is washed out of the implant, the distal portion of the implant is open (e.g., not blocked by the agent) to deliver the second therapeutic agent 58a. Washing out the initial agent 58 from the device helps ensure that the second agent (which again reduces or prevents side effects of the first agent) reaches the desired anatomical target tissue. If the device is not washed out and still contains the therapeutic agent 58, the second agent 58a would have to travel around the first agent within the implant or elute / flow out of the implant through a side port (more proximal and therefore further from the posterior target tissue). Either approach may result in the second agent 58a not being able to reach the desired target in the posterior region of the eye (at least in therapeutically effective concentrations).

[0275] In yet another embodiment, a device configured to flush its therapeutic drug contents out of the distal end of the device is useful when assessing the efficacy and / or functionality of the device after implantation. At such times, it may be advantageous to be able to deliver a second drug (possibly ameliorating side effects) or a different concentration of drug. That is, this can be done by flushing the implant with the second drug or a new concentration of the first drug.

[0276] In some embodiments, the agent 58a delivered secondarily and / or in conjunction with flowing the first therapeutic agent 58 is in a fluid, semi-fluid, or fluid-like form. In some embodiments, particulates that behave like a fluid (e.g., they have liquid-like flow properties) are used. In some embodiments, the second agent 58a is configured to have its own desired elution profile. In such cases, the second agent 58a is optionally housed or contained in a structure capable of controlled release. In some embodiments, this involves mixing the therapeutic agent with one or more polymers that release the therapeutic agent from the mixture at a known elution rate (e.g., form a "matrix"). In some embodiments, the one or more polymers are selected so that they can be readily interconverted between a liquid or semi-liquid state and a solid or semi-solid state. In some embodiments, the interconversion results from an external stimulus (e.g., radio frequency, light, etc.). In some embodiments, the interconversion is induced by temperature or pressure. For example, in some embodiments, the polymer is liquid or semi-liquid at room temperature, but becomes solid or semi-solid when exposed to elevated temperatures (e.g., physiological temperatures). In this way, a polymer matrix can be used to transport the therapeutic agent in a desired manner. The drug may be retained at the desired target site, thereby improving delivery accuracy and reducing washout due to ocular fluid flow. In some embodiments, the polymer is optionally biodegradable (so that repeated administration does not result in accumulation of the polymer at the delivery site). In some embodiments, the polymer is a mixture of polymers configured to mimic membrane-bound structures (e.g., micelles or vesicles). In some such embodiments, the drug is incorporated into the micelles or vesicles and mixed with the polymer so that it elutes at a certain rate (based on the known properties of the polymer). Similarly, such micelles or vesicles are optionally mixed with a polymer matrix that can be easily interconverted between a liquid or semi-liquid state and a solid or semi-solid state.

[0277] It should be understood that the elements discussed above should not be construed as limiting the implant to the specific combinations or embodiments described, but rather the features discussed are freely interchangeable, allowing flexibility in constructing drug delivery implants according to the present disclosure.

[0278] <Delivery device>

[0279] 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.

[0280] 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 to 30 mm in some embodiments. In some embodiments, the radius of the distal curvature is about 20 mm.

[0281] In some embodiments, the delivery instrument has a distal angle 88 (having a dimension shown as χ in FIG. 21). 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 include a small radius of curvature at 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.

[0282] In other embodiments, a curved distal end is preferred, in which the height of the delivery device / shunt assembly (dimension 90 in FIG. 22) is less than about 3 mm in some embodiments, and less than 2 mm in other embodiments.

[0283] 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 penetrate only corneal and / or limbal tissue. In another embodiment, 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.

[0284] To deliver some embodiments of the drug eluting ocular implant, the device has a cross-section small enough that when the device is withdrawn from the eye, the insertion site will self-seal without sutures. The outer dimensions of the delivery device are preferably about 18 gauge or smaller, and about 27 or 30 gauge or larger.

[0285] 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 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 gauge) so that the incision is self-sealing, and implantation is performed in a closed chamber with or without viscoelastic properties. A self-sealing incision can also be made by a conventional "tunneling" procedure in which a spatula-shaped scalpel is used to make a generally inverted V-shaped incision through the cornea. In a preferred embodiment, 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 position the ocular implant or can cooperate with a delivery instrument to allow 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.

[0286] 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.

[0287] In some embodiments, an over-the-wire system is used to deliver the implant. The implant can be delivered over a 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.

[0288] 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.

[0289] In some embodiments, the delivery instrument 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 diameter of the trocar is about 0.001 inches to about 0.01 inches. In some embodiments, the diameter of the trocar is 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, or 0.01 inches.

[0290] 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.

[0291] 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 to 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 snug-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.

[0292] The delivery instrument can include a distal end having a beveled shape. The delivery instrument can include a distal end having a spatula shape. The bevel or spatula shape may or may not include a recess for containing the implant. The recess can include a pusher or other suitable means for pushing or expelling the implant.

[0293] The delivery instrument can be configured to deliver multiple implants, and in some such embodiments, the implants can be arranged vertically (or serially if the number of implants is greater than two) within the device.

[0294] <Procedure>

[0295] To deliver some embodiments of the ocular implant, the implant is placed in a closed chamber with or without viscoelastic properties.

[0296] 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 Application Publication No. 2004 / 0050392, filed August 28, 2002 (U.S. Patent No. 7,331,984, granted February 19, 2008), which is incorporated by reference in its entirety and made a part of this specification and 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.

[0297] 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 described in U.S. Patent Application Publication No. 2004 / 0050392, filed Aug. 28, 2002 (U.S. Patent No. 7,331,984, granted Feb. 19, 2008), U.S. Patent Application Publication No. 2002 / 0133168 (now abandoned), entitled "APPLICATOR AND METHODS FOR PLACING A TRABECULAR SHUNT FOR GLAUCOMA TREATMENT," and U.S. Patent Application Publication No. 2003 / 0133168 (now abandoned), entitled "APPLICATOR AND METHODS FOR PLACING A TRABECULAR SHUNT FOR GLAUCOMA TREATMENT," filed Mar. 16, 2001, each of which is incorporated herein by reference and made a part of this disclosure. This invention is disclosed in U.S. Provisional Patent Application No. 60 / 276,609 (now expired), entitled "Polymer-Based Fluorescent Treatment."

[0298] 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. 20F. 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. The 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.

[0299] In some embodiments, the retainer comprises a clamp. In some embodiments, the device further comprises a spring in the hand piece configured to be loaded when the drug delivery implant is retained by the retainer. The spring can be at least partially unloaded upon actuation of the actuator to release the drug delivery implant from the retainer.

[0300] In various embodiments, the clamp includes a plurality of jaws configured to apply a clamping force to at least a proximal portion of the drug delivery implant.The retainer can also include a plurality of flanges.

[0301] 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 preferably have a deflection range of about 45 degrees from the long axis of the handpiece. The delivery device can further include an irrigation port in the elongate tip.

[0302] 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 passed through a corneal incision and positioned in 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 that actuates the retainer to release the drug delivery implant from the retainer. The retainer is configured to retain and release the drug delivery implant.

[0303] The delivery instrument can be advanced through an insertion site in the cornea and advanced across or posteriorly to the globe into the anterior chamber angle, positioned at the base of the angle. Using the angle as a reference point, the delivery instrument can be further advanced generally posteriorly to advance the implant into the iris inside the angle.

[0304] 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.

[0305] 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.

[0306] 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.

[0307] In one embodiment, the drug delivery implant is secured to another portion of the iris or other intraocular tissue to aid in fixation of the implant. In one embodiment, this additional fixation can be achieved using a biocompatible adhesive. In another embodiment, one or more sutures can be used. In another embodiment, the drug delivery implant is held in place substantially by interaction of the outer surface of the implant body with the surrounding tissue of the anterior chamber angle.

[0308] FIG. 23 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. 23. In another embodiment, the first incision can be made to allow for a larger insertion angle of the tool (see, e.g., FIGS. 24-26). 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.

[0309] 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 substantially coaxial with the long axis of the gripping end of the surgical tool. The drug delivery implant is placed through the first incision.

[0310] 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.

[0311] 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.

[0312] 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.

[0313] 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.

[0314] 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 appreciated 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.

[0315] As discussed herein, in some embodiments, the drug delivery implant further includes a shunt comprising 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.

[0316] In some embodiments, it is desirable to deliver the drug delivery implant ab interno across the eyeball through a small incision at or near the limbus (FIG. 24). Depending on the overall geometry of the system, it is advantageous for the delivery instrument to include a distal curve or a distal angle. 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.

[0317] 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, and through the ciliary muscle attachment until the drug delivery implant outlet is located in the uveoscleral pathway (e.g., adjacent the suprachoroidal space defined between the sclera 11 and choroid 12). FIG. 24 illustrates a transocular implantation technique that may be used with the delivery device inserted well above the limbus 21. In other embodiments (see, for example, FIG. 25), 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 device while simultaneously pushing the pusher to maintain the drug delivery implant outlet in a posterior region of the suprachoroidal space near the macula 34, as shown in FIG. 26. The implant is released from the delivery instrument, the delivery instrument is retracted proximally, and the delivery instrument is withdrawn from the anterior chamber through the incision.

[0318] In some embodiments, to reduce intraocular pressure in glaucoma patients, it is desirable to implant a drug delivery implant through which aqueous humor continuously flows out through a 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 (ab interno) through a small incision at the limbus 21.

[0319] In some embodiments, a microinvasive method of implanting a drug delivery implant is provided. In some such embodiments, an extraocular 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 and simultaneously delivers a drug. In some embodiments, the implant passes fluid from the anterior chamber to the suprachoroidal space, removing fluid (e.g., aqueous humor) from the anterior chamber and helping to reduce anterior chamber pressure buildup.

[0320] In some embodiments (see, e.g., FIG. 27), a window (e.g., a slit or other small incision) is surgically made (without penetration) through the conjunctiva and sclera 11 at the surface of the choroid 28. In some embodiments, the slit is perpendicular to the optical axis of the eye. In some embodiments, a depth stop is used in conjunction with the cutting device. In certain embodiments, the cutting device is one of a diamond or metal blade, a laser, or the like. In some embodiments, the initial incision is made with a sharp device, and the final portion of the incision at the choroidal surface is made with a less sharp instrument, thereby reducing the risk of damaging the highly vascular choroid. In some embodiments, the slit is made tangential or nearly tangential to the sclera to facilitate entry and manipulation of the implant.

[0321] In some embodiments, a small core of the sclera is removed at or near the pars plana, again without penetrating the choroid. To avoid penetrating the choroid, the thickness of the sclera can optionally be measured using optical coherence tomography (OCT), ultrasound, or visual fixation of the eye during the surgical procedure. In such embodiments, the core of the sclera is removed with a punching instrument (e.g., a rotary or static punch), optionally including a depth stop gauge to ensure the incision is at the proper depth. In another embodiment, a laser, diamond blade, metal blade, or another similar cutting device is used.

[0322] After the window or slit is formed in the sclera and the suprachoroidal space is exposed, the implant 40 can be inserted into the window or slit and advanced in multiple directions using the instrument 38a (see, e.g., Figs. 27B-27C). The instrument 38a can be used to move the implant 40 backward, forward, upward, or downward. The instrument 38a is specifically designed to advance the implant into place without damaging the choroid or other structures. The instrument 38a can then be removed, leaving the implant 40 behind. In some embodiments, the conjunctival and scleral window is small enough to self-seal the incision. In some embodiments, it can be a larger window or slit that can be sealed by sutures, staples, tissue common wound adhesive, or the like. The slit or window according to these embodiments can be, for example, 1 mm or less in length or diameter. In some embodiments, the length of the incision is in the range of about 0.2 to about 0.4 mm, about 0.4 to about 0.6 mm, about 0.6 mm to about 0.8 mm, about 0.8 mm to about 1.0 mm, about 1.0 to about 1.5 mm, and overlapping ranges therein. In some embodiments, larger incision (slit or window) sizes are used.

[0323] In some embodiments, the implant 40 is tubular or elliptical tubular in shape. In some embodiments, such a shape facilitates passage of the implant through small openings. In some embodiments, the implant 40 has a rounded closed distal end, while in other embodiments, the distal end is open. In some embodiments using an open-ended implant, the open end is filled (e.g., temporarily blocked) with a portion of the insertion tool to prevent tissue blockage during advancement of the implant (e.g., into the suprachoroidal space). In some embodiments, the implant is an implant as described herein and includes a lumen containing a drug that elutes through the implant's perforations, pores, or drug release regions. As discussed herein, drug elution, in some embodiments, is targeted toward the posterior portion of the eye (e.g., the macula or optic nerve) to deliver a therapeutic agent (e.g., a steroid or anti-VEGF) to treat retinal or optic nerve disease.

[0324] In some embodiments, the implant 40 and the implantation tool 38a are designed to have a suitable tip to advance the implant and penetrate the anterior chamber without incising the sclera. In some embodiments, the tip that penetrates the anterior chamber is part of the implant, and in some embodiments, it is part of the insertion tool. In such embodiments, the implant acts as a conduit (e.g., a shunt) for aqueous humor to pass from the anterior chamber to the suprachoroidal space to treat glaucoma or ocular hypertension. In some embodiments, the implant is configured to deliver a drug to the anterior chamber to treat glaucoma. In some embodiments, the drug is configured (e.g., produced) to elute over a relatively long period of time (e.g., weeks to months or even years). Non-limiting examples of such drugs are beta blockers or prostaglandins. In some embodiments, a single implant is inserted, and in other embodiments, two or more implants are implanted in this manner, in the same or different locations, with any combination of aqueous humor conduits or drug delivery mechanisms.

[0325] FIG. 28 shows an illustrative transocular method of placing any of the various implant embodiments taught or suggested herein at an implantation site within the eye 10. The delivery device 100b generally includes a syringe portion 116 and a cannula portion 118. The distal section of the cannula 118 optionally includes at least one irrigation hole 120 and a distal space 122 for holding the drug delivery implant 30. The proximal end 124 of the lumen of the distal space 122 is blocked from the remaining lumen of the cannula portion 118. The delivery device of FIG. 28 can be used with any of the various drug delivery implant embodiments taught or suggested herein. In some embodiments, the target implant site is the inferior portion of the iris. It should be understood that the angles of the delivery device shown in FIG. 28 are illustrative and that in some embodiments, angles that are shallower or less shallow than those shown may be preferred.

[0326] 29 illustrates an exemplary method for placing any of the various implant embodiments taught or suggested herein at an implant site on the same side of the eye. In one embodiment, the drug delivery implant is inserted into the anterior chamber 20 of the eye 10 against the iris using an applicator or delivery device 100c that creates a small puncture in the eye from the outside. In some embodiments, the target implant site is the inferior portion of the iris.

[0327] 30 illustrates a drug delivery implant according to some embodiments disclosed herein affixed to the iris 13 of the eye 10 according to some implantation methods disclosed herein. It should be understood that the iris is only one of many tissues to which the implants described herein can be affixed.

[0328] 31 illustrates another possible embodiment of the placement of a drug delivery implant in accordance with some embodiments disclosed herein. In one embodiment, the outer shell 54 of an implant in accordance with some embodiments disclosed herein is shown positioned in the anterior chamber angle (cross section). In one embodiment, the drug delivery implant can be positioned entirely within the anterior chamber angle using transocular delivery methods and devices. The drug delivery implant substantially follows the curvature of the anterior angle. In some embodiments, the implant is positioned substantially within the anterior chamber angle along the inferior portion of the iris.

[0329] In some embodiments, the placement of the implant may result in the drug target being upstream of the natural flow of aqueous humor. For example, aqueous humor may flow from the ciliary body processes to the anterior chamber angle, creating a reverse fluid flow that the drug released from the implant may need to travel to contact the target tissue, depending on the implantation site of an embodiment. Thus, in some embodiments, for example, when the target tissue is the ciliary body processes, the eluted drug must diffuse through the iris tissue to travel from the anterior chamber to the target receptors in the ciliary body processes in the posterior chamber. The diffusion of the drug through the iris and the requirement of aqueous humor flow may limit the amount of eluted drug that reaches the ciliary body in some cases.

[0330] To overcome these challenges, certain embodiments include placing a peripheral iridotomy (PI) or a PI with a stented device adjacent to the drug-eluting implant to facilitate direct delivery of the drug to the intended site of action (i.e., the target tissue). The formation of the PI opens a relatively large communication channel between the posterior and anterior chambers. Although there is still a net flow of aqueous humor from the posterior chamber to the anterior chamber, the relatively large diameter of the PI substantially reduces the linear flow rate. Thus, the eluted drug can diffuse through the PI without significant resistance from the aqueous humor flow. In certain such embodiments, a portion of the implant has a structure that penetrates the iris and elutes the drug directly into the posterior chamber at the ciliary body. In another embodiment, the implant is implanted and / or fixed to the iris and elutes the drug directly into the posterior chamber and adjacent ciliary body.

[0331] Figure 22 shows a longitudinal section of the anterior segment of the human eye and illustrates another embodiment of a delivery device 38 that can be used with the drug delivery implant embodiments described herein. In Figure 22, 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.

[0332] The delivery device / implant assembly can reach the iridocorneal angle by passing between the iris 13 and the cornea 12. Thus, the height of the delivery device / shunt assembly (dimension 90 in FIG. 22) is less than about 3 mm in some embodiments, and less than 2 mm in other embodiments.

[0333] 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.

[0334] Depending on the overall geometry of the drug delivery implant system, it may be advantageous for the delivery device 38 to incorporate a distal curve 86 as shown in FIG. 22, a distal angle 88 as shown in FIG. 21, or a combination thereof. The distal curve (FIG. 23) 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, in the design of FIG. 21, the drug delivery implant may be attached to the "elbow", i.e., the straight section of the delivery device distal to the angle 88. 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 section 92.

[0335] The distal curve 86 of the delivery instrument 38 may be characterized as having a radius of about 10 to 30 mm in some embodiments, and about 20 mm in some embodiments. The distal angle of the delivery instrument in one embodiment shown in FIG. 21 may be characterized as about 90 to 170 degrees relative to the axis of the proximal section 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 section 94 to the distal section 92 of the delivery instrument. The length of the distal section 92 may be about 0.5 to 7 mm in some embodiments, and about 2 to 3 mm in some embodiments.

[0336] 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. Such a pocket exposes more of the choroidal and scleral tissue area, provides lubrication and tissue protection during implantation, and increases uveoscleral flow in embodiments where the drug delivery implant includes a shunt to reduce intraocular pressure (IOP). In some embodiments, a 25 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 completed.

[0337] In some embodiments, a 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. The hyperosmolar agent can be, for example, glucose, albumin, HYPAQUE™ medium, glycerol or poly(ethylene glycol). As the patient recovers, the hyperosmolar agent is decomposed or flushed out, resulting in a stable and tolerable low IOP, and can avoid transient hypotony.

[0338] Controlled Drug Release

[0339] 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 produce a desired drug release profile.

[0340] As mentioned above, the drug delivery implant can be made from any biologically inert and biocompatible material that has the desired properties. In some embodiments, desirable properties include permeability to liquid water or water vapor, which allows the implant to be manufactured, loaded with drug, sterilized in a dry state, and subsequently rehydrated upon implantation. Additionally, implants constructed from materials that contain microscopic pores between the polymer chains are also desirable. These pores can interconnect to form channels of water through the implant material. In some embodiments, the resulting channels are convoluted, thereby forming a tortuous path along which the solubilized drug travels during the elution process. The implant material is also advantageously permeable to the drug such that the implant is of a practical size for implantation. Thus, in some embodiments, the implant material is permeable to the drug to be delivered, and the implant is of a size that is entirely contained within the subject's eye. The graft material will also ideally have sufficient elasticity, flexibility and extensibility to remain untwisted, not tear, not puncture, and have a patent lumen during and after implantation as well as conform to the target anatomy during and after implantation, hi some embodiments, the graft material is advantageously practically processable, for example, by molding, extrusion, thermoforming, and the like.

[0341] Illustrative examples of materials suitable for the shell include polypropylene, polyimide, glass, nitinol, polyvinyl alcohol, polyvinylpyrrolidone, collagen, chemically treated collagen, polyethersulfone (PES), poly(styrene-isobutyl-styrene), polyurethane, ethyl vinyl acetate (EVA), polyetherether ketone (PEEK), Kynar (Polyvinylidene Fluoride; PVDF), polytetrafluoroethylene (PTFE), polymethylmethacrylate (PMMA), Pebax, acrylics, polyolefins, polydimethylsiloxane and other silicone elastomers, polypropylene, hydroxyapetite, titanium, gold, silver, platinum, other metals and alloys, ceramics, plastics, and mixtures or combinations thereof. Other suitable materials for use in the construction of certain embodiments of the implant include, but are not limited to, poly(lactic acid), poly(tyrosine carbonate), polyethylene-vinyl acetate, poly(L-lactic acid), poly(D,L-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, copolymers or block copolymers, polyester urethanes, polyester amides, polyester ureas, polythioesters, thermoplastic polyurethanes, silicone modified polyether urethanes, poly(carbonate urethanes), or polyimides. Thermoplastic polyurethanes are polymers or copolymers that may include aliphatic polyurethanes, aromatic polyurethanes, polyurethane hydrogel-forming materials, hydrophilic polyurethanes (such as those described in U.S. Pat. No. 5,428,123, which is incorporated herein by reference in its entirety), or combinations thereof.Non-limiting examples include elastanes (poly(ether urethanes)), such as Elasthane® 80A, Lubrizol, Tecophilic®, Pellethane®, carbothane®, Tecothane®, Tecoplast®, Estane®, etc. In some embodiments, polysiloxane-containing polyurethane elastomers are used, including Carbosil® 20 or Pursil® 20 80A, Elast-Eon®, etc. Hydrophilic and / or hydrophobic materials can be used. Non-limiting examples of such elastomers are described in U.S. Pat. No. 6,627,724, which is incorporated herein by reference in its entirety. Poly(carbonate urethanes) include Bionate® 80A or similar polymers. In some embodiments, such silicone-modified polyether urethanes are particularly advantageous due to the improved biostability of the polymer imparted by the inclusion of silicone. Additionally, in some embodiments, oxidative stability and thrombogenicity are improved compared to unmodified polyurethanes. In some embodiments, silicone modified polyether urethanes are used to reduce angiogenesis, cell adhesion, inflammation, and / or protein adsorption. In another embodiment, the degree of silicone (or other modifier) ​​can be adjusted accordingly if angiogenesis, cell adhesion, or protein adsorption is preferred (e.g., to help immobilize the implant). Additionally, in some embodiments, silicone modification reduces the coefficient of friction of the polymer, reducing trauma during implantation of the devices described herein. In some embodiments, silicone modification is another variable that can be used to adjust the permeability of the polymer in addition to the other mechanisms described herein. Additionally, in some embodiments, silicone modification of the polymer is achieved by adding silicone-containing surface-modifying end groups to the base polymer. In another embodiment, fluorocarbon or polyethylene oxide surface-modifying end groups are added to the base polymer.In some embodiments, one or more biodegradable materials are used to construct all or a portion of the implant or any other device disclosed herein. Such materials include any suitable material that, when placed in the human or animal body, degrades or erodes over time, whether due to a specific chemical reaction or enzymatic process, or in the absence of such a reaction or process. Thus, as the term is used herein, biodegradable materials include bioerodible materials. In such biodegradable embodiments, the degradation rate of the biodegradable shell is another variable (of many) that can be used to tailor the drug elution rate from the implant.

[0342] In some embodiments, such as when a drug is sensitive to moisture (e.g., liquid water, water vapor, humidity) or when contact with moisture may adversely affect the long-term stability of the drug, it may be desirable to utilize a material for the implant, or at least a portion of the implant, that is water-resistant, water-impermeable, or waterproof so as to provide an effective barrier to the ingress of liquid water and / or water vapor, particularly at or near human body temperature (e.g., about 35-40° C. or 37° C.). This can be accomplished by using a material that is itself water-resistant, water-impermeable, or waterproof.

[0343] However, in some circumstances, even materials that are generally considered water impermeable may allow enough water to enter the implant to adversely affect the drug in the implant. For example, it may be desirable to have water ingress of no more than 5% by weight of the drug over a one-year period. In one embodiment of the implant, this is about 1×10 -3 g / m 2 / day or less. This is perhaps on the order of one-tenth the water vapor transmission rate of some polymers that are generally considered to be water resistant or water impermeable. Thus, in some cases it may be desirable to make a material more water resistant or water impermeable.

[0344] The water resistance or water impermeability of a material can be increased by any suitable method. Such treatment methods include coating the material (including lamination) or mixing the material with a component that renders it water resistant or impermeable. For example, such treatments can be applied to the implant (or part of the implant) itself, can be applied to the material prior to fabrication (e.g., coating a polymer tube), or can be applied during formation of the material itself (e.g., by mixing a resin with the material before molding the resin into a tube or sheet). Such treatments can include, but are not limited to, one or more of the following: Coating or laminating the material with a hydrophobic polymer or other material to make it more water resistant or impermeable; mixing the material with a hydrophobic or other material to make it more water resistant or impermeable; mixing or treating the material with a substance that fills microscopic gaps or pores in the material allowing the ingress of water or water vapor; coating and / or mixing the material with a water scavenger or hygroscopic material that absorbs, adsorbs or reacts with water to make the material more water resistant or impermeable.

[0345] One type of material that can be employed as a coating to enhance water resistance and / or water impermeability is inorganic materials. Inorganic materials include, but are not limited to, metals, metal oxides and other metal compounds (e.g., metal sulfides, metal hydrides), ceramics, and main group elements and their compounds (e.g., carbon (e.g., carbon nanotubes), silicon, silicon oxide). Examples of suitable materials include aluminum oxide (e.g., Al 2 O 3 ) and silicon oxide (e.g., SiO 2). The inorganic material can be advantageously applied onto the material (at any stage of the manufacture of the material or implant) by techniques such as those known in the art for forming extremely thin coatings on substrates, e.g., vapor deposition, atomic layer deposition, plasma deposition, and the like. Such techniques can deposit extremely thin coatings (e.g., about 20 nm to 40 nm thick, including about 25 nm thick, about 30 nm thick, and about 35 nm thick) onto substrates, including polymeric substrates, and can form coatings on the exterior and / or interior luminal surfaces of small tubes, including those of a size suitable for use in the implants disclosed herein. Such coatings can exhibit excellent resistance to water or water vapor transmission while being at least reasonably flexible so as not to impair the performance of implants where flexibility is desired.

[0346] In embodiments where a therapeutic agent is delivered by a flexible tethered implant (see, e.g., Figures 16-17), one or more flexible sheets or disks can be used simultaneously to control the dose or duration of treatment. Similarly, the materials used in the construction of the sheets or disks and / or coatings thereover can be tailored to control the release rate of the drug, as discussed below.

[0347] The drug carried by the drug delivery implant can be in any form that can be adequately retained within the device for a period of at least several days, and in some embodiments up to several weeks, and in certain preferred embodiments up to several years, resulting in controlled elution of the endogenous drug(s). Certain embodiments utilize drugs that are readily soluble in ocular fluids, while other embodiments utilize drugs that are partially soluble in ocular fluids.

[0348] For example, the therapeutic agent can be in any form, including, but not limited to, compressed pellets, solids, capsules, multiple particles, liquids, 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 allow for recharging by injection into the inner lumen(s). As noted above, in some embodiments, loading and / or recharging of the device is performed with a syringe / needle that delivers the therapeutic agent. In some embodiments, the microtablets are delivered through a needle that is about 23 gauge to about 32 gauge, including 23-25 ​​gauge, 25 to 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.

[0349] 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 tailor the elution profile, the compound(s) may also be in any form that is compatible with the drug and can be adequately retained by the implant.

[0350] In some embodiments, the treatment of a particular condition with a drug released from the 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, the drug delivery shunt delivers steroids to an ocular target tissue, such as the retina or other target tissues described herein, thereby treating a retinal condition, but may also induce an increase in intraocular pressure that may result from local inflammation or fluid accumulation. In such embodiments, the shunt function reduces the undesirable increase in intraocular pressure by carrying away accumulated fluid. Thus, in some embodiments, the implant, functioning as both a drug delivery device and a shunt, may not only serve to deliver a therapeutic agent, but may also simultaneously drain accumulated fluid, thereby helping to reduce the side effects of the drug. Such embodiments may be deployed in certain ocular conditions, or in any other physiological conditions in which the delivery of the drug coincidentally causes fluid accumulation that needs to be suppressed by the shunt function of the implant. In some such embodiments, especially when the target tissue is sensitive to pressure or has limited space or capacity to expand in response to accumulated fluid, it is necessary to evacuate the accumulated fluid to prevent tissue damage or loss of function. The eye and the brain are two non-limiting examples of such tissues.

[0351] 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. A preferred biodegradable material includes 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.

[0352] In some embodiments, it may be desirable to define a specific 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 provides a means to control the delivery rate of the drug contained in the therapeutic agent. Changes in 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 achieving a desired duration or alternative release profile of therapeutic agent delivery to the eye.

[0353] In another embodiment employing PLGA copolymers, the biodegradation rate of the PLGA copolymer can be controlled by varying the ratio of lactic acid units to glycolic acid units in the copolymer.

[0354] Yet another embodiment may utilize a combination of varying the average molecular weight of the copolymer components and varying the ratio of lactic acid to glycolic acid in the copolymer to obtain a desired biodegradation rate.

[0355] As mentioned above, the outer shell of the implant comprises a polymer in some embodiments. Moreover, the shell may further comprise one or more polymer coatings at various locations on or within the implant. The outer shell and any polymer coatings are optionally biodegradable. The biodegradable outer shell and biodegradable polymer coatings may 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.

[0356] As mentioned above, some embodiments of the implant include a polymeric shell that is permeable to ocular fluid in a controlled manner depending on the components used to form the shell. For example, the concentration of polymer subunits determines the permeability of the resulting shell. Thus, the composition of the polymers that make up the polymeric shell determines the rate of passage of ocular fluid through the polymer and, if biodegradable, the rate of biodegradation in ocular fluid. The permeability of the shell also affects the release of the drug from the shell. Furthermore, as mentioned above, drug release regions formed on the shell change the release profile of the drug from the implant. Control of the release of the drug can be further controlled by coatings in or on the shell that form drug release regions or change the properties of the drug release regions (e.g., a coating on a drug release region thickens the region and therefore slows the drug release rate).

[0357] For example, a given combination of drug and polymer gives rise to a characteristic diffusion coefficient D as follows:

[0358]

number

[0359] Where D = diffusion coefficient (cm 2 / sec)

[0360] A = area of ​​drug release region (Ci-Co) = Drug concentration difference between inside and outside the device

[0361] d = thickness of drug release region

[0362] Thus, the area and thickness of the drug release regions are variables that in part determine the drug elution rate from the implant, and are also variables that can be controlled during the manufacturing process of the implant. In some embodiments using poorly soluble drugs, the drug release regions can be made thin (small d), or have a large total area (large A), or a combination of the two (as determined by the structural sufficiency of the outer shell). In either case, the end result is an increased drug elution rate that can compensate for the low solubility of the drug based on the structure and design of the implant.

[0363] In contrast, in some embodiments using highly soluble drugs, the regions of drug release are made of substantially the same thickness as the remainder of the shell, are made of a smaller area, or a combination thereof.

[0364] Additionally, certain embodiments use additional polymer coatings to reduce drug elution by (i) increasing the effective thickness (d) of the drug release region or (ii) decreasing the total permeability of that portion of the implant (drug release region + coating). In yet another embodiment, multiple additional polymer coatings are used. Drug release from various regions of the implant is controlled by covering different or overlapping portions of the implant and the associated drug release region on the outer shell to control the drug release pattern from the entire implant. For example, an implant having at least two drug release regions can be coated with two additional polymers, both of which completely cover the release region and only one of the regions with a single polymer. Thus, the drug elution rates from the two drug release regions can be different, for example, controlled so that the drug is released sequentially from the two regions. In another embodiment, the two regions can release at different rates. In embodiments with multiple internal lumens, different concentrations or different drugs can also be released. It is understood that these variables can be controlled to change the rate or duration of drug release from the implant so that a desired elution profile or treatment plan can be created.

[0365] In some embodiments described herein, there are no direct through holes or through openings that are required or utilized to specifically promote or inhibit drug elution. Thus, in these embodiments, there is no direct contact between the drug core (which may be at a very high concentration) and the ocular tissue adjacent to the site where the implant is placed. In some cases, direct contact between the high concentration of drug in the implant and the ocular tissue may result in localized cytotoxicity and localized cell death.

[0366] However, it should be understood that in some alternative embodiments disclosed herein, the number, size and location of one or more orifices through the outer shell of the implant can be altered to obtain a desired drug elution profile. Increasing the number, size or both of the orifices relative to the surface area of ​​the implant increases the amount of ocular fluid passing through the shell and contacting the therapeutic agent inside the implant. Similarly, decreasing the orifice:shell area ratio reduces ocular fluid entering the implant, thereby decreasing the rate of drug release from the implant. Additionally, if one or more orifices are closed during implantation or after their presence in the eye, the multiple orifices provide redundant communication between the ocular environment in which the implant is implanted and the interior of the implant. In another embodiment, the outer shell can include one (or more) orifices at the distal tip of the implant. As discussed above, the shape and size of this orifice is selected based on the desired elution profile. In some embodiments, a biodegradable polymer plug is placed in the distal orifice, thereby acting as a synthetic cork stopper. Tissue trauma or coring of the ocular tissue during the implantation process is also reduced, preventing blockage or partial closure of the distal orifice. Additionally, the polymer plug can be tailored to biodegrade over a known period of time, ensuring that the implant is fully deployed before drug elution occurs. Yet another embodiment includes a combination of a distal orifice and multiple orifices located more proximally in the shell, as described above.

[0367] Additionally, the addition of one or more permeable or semi-permeable coatings on the implant (having orifices or regions of drug release) can also tailor the elution profile. Additionally, combinations of these various elements can be used in some embodiments to provide multiple ways of controlling the drug release profile.

[0368] A further benefit of the embodiments described herein is the broad range of possible uses of some ocular therapeutic drugs. For example, drugs that are highly soluble in ocular fluids may have limited applicability in treatment regimens because their efficacy is limited to conditions treatable by acute drug administration. However, when combined with the implants disclosed herein, such drugs can be utilized in long-term treatment regimens. Highly soluble drugs disposed within the distal portion of the implant that includes one or more drug release regions can be prepared to form a specific long-term controlled release profile.

[0369] Instead of or in addition to one or more drug release regions, one or more polymeric coatings can be placed on the exterior or interior lumen of the implant shell to encapsulate or partially encapsulate the drug. In some embodiments including one or more orifices, the polymeric coating is the first part of the implant to contact ocular fluid and therefore the first control of the rate of inflow of ocular fluid into the drug-containing interior lumen of the implant. By modifying the composition of the polymeric coating, the rate of biodegradation (if biodegradable), and the porosity of the polymeric coating, the rate at which the drug contacts and solubilizes with ocular fluid can be controlled. Thus, the rate at which the drug is released from such embodiments of the implant to the target tissue of the eye is highly controlled. Similarly, drugs with low ocular fluid solubility can be placed in an implant coated with a rapidly biodegradable or highly porous polymeric coating to increase the flow of ocular fluid over the drug in the implant.

[0370] In certain embodiments described herein, the polymer coating encases the therapeutic agent within the lumen of the implant. In some such embodiments, ocular fluid passes through the outer shell of the implant and contacts the polymer layer. Such embodiments may be particularly useful when the implant includes one or more orifices and / or when the drug being delivered is a liquid, slurry, emulsion, or particles, as it is believed that the polymer layer not only helps control the elution of the drug, but also provides a structural barrier to prevent the drug from leaking or being lost in an uncontrolled manner through the orifice to the outside. However, the internal placement of the polymer layer may also be used for implants in which the drug is in any form.

[0371] In some ocular diseases, treatment may require a defined kinetic profile of drug administration to the eye. 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 form a particular kinetic profile of drug release. Additionally, the design of the implant itself, including the thickness of the shell material, the thickness of the shell in the drug release region, the area of ​​the drug release region, and the area and / or number of any orifices in the shell, provide a means to form a particular drug release profile. Similarly, PLGA copolymers and / or other controlled release materials and excipients can be used to form a particular kinetic profile of the release of the formulated drug. By adjusting the ratio of lactic acid to glycolic acid in the copolymer and / or the average molecular weight of the polymer or copolymer that contains the drug therein (optionally together with one or more other excipients), sustained release of the drug, or other desired release profile, can be obtained.

[0372] In certain embodiments, zero order release of the drug can be achieved by manipulating any of the features and / or variables discussed above, either alone or in combination, such that the properties of the implant become the primary factors controlling drug release from the implant. Similarly, in embodiments employing PLGA mixed with drug, the ratio of lactic acid to glycolic acid and / or the average molecular weight of the copolymer-drug composition can be adjusted to modulate the release kinetics based on a combination of implant structure and the biodegradability of the PLGA copolymer.

[0373] In another embodiment, pseudo-zero order release (or another desired release profile) can be achieved by adjusting the composition of the implant shell, the structure and dimensions of the drug release regions, the composition of any polymer coating, and the use of certain excipients or formulations (PLGA copolymers). Additive action over time mimics true zero order kinetics.

[0374] For example, in one embodiment, an implant having a polymer coating that allows ocular fluid to flow into the implant at a known rate can include a series of pellets in which PLGA is mixed with one or more drugs, and the pellets can include at least two PLGA copolymer formulations. Based on the formulation of the first therapeutic agent, each subsequent agent can be mixed with PLGA such that a known amount of drug is released per given unit time. Since each copolymer biodegrades or erodes at its individual desired rate, the total amount of drug released to the eye over time is effectively released with zero-order kinetics. Furthermore, it should be understood that the embodiments employing the drug partitions described herein and working in conjunction with pellets having multiple PLGA formulations are believed to add another level of control over the resulting drug release rate and kinetic profile.

[0375] Discontinuous or pulsed release may be desirable. This can be accomplished, for example, by fabricating an implant with multiple sublumens, each connected to one or more drug release regions. In some embodiments, an additional polymer coating is used to prevent drug release from one drug release region at a given time while allowing drug to elute from another drug release region at that time. Another embodiment further uses one or more biodegradable barriers as described above to provide a permanent or temporary physical obstacle within the implant to further fine-tune the width or duration of periods of low or no drug release from the implant. Additionally, the length of the drug holiday period can be controlled by controlling the biodegradation rate of the barrier. In some embodiments, biodegradation of the barrier can be initiated or enhanced by an external stimulus. In some embodiments, intraocular injection of a fluid stimulates or enhances the biodegradation of the obstacle. In some embodiments, the externally derived stimulus is one or more of the application of heat, ultrasound, and radio frequency or laser energy.

[0376] Certain embodiments are particularly advantageous because the regions of drug release, as not being open orifices, minimize tissue trauma or coring of the ocular tissue during the implantation process. Furthermore, because the regions are of known thickness and area (and therefore known drug release profile), they can in some cases be manufactured to ensure that the implant is fully positioned before drug elution occurs.

[0377] Placing the drug inside the outer shell can also be used as a mechanism to control drug release. Depending on the condition being treated, in some embodiments the lumen can be at a distal location, and in other embodiments at a more proximal location. In embodiments employing nested or concentric tube devices, the drug(s) can be placed in either the lumen formed between the nested or concentric polymer shells.

[0378] Further control of drug release can be obtained in certain embodiments having multiple lumens by the location of drug placement. For example, when drug release is desired soon after implantation, the drug is placed in a first release lumen in the implant where the therapeutic agent has a short time period from implantation to exposure to ocular fluid. This can be done, for example, by placing the first release lumen in close proximity to a drug release area with a thin shell thickness (or large area, or both). A second drug placed in a second release lumen, which has a longer time period before exposure to ocular fluid, elutes the drug into the eye after the release of the first drug begins. This can be done by placing the second release lumen in close proximity to a drug release area with a thicker shell or smaller area (or both). In some cases, this second drug mitigates side effects due to the release and activity of the first drug.

[0379] It should also be understood that the above-mentioned multiple lumens are also useful for obtaining a specific concentration profile of the released drug.For example, in some embodiments, a first release lumen can contain a drug with a first drug concentration, and a second release lumen can contain the same drug with a different concentration.A desired concentration profile can be tailored by utilizing drugs with different drug concentrations and placing them in the implant to control the start time of drug elution and therefore the concentration in ocular tissue.

[0380] Additionally, the location of drug placement can be utilized to provide a period of drug release followed by a period of no drug release. For example, a drug can be placed in a first release lumen such that the drug is released to the eye immediately after implantation. A second release lumen can remain drug-free or can include an inert bioerodible material that provides a period of no drug release. A third release lumen containing the drug can then be contacted with ocular fluid to initiate a second period of drug release.

[0381] It will be appreciated that the ability to vary any one or combination of the properties of the shell, the properties of any polymer coating, the optional polymer-drug mixture, the size and number of regions of drug release, the size and number of orifices, and the location of the drug within the implant provides great flexibility in controlling the rate of drug delivery by the implant.

[0382] Drug elution profiles can also be controlled by utilizing multiple drugs contained within the same internal lumen of the implant, separated by one or more plugs. By way of example, in an implant containing a single drug release region at the distal tip of the implant, ocular fluid entering the implant will primarily contact the most distal drug until the most distal drug is substantially eroded and eluted. During this period, ocular fluid passes through the first semi-permeable partition and begins to erode the second drug located proximal to the plug. As discussed below, the composition of these first two drugs, and the properties of the first plug and drug release region can each be controlled to obtain an overall desired elution profile, such as increasing concentration over time, time-dependent delivery, etc. of two different doses of drugs. Different drugs can also be deployed sequentially through similar implant embodiments.

[0383] If separation of the two drugs is desired, a partition can be used. The partition can, in some cases, be biodegradable at the same or slower rate than the drug delivered by the implant. The partition is designed for the internal dimensions of a given implant embodiment so that, when placed in place within the internal lumen of the implant, it blocks the more proximal portion of the lumen from the distal portion of the lumen. Thus, the partition forms individual compartments within the internal lumen. A first drug can be placed in the more proximal compartment, and a second drug, a second concentration of the first drug, or an adjuvant agent can be placed in the more distal compartment. Thus, as described above, the influx of ocular fluid and the release rate of the drug can be controlled, and the drugs can be released serially, sequentially, or alternately over time.

[0384] The dividers can also be used to provide separate compartments for therapeutic agents or compounds that may react with each other, but that it is desirable for the reaction to occur at or near the ocular tissue, rather than simply within the implant lumen. By way of illustration, if two compounds are each inactive in the presence of the other (e.g., a prodrug and a modifier), the two compounds can still be delivered with a single implant having at least one region of drug release associated only with the lumen containing one of the drugs. After the compounds elute from the implant into the ocular cavity, they should mix and become active near the target tissue. As can be seen from the above, when more than two drugs are delivered in this manner, it would be desirable to utilize a greater number of dividers suitable for isolating the drugs.

[0385] In certain embodiments, the proximal obstruction serves to seal the therapeutic agent within the distally located internal lumen of the implant. The purpose of such obstruction is to ensure that ocular fluid from any more distally located ocular fluid entry points is the primary source of ocular fluid in contact with the therapeutic agent. Similarly, a drug-impermeable seal is formed that prevents forward elution of the drug. Preventing forward elution not only prevents dilution of the drug with ocular fluid originating from the anterior portion of the eye, but also limits potential side effects of the drug delivered by the device. Limiting drug elution to sites originating from distal regions of the implant increases delivery of the drug to target sites in more posterior regions of the eye. In fully biodegradable embodiments, the proximal cap or obstruction can include a biocompatible biodegradable polymer that is characterized by a slower rate of biodegradation than any drug delivered by the implant. It should be appreciated that the proximal cap is useful in embodiments having a single central lumen that spans the length of the implant, allowing recharging of the implant after the first dose of drug has been sufficiently eluted. In those embodiments, a single central lumen is present for placing new drug into the distal portion of the device, but is preferably sealed off at or near the proximal end to avoid dilution or elution of the forwardly directed drug.

[0386] Similar to the multiple longitudinal compartments that can be formed in the implant, drugs can also be placed within one or more nested lumens. By sequentially placing a particular desired drug or concentration of drug within the nested lumens, controlled release or kinetic profiles can be obtained similar to those described above.

[0387] As mentioned above, wicks can also be used to control the release characteristics of various drugs within the implant. One or more wicks introduced into different internal lumens of the implant can help move ocular fluids quickly into the lumen where the ocular fluids can interact with the drug. Drugs that require more ocular fluid for their release can be placed in the lumen where the wick can provide more ocular fluid than the orifice alone. One or more wicks can be used in some embodiments.

[0388] In some embodiments, the drug can be sized to further tailor the release profile by increasing or restricting ocular fluid flow into the space between the drug and the internal lumen wall. For example, if a first solid or semi-solid drug is optimally eluted more rapidly than another solid or semi-solid drug, it may be desirable to form the first drug with dimensions that provide a substantial gap between the drug and the internal lumen wall, as ocular fluid entering the implant will contact the drug over a larger surface area. The dimensions of such drugs can be easily modified based on the elution and solubility characteristics of a given drug. Conversely, in embodiments that include a drug sized to leave minimal space between the therapeutic agent and the internal lumen wall, initial drug elution can be delayed. In yet another embodiment, the entire implant lumen is filled with drug to maximize the drug release period or limit the need to recharge the implant.

[0389] Certain embodiments may include a shunt in addition to the drug delivery portion of the implant. For example, after the implant is placed (in an anterior-posterior direction) in the desired intraocular cavity, the shunt portion of the implant, including at least one outflow channel, may be inserted into the physiological outflow space (e.g., secured to the trabecular meshwork and releasing fluid into Schlemm's canal). In some embodiments, the multiple openings thus help maintain the patency and operability of the drainage shunt portion of the implant. Furthermore, as described above, the multiple openings may help reduce any undesirable side effects, including excess fluid production or accumulation, that may result from the action of a therapeutic agent delivered by the implant.

[0390] As mentioned above, a long period of drug release is desirable. In some embodiments, the implant according to the embodiments described herein can deliver the drug at a controlled rate to the target tissue for several (i.e., at least 3) months. In some embodiments, the implant can deliver the drug at a controlled rate to the target tissue for about 6 months or more, including 3, 4, 5, 6, 7, 8, 9, 12, 15, 18, and 24 months, without the need for recharging. In yet other embodiments, the period of controlled drug release (without recharging the implant) is greater than 2 years (e.g., 3, 4, 5 years or more). It is understood that other time frames, including ranges bounded by, overlapping, or including two or more of the above values, are also used in some embodiments.

[0391] In relation to the controlled release of drugs to target tissues, it is desirable that a dose of drug(s) is delivered over a period of time in some embodiments. That is, in some embodiments, the total drug load, e.g., total steroid load, delivered to the target tissue over the life of the implant ranges from about 10 to about 1000 μg. In some embodiments, the total drug load ranges from 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 ranges from 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 ranges from about 200 to about 500 μg, 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, a...

Claims

1. 1. A drug delivery ocular implant comprising: an outer shell having an open proximal end and a distal end, the outer shell being shaped to define an interior space; at least one drug disposed within the interior space; a cap structure disposed within the interior space, the cap structure including a membrane incorporated therein, the membrane being permeable or semi-permeable to the at least one drug, and a seal; A drug delivery ocular implant comprising:

2. 10. The drug delivery ocular implant of claim 1, further comprising a fluid inflow path and a fluid outflow path disposed at or near the distal end of the shell, the fluid inflow path and the fluid outflow path configured to deliver ocular fluid to a physiological outflow path.

3. The drug delivery ocular implant of claim 2 , wherein the fluid outflow pathway is disposed within a retention protrusion extending from the distal end of the outer shell.

4. The drug delivery ocular implant of claim 1 , wherein the seal is configured to control the flow of ocular fluid to and drug from the drug delivery ocular implant.

5. The drug delivery ocular implant of claim 1 , wherein the seal is disposed distal to the membrane.

6. The drug delivery ocular implant of claim 1 , wherein the seal is disposed proximal to the membrane.

7. The drug delivery ocular implant of claim 1 , wherein the membrane is disposed between the first and second portions of the seal.

8. The drug delivery ocular implant of claim 1 , further comprising a retention protrusion extending from said distal end of said shell.

9. The drug delivery ocular implant of claim 1 , further comprising a retention protrusion extending from an outer surface of said shell.

10. The drug delivery ocular implant of claim 9 , wherein the retention protrusion extends around the periphery of the outer surface of the shell.

11. The drug delivery ocular implant of claim 1 , wherein the cap structure is disposed within a proximal portion of the interior space.

12. The drug delivery ocular implant of claim 1 , wherein the membrane comprises ethylene vinyl acetate.

13. 2. The drug delivery ocular implant of claim 1, wherein said at least one drug is bimatoprost, latanoprost, travoprost, or unoprostone.

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