Bioabsorbable ophthalmic drug delivery device

Abstract

This invention relates to a delivery device for bioabsorbable ocular drugs. Specifically, this invention relates to an ocular implant configured for implantation in the eye of a subject, comprising an elongated outer shell (54), an inner plug (210) containing hydrogel, and a drug reservoir comprising a drug (62), wherein the drug is configured to pass through at least a portion of the inner plug to control elution of the drug through the outer shell. The implant is made of a biodegradable material.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201780038262.9, filed on April 20, 2017, entitled "Biologically Absorbable Ophthalmic Drug Delivery Device".

[0002] Related Applications

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 325,378, filed April 20, 2016, the entire contents of which are incorporated herein by reference. BACKGROUND

[0004] The present disclosure relates to implantable intraocular drug delivery devices configured to provide targeted and / or controlled release of a drug to a desired intraocular target tissue, and to methods of using such devices to treat ocular diseases and conditions. In certain embodiments, the present invention is also particularly directed to the treatment of ocular diseases with drug delivery devices implanted intraocularly, wherein some or substantially the entire device is made of biodegradable material.

[0005] The eye of a mammal is a specialized sensory organ capable of light reception and capable of receiving visual images. Many pathologies can impair or completely eliminate the ability of an individual to perceive visual images, including ocular trauma, infection, degeneration, vascular irregularities, and inflammation problems. The central part of the retina is called the macula. The macula, responsible for central vision, fine visualization, and color differentiation, can be affected by diseases such as age-related macular degeneration (wet or dry), diabetic macular edema, idiopathic choroidal neovascularization, or high myopia macular degeneration.

[0006] Other pathologies such as intraocular pressure abnormalities also affect vision. About 2% of the population in the United States suffers from glaucoma, a group of eye diseases including a wide range of clinical manifestations and etiologies, but unified by increased intraocular pressure. Glaucoma causes pathological changes in the optic nerve, visible on the optic disc, and it causes a corresponding loss of visual field, which can lead to blindness if left untreated. Increased intraocular pressure is the only risk factor associated with treatable glaucoma, so reducing intraocular pressure is the main therapeutic goal in all glaucomas and can be achieved by drug therapy, surgical therapy, or a combination of them.

[0007] Many pathologies of the eye progress due to the difficulty of administering therapeutic agents to the eye in sufficient amounts and / or for the duration of time required to ameliorate the pathological symptoms. Typically, uptake and processing of the drug occurs before the drug reaches the target site in the eye. Due to this metabolism, systemic administration can require undesirably high concentrations of the drug to achieve therapeutic levels at the target site in the eye. This is not only impractical or expensive, but can also result in a higher incidence of side effects. Local administration can potentially be limited by the limited diffusion across the cornea, or dilution of the locally administered drug by the action of the tear fluid. Even those drugs that cross the cornea can be depleted from the eye by the flow of intraocular fluids, and transferred to the general circulation. Thus, means for ocular administration of therapeutic agents in a controlled and targeted manner can address the limitations of other delivery routes. SUMMARY

[0008] Various embodiments disclosed herein relate to a drug delivery ocular implant. The ocular implant includes a housing having a proximal end and a distal end, and the housing is shaped to define an internal cavity. A drug can be positioned within the internal chamber.

[0009] In various embodiments, a drug delivery ocular implant or device is provided, comprising: an elongated housing having a proximal end, a distal end, the housing shaped to define an internal cavity; and at least a first drug positioned in the internal cavity, wherein the housing comprises a biodegradable polymer. The housing is preferably tubular or cylindrical.

[0010] According to the disclosure herein, any of the implants described can comprise a shell of biodegradable polymeric material, including homopolymers, polymeric blends, and copolymers, such as random copolymers and block copolymers.

[0011] Biodegradable materials suitable for making the implants and components thereof include, but are not limited to, the following: poly(esters), poly(ester amides) (PEA), poly(ester carbonates) (PEC), poly(lactic acid) (PLA), poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), poly(DL-lactic acid) (PDLLA), polyglycolide (PGA), polycaprolactone (PCL), copolymers such as poly(lactic-co-glycolic acid) (PLGA), poly(hydroxyalkanoates), poly(3-hydroxybutyrate) (PHB), PHB copolymerized with 3-hydroxyvalerate (PHBV), poly(propylene fumarate) (PPF), poly(anhydrides) (PAA), poly(butylene succinate) (PBS), poly(ethylene succinate) (PES), poly(hydroxyalkanoate) (PHA), poly(cyanoacrylate) (PCA), polyacetals, polyorthoesters (POE), polycarbonates including poly(trimethylene carbonate) (PTMC), polyphosphazenes, polyphosphoesters, and blends, copolymers, and combinations of the foregoing; and natural polymers including, but not limited to, modified poly(saccharides) such as starch, cellulose, and chitosan.

[0012] In various embodiments, the device can have a length of 1-7 mm, including 2-5 mm. In some embodiments, the device has a pointed tip that narrows near the distal end of the implant. In other embodiments, the device can have a length of about 15-30 mm, 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. In some embodiments, the housing of the device can be flexible and / or curved.

[0013] In various embodiments, an ocular implant can be implanted into an eye of a subject. The implant can include an elongated housing comprising a bioerodible material and shaped to define an internal lumen, an internal plug within the internal lumen comprising a hydrogel, and a drug reservoir within the internal lumen comprising a drug. The drug can pass through at least a portion of the internal plug to control elution of the drug through the housing.

[0014] In various embodiments, the drug reservoir is positioned proximal to the internal plug. In various embodiments, the internal plug is positioned proximal to a distal-most end of the internal lumen. In various embodiments, the elongated housing comprises one or more apertures positioned near a distal end of the housing, wherein the apertures are configured to control elution of the drug through the hydrogel and out of the implant. In various embodiments, the implant includes a coating around at least a portion of the housing.

[0015] In various embodiments, the implant includes a proximal barrier. The proximal barrier can form an end cap proximal to the housing. In various embodiments, the proximal barrier is positioned within the housing proximal to the drug reservoir.

[0016] In various embodiments, the housing is configured to begin bio-eroding after all or substantially all of the drug is eluted from the lumen of the implant. In various embodiments, the housing is configured to begin bio-eroding while at least a portion of the drug to be eluted from the lumen of the implant remains in the lumen. In various embodiments, the implant further includes a fluid flow channel. In various embodiments, the implant is configured for implantation within an eye of a subject, and wherein the fluid flow channel drains intraocular fluid to a physiologic outflow space. In various embodiments, the hydrogel surrounds at least a portion of the drug in the lumen.

[0017] The ocular implant can include one or more retention features configured to secure or anchor the ocular implant in ocular tissue. Such retention projections optionally include one or more of a ridge, a rib, and / or a barb. In some embodiments, the retention projections are flexible.

[0018] The implants provided herein optionally anchor (e.g., any mechanism or element that allows the implant to be permanently or transiently affixed, secured, or otherwise attached) to or within intraocular tissue such as a ciliary muscle, ciliary muscle tendon, ciliary zonules, trabecular meshwork, iris, iris root, lens cortex, lens epithelium, to the lens capsule, sclera, scleral spur, choroid, or within the Schlemm’s canal, or to or within the Schlemm’s canal.

[0019] The ocular implant can be configured to be positioned within the supraciliary space, suprachoroidal space, Schlemm’s canal, anterior chamber, vitreous humor, or capsular bag. The ocular implant can be positioned within the supraciliary space, suprachoroidal space, Schlemm’s canal, anterior chamber, vitreous humor, or capsular bag.

[0020] In various embodiments, the housing has a substantially uniform thickness. In various embodiments, the housing is permeable or semi-permeable to the drug contained therein, allowing at least about 5%, 10%, 15%, 20%, or more of the total amount of the first drug to elute to occur through the portion of the shell having the first thickness. In some embodiments, all or substantially all of the total elution of the drug occurs through the housing. In other embodiments, the housing is impermeable or substantially impermeable to the drug contained within the device, such that less than 5% of the elution occurs through the housing, including less than 2%, less than 1%, or substantially no elution occurs.

[0021] In some embodiments, the outer shell comprises one or more regions that are different from the bulk of the outer shell in terms of drug release rate. These regions can allow for increased or decreased drug release compared to the bulk of the outer shell. For example, these regions can be characterized by the presence or absence of a coating that delays drug release, or be thinner or thicker to alter the rate of drug release. In those embodiments having regions of reduced shell thickness, such regions can be produced by any suitable means, including one or more of ablation, stretching, etching, milling, and molding. The regions can be any pattern on or around the implant, including a spiral pattern, patches, rings, and / or bands.

[0022] In some embodiments, the wall of the outer shell comprises at least one aperture, orifice, or hole. In some embodiments, the wall of the outer shell comprises a plurality of apertures, orifices, or holes, which can be positioned randomly or in a patterned array. The apertures, orifices, or holes in the wall of the outer shell can be patent or covered by one or more coatings or membranes. In some embodiments, where the device comprises a plurality of apertures, orifices, or holes through the outer shell, at least a portion of the plurality can be closed by a membrane permeable to the drug.

[0023] In various embodiments, elution of the drug (e.g., a protein therapeutic) is regulated by diffusion from the device through orifices (as described above) or other apertures, holes, channels, pores, or preferably micropores provided through the tube wall, or by a cap or plug or membrane at the end of the tube. The diameter of such elution-regulating features is configured to be large enough to allow passage of the protein drug molecules. In various embodiments, the diameter of these features is at least about 0.05, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3 microns (or greater). In various embodiments, the thickness of the tube wall, cap, plug, or membrane can range from about 10 microns to about 2 millimeters, such as from about 10 microns to about 50 microns, from about 50 to about 100 microns, from about 100 to about 150 microns, from about 150 microns to about 200 microns, and any range therebetween. In some preferred embodiments, the range can be from about 50 to about 200 microns.

[0024] In various embodiments, elution or diffusion of the drug through the elution features (apertures, holes, channels, pores, or preferably micropores, etc.) generally follows the Fick equation at any point in time, such that the rate of elution is proportional to the concentration gradient from the interior of the device to the exterior of the device. In various embodiments, the combined open area of the elution features and the diffusion coefficient of the protein drug define the rate, and the rate of elution is inversely proportional to the length and tortuosity of the elution features.

[0025] Depending on the implementation method, the elution feature can be formed by laser processing; or by extracting a highly soluble material of a suitable particle size blended into a bioabsorbable matrix; or by sintering bioabsorbable powder.

[0026] The elution characteristics are designed to provide an elution rate of the protein drug, combined with the clearance rate of the eye, to produce a therapeutic concentration of the protein drug in the eye. This elution rate can be from about 0.1 to about 20 micrograms per week, including about 0.1 to about 20 micrograms per week, about 0.5 to about 20 micrograms per week, about 1.0 to about 20 micrograms per week, about 5.0 to about 20 micrograms per week, about 10.0 to about 20 micrograms per week, about 10.0 to about 15 micrograms per week, about 7 to about 15 micrograms per week, about 2 to about 10 micrograms per week, and preferably 2 to 6 micrograms per week. In several embodiments, other amounts between those listed ranges have also been achieved.

[0027] In several embodiments, the surface erosion of the bioabsorbable material of the implant provides a self-cleaning function, thereby allowing adhered proteins, polysaccharides, cells or other biological materials to detach from the device, preventing the elution feature from becoming clogged.

[0028] In some embodiments disclosed herein, a coating is provided, preferably a biodegradable polymer coating. In some embodiments, two or more polymer coatings are located on the surface of the housing, and in some such embodiments, each coating has a unique biodegradation rate in intraocular fluid (including substantially non-biodegradable). In some embodiments, the coating alters the drug release rate (increasing or decreasing) and / or alters the biodegradation rate of the material covered by the coating (increasing or decreasing).

[0029] The device can be implemented to elute one or more drugs by means of the shell alone, by means of one or more caps (including drug release elements), by means of one or more open openings or perforations in the shell and / or cap membrane, or by means of any combination thereof.

[0030] In several embodiments, at least the distal portion of the lumen, about 5 mm to about 10 mm, contains the drug.

[0031] In several implementations, the first drug is eluted from the implant for at least one year, including two, three, four, five years or longer.

[0032] Some of the implementation methods described herein allow drugs to be eluted from the implant using zero-order or pseudo-zero-order kinetics.

[0033] In several embodiments, the implant as described herein may optionally include a cavity configured to deliver intraocular fluid from a first location in the eye to one or more other locations, thereby reducing intraocular pressure. In some such embodiments, the housing includes two cavities, which may be coaxial or side-by-side, one cavity being an inner cavity for containing at least one drug, while the other cavity serves as a conduit to facilitate the transport of aqueous humor from the anterior chamber to another location in the eye, such as the suprachoroidal space or Schlemm's canals, thereby reducing intraocular pressure.

[0034] In several embodiments, the device includes a cap structure for releasing or eluting one or more drugs. In some embodiments, the cap is a special type of cap, referred to herein as a drug-release element. The cap may be placed on any one or both of the proximal or distal ends of the device housing. Several embodiments include one or two caps or drug-release elements. Depending on the placement of the elements, the device may deliver drugs anteriorly, rearward, or both. Therefore, the device can treat conditions in the anterior and / or posterior segments of the eye.

[0035] In several embodiments, the implant includes a cap configured to reversibly or irreversibly interact with the proximal end of the outer shell. The cap includes at least one opening, and in some embodiments, multiple openings are provided. In particular embodiments, the total surface area of ​​one or more openings can be selected based on the desired rate of elution of a first drug from the implant.

[0036] In several embodiments, a cap is placed on the proximal end of the outer shell, allowing the membrane to be held between the cap and the proximal end of the outer shell. In some embodiments, the cap is a press-fit cap, while others employ a rolled-up cap, a screw cap, or other types of cap. In several embodiments, the membrane is permeable to at least a first drug and intraocular fluid (and / or the aqueous component of the intraocular fluid). In several embodiments, the membrane (once the cap is positioned) closes at least one opening so that elution of at least the first drug occurs solely through the membrane (e.g., compressing the membrane by the cap also seals other unintended drug release pathways of the implant). In several embodiments, a distally positioned seal is placed within the cavity to restrict fluid communication between the intracavitary space and the ocular space to fluid communication occurring through the membrane. In several embodiments, a selected combination of membrane and opening dimensions (e.g., surface area) is adjusted to a specific desired elution rate for the first active agent. In several embodiments, the membrane thickness is about 50 and about 100 micrometers.

[0037] Ocular implants may include a special type of cap referred to herein as a drug-delivery element, configured to release a drug from an inner chamber, also referred to herein as an internal cavity or lumen. The drug-delivery element may include a distal sealing member including at least one opening, a proximal sealing member including at least one opening, and a membrane compressed between the distal and proximal sealing members. A retainer may be configured to hold the drug-delivery element in place relative to the housing. The drug-delivery element may be configured such that the drug passes through at least one opening in the distal sealing member, through the compressed membrane, through at least one opening in the proximal sealing member, and exits from the proximal end of the housing.

[0038] The retainer may include one or more tabs that are foldable to engage the proximal sealing member. In some embodiments, the one or more tabs may be folded to engage a diaphragm. The housing may include one or more slots, and the retainer may extend into one or more slots and be positioned proximal to the proximal sealing member. The lateral length of the retainer may be greater than the inner diameter of the chamber adjacent to the retainer and less than or equal to the outer diameter of the housing adjacent to the retainer. In some embodiments, the chamber may include a shelf, and the distal sealing member may be positioned against the shelf.

[0039] The membrane of the cap or drug delivery element may comprise ethylene-vinyl acetate, which may have a vinyl acetate concentration of about 10% to about 30%, but other concentrations as discussed herein may be used. Other membranes may be used, including those that are biodegradable. The membrane may also have a biodegradable or non-biodegradable coating. The ocular implant may be configured such that the membrane in the compressed state has a thickness of about 75 micrometers to about 125 micrometers and / or such that the membrane is compressed by about 20 micrometers to about 40 micrometers in the uncompressed state, but other thicknesses and compression amounts may be used as discussed herein.

[0040] The drug delivery element can provide an elution rate between approximately 15 nanograms / day and approximately 35 nanograms / day, but other elution rates can be used. The ocular implant can be configured to hold a drug volume of approximately 40 nanoliters to approximately 150 nanoliters, but other volumes can be used.

[0041] In several embodiments, a valve is provided within the housing that reversibly opens to allow at least a first drug to enter the lumen. In some embodiments, a valve is provided at the distal end of the housing, wherein the valve reversibly opens to allow at least the first drug to flow from the lumen to a target site outside the implant.

[0042] Various embodiments of the implants disclosed herein may include one or more barriers placed within the lumen to restrict the eluent of the anterior (or, in some embodiments, the posterior) portion of a drug, and / or barriers comprising one-way valves positioned to allow fluid to pass through the implant in a proximal-to-distal direction. In some embodiments, one or more barriers are placed within the lumen that may facilitate the simultaneous (or sequential) eluenting of one or more drugs into the anterior and / or posterior chambers for targeting.

[0043] In several embodiments, the first drug is a β-adrenergic receptor antagonist. The β-adrenergic receptor antagonist may be a selective β-adrenergic receptor antagonist or a non-selective β-adrenergic receptor antagonist. In several embodiments, the selective β-adrenergic receptor antagonist is selected from betalol and levometalol, and combinations thereof. In several embodiments, the non-selective β-adrenergic receptor antagonist is selected from timolol, levobunolol, certeolol, and meterol, and combinations thereof. In several embodiments, at least one drug is used, and in some embodiments, at least one first drug is timolol.

[0044] In some implementations, the drug may be formulated as an oil.

[0045] In some embodiments, the drug may include prostaglandins, prostaglandin analogs, prostaglandin inhibitors, β-adrenergic receptor antagonists, or combinations thereof, but other drugs may be used as discussed herein. In some embodiments, the drug may include travoprost and / or its prodrug. In other embodiments, the drug includes alprostadil and / or its modified or prodrug forms.

[0046] Furthermore, in several embodiments, a second agent may optionally be provided. In several embodiments, the second (or third, etc.) agent produces a synergistic effect when combined with the first agent. In other embodiments, the second agent reduces one or more side effects associated with the first agent.

[0047] In some embodiments, one or more drugs are contained in micelles or vesicle structures or combined with a biodegradable polymer configured to release the drug at a known rate.

[0048] In several embodiments, the first drug is present as one or more microtablets, wherein the microtablets have a density of about 0.7 g / cc to about 1.6 g / cc, an 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 several embodiments, the first drug is present in an amount of at least 70% by weight of the total weight of the one or more microtablets. In several embodiments, the surface area to volume ratio of the microtablets is about 13 to 17. In several embodiments, the microtablets have a size that allows the microtablets to pass through a conduit with an inner diameter of about 23 to 25.

[0049] In a further embodiment, the microtablets may optionally be coated with a coating that modulates the release of the first drug from the microtablets. In some embodiments, the coating is a polymer coating.

[0050] This article also provides a method for treating ocular conditions or ailments in intraocular target tissues, comprising: creating an opening in the temporal portion of the eye to access the anterior chamber of the eye; advancing a delivery device associated with a drug delivery ocular implant through the opening and through the anterior chamber of the eye; inserting the drug delivery ocular implant into the ocular tissue; positioning the implant at the desired location in the eye; and retrieving the delivery device from the eye, wherein a sufficient amount of drug is eluted from the implant to treat the ocular condition or ailment. In some embodiments, a treatment effect lasting from at least one year to up to five years is achieved.

[0051] In some embodiments, the device is positioned such that at least one of one or more regions of the drug release or cap structure is located near the intraocular target. In many embodiments, the intraocular target is located 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 blood vessels. In many other embodiments, the intraocular target is located in the anterior chamber of the eye.

[0052] In several embodiments, inserting a drug-delivery ocular implant into ocular tissue includes placing at least a portion of the implant in an ocular portion selected from the group consisting of the uveal-scleral outflow pathway, the suprachoroidal space, the anterior chamber, the capsular pocket, the vitreous fluid, and Schlemm's canals. Attached Figure Description

[0053] These and other features, aspects, and advantages of this disclosure will now be described with reference to the accompanying drawings of embodiments, which are intended to be illustrative and not limiting. It will be readily understood by those skilled in the art that the features depicted in the illustrative embodiments can be combined in ways not explicitly depicted but contemplated and disclosed herein.

[0054] Figure 1 A schematic cross-sectional view of an eye is shown.

[0055] Figure 2A Another drug delivery implant incorporating a shunt is shown according to an embodiment disclosed herein.

[0056] Figure 2B A cross-sectional view is shown of an embodiment of a retention feature disposed on a drug delivery implant according to an embodiment disclosed herein.

[0057] Figures 3A-3D Various drug delivery implants according to embodiments disclosed herein are shown.

[0058] Figure 4A A cross-sectional view of an embodiment of a drug delivery implant according to the embodiments disclosed herein is shown.

[0059] Figure 4B A cross-sectional view of an embodiment of a drug delivery implant according to the embodiments disclosed herein is shown.

[0060] Figure 4C A cross-sectional view of an embodiment of a drug delivery implant according to the embodiments disclosed herein is shown.

[0061] Figures 5A-5B Various drug delivery devices according to embodiments disclosed herein are shown.

[0062] Figure 6A and Figure 6B Various features of an elongated delivery device according to several embodiments disclosed herein are described.

[0063] Figure 6C One embodiment of a delivery apparatus according to the embodiments disclosed herein is shown.

[0064] Figure 6D An implantation configuration of a drug delivery device according to an embodiment disclosed herein is shown.

[0065] Figure 7 A device for implanting a drug delivery apparatus according to an embodiment disclosed herein is shown.

[0066] Figure 8 A device for implanting a drug delivery apparatus according to an embodiment disclosed herein is shown.

[0067] Figure 9 A schematic cross-sectional view of an eye with a delivery device propelled through the anterior chamber, containing an implant, is shown. The size of the implant has been enlarged for illustrative purposes.

[0068] Figure 10Additional implantation procedures according to several embodiments disclosed herein are illustrated. For illustrative purposes, the size of the implant has been enlarged.

[0069] Figure 11 A schematic cross-sectional view of an eye with a delivery device advanced near the anterior chamber angle is shown. The size of the implant has been enlarged for illustrative purposes.

[0070] Figure 12 A schematic cross-sectional view of an eye with a delivery device is shown, in which an implant is inserted, extending from the anterior chamber through the suprachoroidal space and terminating near the macula.

[0071] Figure 13A This is a distal exploded perspective view of the drug-releasing element.

[0072] Figure 13B yes Figure 13A A proximal breakdown perspective view of the drug-releasing element.

[0073] Figure 14 This is a cross-sectional view of an implant with a drug delivery element.

[0074] Figure 15 This is a partial cross-sectional view of an implant with a drug delivery element.

[0075] Figure 16 This is a perspective view of an exemplary embodiment of a seal used with a drug-delivery ocular implant.

[0076] Figure 17 This is a perspective view of an exemplary embodiment of a proximal sealing member used with a drug-delivery ocular implant.

[0077] Figure 18 A perspective view showing an exemplary embodiment of an eye implant is shown.

[0078] Figure 19 It shows Figure 18 A side view of an exemplary embodiment of an eye implant.

[0079] Figure 20 It shows Figure 18 A cross-sectional view of an exemplary embodiment of an eye implant.

[0080] Figures 21A-21B Drug concentration and elution data according to various embodiments described herein are presented. Figure 21A The changes in drug concentration over time were depicted, and Figure 21B The variation of drug elution rate from the prophetic implant over time was depicted.

[0081] Figures 22A-22BDrug elution data according to several embodiments described herein are presented. Figure 22A The variation of drug elution rate from the implant over time was depicted. Figure 22B The variation of drug elution rate from the implant over time was depicted. Detailed Implementation

[0082] Figure 1 The anatomy of the eye is shown, including the sclera 11 connecting the cornea 12 at the limbus 21, the iris 13, and the anterior chamber 20 located between the iris 13 and the cornea 12. The eye also includes the lens 26, the ciliary body 16, and the Schlem's canals 22 disposed behind the iris 13. The eye also includes a uveal-scleral outflow pathway for removing a portion of fluid from the anterior chamber and includes a suprachoroidal or supraciliary space located between the choroid 28 and the sclera 11. The eye also includes a posterior region 30, which includes the macula 32.

[0083] Topical ocular administration of drugs may require direct injection or administration, but can also include the use of drug-eluting implants, a portion of which may be positioned near the target site within the eye or within the ocular cavity where the target site is located (e.g., the anterior chamber, posterior chamber, or both). The use of drug-eluting implants can also allow for targeted delivery of drugs to specific ocular tissues, such as the macula, retina, ciliary body, optic nerve, or the vascular supply to certain areas of the eye. Depending on the pathology, the use of drug-eluting implants may also provide the opportunity to administer a controlled dose of drug at the desired timeframe. For example, some pathologies may require drug release at a constant rate for several days, others may require release at a constant rate for up to several weeks, still others may require a periodic or variable release rate for a period of time, and even still others may require a period without release (e.g., a "drug vacation").

[0084] In some cases, once drug delivery is complete, the implant can provide additional functions, such as maintaining the patency of fluid flow pathways within the ocular cavity, serving as a reservoir for future administration of the same or different therapeutic agents, or acting as a scaffold to maintain the patency of fluid flow paths or channels from a first location to a second location. Conversely, it may be desirable for the implant to be partially or fully biodegradable so that it can be removed from the eye after all or almost all of the drug has been delivered.

[0085] For the bioabsorbable drug delivery of protein drugs (e.g., anti-VEGF proteins and / or monoclonal antibodies or antibody fragments) and other drugs, various methods exist, such as mixing protein molecules with bioabsorbable polymers like PLA, PLGA, polyvinyl alcohol (PVA), cross-linked polyacrylic acid (carbomer), and hydroxypropyl methylcellulose (HPMC), as well as other polyesters or polyether amides. Various configurations, including rods, gels, micelles, nanoparticles, and combinations of these materials, have previously been disclosed. The applicant has found that these methods are disadvantageous due to, for example, possible protein inactivation and aggregation during the formulation process. Aggregation can be detrimental, for example, by reducing the lifetime of the delivered protein drug by inhibiting the desired elution profile. Moreover, this method may not significantly prolong the protein's residence time in the eye relative to the clearance rate of the protein alone.

[0086] However, in several embodiments disclosed herein, bioabsorbable (e.g., biodegradable or bioerodible) devices overcome this limitation. In several embodiments, all (or substantially all or part) of the bioabsorbable material used to construct the device may comprise PLA, PLGA, polycaprolactone, other polyesters, polyetheramides, or other polyamides. Combinations may also be used in several embodiments. The bioabsorbable material may be a hydrogel comprising polyethylene glycol, polyethylene oxide, polyethylene oxide-co-propylene oxide, co-polyethylene oxide block or random copolymers, polyacrylamide and polyvinyl alcohol, poly(vinylpyrrolidone). The hydrogel may alternatively or additionally comprise one or more polymers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, polyvinyl acetate, polyvinyl alcohol, gelatin, and polyvinylpyrrolidone. Such polymers may, for example, form an interpenetrating network. In some embodiments, the polymer may help increase the mechanical strength of the hydrogel. In some embodiments, specific polymers may be selected to modulate the permeability of the hydrogel. In some embodiments, the hydrogel is advantageously non-toxic, water-soluble, biodegradable, hydrophilic, highly absorbent, and / or flexible. In some embodiments, the hydrogel may be optically transparent to reduce or minimize interference with the patient's vision.

[0087] Hydrogels can be manufactured by various methods and implemented in various forms. In some embodiments, hydrogels can be formed from synthetic (e.g., poly(ethylene glycol), poly(hydroxyethyl methacrylate)) and / or naturally occurring polymers (e.g., collagen, hyaluronic acid, heparin). Depending on the reactivity of the constituent materials, gelation can be induced using methods such as pH, temperature, coulombic interactions, covalent bonding, non-covalent interactions, and / or polymerization. For example, covalent bonding and / or polymerization can be accomplished through chemical reactions such as free radical polymerization of vinyl groups; amide bond formation between amine and ester groups (e.g., using an active ester of n-hydroxysuccinimide); and / or Diels-Alder reactions between furan and maleimide moieties. The reactive components can be delivered into a mold or tube. For example, the hydrogel can be shaped into a mold (e.g., a tube). In some embodiments, the hydrogel can be removed from the mold and / or extruded from the tube. In some embodiments, the hydrogel can be transferred into the shell of an implant. In some embodiments, the reactive components can be delivered directly into the shell. For example, the hydrogel can be formed within the shell.

[0088] In some embodiments, the hydrogel can form a coating material covering all or part of the implant and / or any orifices (all or part). In some embodiments, as discussed in more detail below, the implant may include a hydrogel plug. For example, a drug may pass through the hydrogel. In some embodiments, the hydrogel may be formed in vitro or in situ. In some embodiments, the drug is embedded in the hydrogel. For example, the hydrogel-drug mixture may include separate solutions of polymers and protein stabilizers. The hydrogel composition can be selected based on many factors, such as crosslinking density (e.g., the ratio of the mass of the crosslinking agent to the mass of the selected monomer), porosity, thickness, tortuosity, the volume fraction of the polymer in the hydrogel, and / or the diffusion permeability of the protein drug.

[0089] Examples of protein stabilizers may include gelatin, sugars (e.g., trehalose, sucrose, etc.), amino acids, nonionic surfactants (e.g., poloxamer), and / or buffer salts. Protein stabilizers can advantageously prevent and / or limit the aggregation and degradation of protein drugs. As mentioned above, this can improve the lifespan of protein drugs. Various formulations can be produced by mixing individual solutions of polymers and protein stabilizers. For example, anti-VEGF drug components and / or proteins can be added to said formulations and protein drug molecules can be embedded in a polymer hydrogel matrix.

[0090] Example formulations containing embedded protein drug molecules may be lyophilized. In some embodiments, the lyophilized material can be directly compressed into tablets of a size suitable for injection into the vitreous cavity of the human eye as soluble implants. For example, tablets may typically be shaped into one or more cylindrical and / or rectangular discs and / or tiles. The compressive force applied to the lyophilized material (including the formulations described herein) can be controlled or adjusted. Advantageously, the density of the tablet can be controlled by adjusting the applied compressive force. For example, since the dissolution rate of a tablet can be related to its density, the dissolution rate of the tablet can be controlled by adjusting the compressive force. For example, the compressive force can be translated into a controlled release rate of the protein drug molecules.

[0091] In several embodiments, the implant can be injected using a specially designed inserter. In some embodiments, one or more tablets may be placed in a reservoir containing an elution control membrane or gel material to control dissolution and diffusion rates and / or contain material delivered to the eye. Advantageously, this minimizes the impact on visual field. Once injected, the implant can slowly dissolve in, for example, the uveal-scleral outflow pathway, the suprachoroidal space, the anterior chamber, the capsular pocket, vitreous fluid, and / or Schlem's canals. The implant gradually releases the protein drug at a concentration capable of providing therapeutic benefit to the patient. In some embodiments, the concentration of the protein drug may be optionally from about 100 to about 150 mg / mL, about 150 to about 200 mg / mL, about 200 to about 250 mg / mL, about 250 to about 300 mg / mL, about 300 to about 350 mg / mL, about 350 to about 400 mg / mL, about 400 to about 450 mg / mL, about 450 to about 500 mg / mL, and / or concentrations between the listed ranges. In some preferred embodiments, the concentration range is from about 200 to about 300 mg / mL. The release rate can last for a long time, for example, 1 to 2 hours, 2 to 6 hours, 6 to 12 hours, 12 to 24 hours, 1 to 2 days, 1 to 7 days, 1 to 2 months, 1 to 6 months, 6 to 12 months, and / or 12 to 24 months or longer. The implant can be used to treat various posterior eye diseases, such as age-related macular degeneration, diabetic macular edema, and / or diabetic retinopathy, as well as other conditions.

[0092] In several embodiments, a mixture of bioabsorbable and non-bioabsorbable materials is used in the delivery device. In several embodiments, possible non-bioabsorbable components include, but are not limited to, sintered materials made of steel, titanium, or non-bioabsorbable polymers. In several embodiments, as discussed in more detail below regarding the structure, the non-bioabsorbable material may form tubular portions, end caps, or membranes of the device. In such embodiments, the bioabsorbable material may optionally form the remainder of the device.

[0093] As discussed in more detail below, various embodiments of the present invention provide near-zero-order elution of protein drugs with extended duration, while utilizing a bioabsorbable shell that allows patients to receive multiple doses consecutively without accumulating large amounts of debris in the eye.

[0094] Implants according to embodiments disclosed herein preferably do not require osmosis or ion gradients to release drugs. Implantation of such an implant minimizes trauma to healthy ocular tissues, thereby reducing ocular morbidity, and / or can be used to deliver one or more drugs in a targeted and controlled release manner to treat multiple ocular pathologies or a single pathology and its symptoms. However, in some embodiments, osmosis or ion gradients are used to initiate, control (fully or partially), or modulate the release of drugs (or multiple drugs) from the implant. In some embodiments, osmotic pressure is balanced between the internal portion of the implant and the intraocular fluid without creating a significant gradient (whether osmosis or ionization). In this embodiment, a variable solute is added to the drug within the device to balance the pressure.

[0095] As used herein, “drug” generally refers to one or more drugs that can be administered alone, in combination with or in combination with one or more pharmaceutically acceptable excipients (e.g., binders, disintegrants, fillers, diluents, lubricants, drug release control polymers, or other agents), adjuvants, or compounds that can be contained within an implant as described herein. The term “drug” is a broad term and may be used interchangeably with “therapeutic agent” and “medicine” or “pharmacological agent,” and includes not only so-called small molecule drugs but also large molecule drugs and biological products, including but not limited to proteins, nucleic acids, antibodies, etc., whether such drugs are natural, synthetic, or recombinant. A drug can refer to a single drug or a combination with the aforementioned excipients. “Drug” can also refer to an active pharmaceutical ingredient or its prodrug, salt, or derivative.

[0096] As used herein, "patient" should be given its general meaning and generally refers to mammals. The term "mammal" includes, but is not limited to, humans, dogs, cats, rabbits, rodents, pigs, sheep, and primates. Furthermore, throughout the specification, ranges of values ​​are given along with a list of values ​​for specific parameters. In these cases, it should be noted that such disclosure includes not only the listed values ​​but also the range of values ​​containing both integer and fractional values ​​between any two listed values.

[0097] As used herein, "biodegradable" generally refers to the property of a material that, once implanted in a human or animal body, is destroyed by any natural processes that occur therein and is typically eliminated from the implantation site. Biodegradability includes, but is not limited to, biodegradability, bioresorbability, and bioabsorbability.

[0098] In several embodiments, a biocompatible drug delivery ocular implant is provided, comprising a shell shaped to define at least one inner cavity containing a drug for release into the ocular space. In some embodiments, the shell is made of a polymer, and in others, the shell has a substantially uniform thickness. The shell is preferably elongated and tubular or cylindrical. In several embodiments, caps are placed at one or both ends of the shell for fully or partially regulating drug delivery. The shell may include one or more holes or openings and / or areas of increased or decreased thickness to alter or adjust the rate of drug delivery from the implant.

[0099] In some embodiments, one or more coating materials are used to cover the implant (all or part) and any orifices (all or part), thereby allowing further control over the rate of drug release from the implant. For example, in some embodiments, the hydrogel described above can form one or more coating materials that cover the implant (all or part) and / or any orifices (all or part) to further control the rate of drug release from the implant. In some examples, the hydrogel forms a coating material along the inner wall of the implant. In some embodiments, the hydrogel forms a membrane through which the drug must be eluted. In some embodiments, multiple coating materials can be used to further control the rate of drug release from the implant. Each coating material can allow the drug to diffuse through each layer at a different rate. Furthermore, in some embodiments, a combination of one or more orifices, one or more layers covering one or more orifices, and regions of reduced thickness is used to adjust the rate of drug release from the implant.

[0100] In some embodiments, the walls of the housing include at least one opening, aperture, or hole. In some embodiments, the walls of the housing include multiple openings, apertures, or holes, which may be randomly positioned or arranged in a patterned array. The openings, apertures, or holes on the housing walls may be open or covered by one or more coatings or membranes. In some embodiments, where the device includes multiple openings, apertures, or holes through the housing, at least a portion of the multiple openings may be sealed with a drug-permeable membrane.

[0101] In several embodiments, the elution of a drug (e.g., a protein therapeutic agent) is modulated from the device via diffusion through an orifice (as described above) or other opening, hole, channel, pore, or preferably through a micropore provided by the tube wall, or through a cap, plug, or membrane at the tube end. The diameter of such elution modulating features is configured to be large enough to allow protein drug molecules to pass through. In several embodiments, the diameter of these features is at least about 0.05, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3 micrometers (or greater).

[0102] In some embodiments, the orifice and / or elution orifice may be tapered. Therefore, the orifice diameter may not be constant. The tapered orifice can be used to adjust and / or regulate the elution of a drug (e.g., a protein therapeutic agent) by the taper of the orifice. In some embodiments, the taper of the orifice forms a conical shape. In some examples, the orifice may be tapered from the inner wall of the housing outward toward the outer wall of the housing. For example, the tapered orifice may have an inner diameter along the inner wall of the housing and an outer diameter along the outer wall of the housing. The inner diameter of the orifice may have a diameter of about 0.025, about 0.05, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3 micrometers (or greater). The outer diameter of the orifice may have a diameter of about 0.025, about 0.05, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3 micrometers (or greater).

[0103] The inner diameter can be smaller than the outer diameter of the orifice. For example, the taper of the orifice can extend radially outward from the inner diameter to the outer diameter. In some embodiments, the following equation can be used to determine the taper angle of the tapered orifice:

[0104]

[0105] In some implementations, the value of tanθ can range from approximately 0 to 1.73. In some implementations, the cone angle relative to the axis extending from the proximal end to the distal end of the implant can include angles of approximately 0 to 5, approximately 5 to 10, approximately 10 to 15, approximately 15 to 20, approximately 20 to 25, approximately 25 to 30, approximately 30 to 35, approximately 35 to 40, approximately 40 to 45, approximately 45 to 50, approximately 50 to 55, approximately 55 to 60, and / or approximately 60 to 65 degrees. Once the implant is placed in the eye, this configuration allows control over the elution rate of the drug. For example, by adjusting the inner and / or outer diameter and / or cone angle of the orifice, the amount of drug eluted from the implant can be more effectively controlled. In some examples, if the cone angle is larger, the drug will elute at a faster rate than when the cone angle is smaller. The size of the inner and outer diameter of the orifice can be selected based on the drug flux or elution rate when the drug passes through the cone orifice. In several embodiments, the elution or diffusion of the drug through the conical orifice typically follows a modified Fick equation at any given time point, such that the flux through the conical orifice is a multiple of the flux through an orifice with a constant diameter:

[0106]

[0107] After implantation at the desired site within the eye, the drug is released from the implant in a targeted and controlled manner, preferably for a prolonged 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 pathologies requiring administration to the posterior chamber, anterior chamber, or specific intraocular tissues (e.g., the macula, ciliary body, or other ocular target tissues). In several embodiments, the implant is configured to be placed in the lacrimal punctum of a subject's eye to deliver one or more therapeutic agents. In several embodiments, the implant is placed in the lacrimal punctum to deliver a therapeutic agent to the tear film to target the cornea or anterior chamber and / or other ocular and / or orbital regions.

[0108] Generally

[0109] In some embodiments, the implant, serving solely as a drug delivery device, is configured to deliver one or more drugs in a controlled manner to the anterior region of the eye, while in other embodiments, the implant is configured to deliver one or more drugs in a controlled manner to the posterior region of the eye. In still other embodiments, the implant is configured to deliver drugs in a controlled manner to both the anterior and posterior regions of the eye simultaneously. In yet other embodiments, the implant is configured such that the drug is released in a targeted manner to specific intraocular tissues, such as the macula or ciliary body. In some embodiments, the implant delivers drugs to the ciliary processes and / or the posterior chamber. In some other embodiments, the implant delivers drugs to one or more of the ciliary muscles and / or tendons (or fibrous bands). In some embodiments, the implant delivers drugs to one or more of the Schlem's canals, trabecular meshwork, suprascleral vein, lens cortex, lens epithelium, lens capsule, sclera, scleral processes, vitreous fluid, choroid, suprascleral space, retinal arteries and veins, optic disc, central retinal vein, optic nerve, macula, fovea, and / or retina. In other embodiments, drug delivery from the implant is typically directed into the ocular cavity. In several embodiments, the implant is configured to be placed in the lacrimal punctum to deliver one or more therapeutic agents (which may target the anterior chamber and / or other ocular regions); or placed in the lacrimal punctum to deliver to the tear film to target the cornea or anterior chamber and / or other ocular and / or orbital regions. It will be understood that each of the embodiments described herein may target one or more of these regions and may also be optionally combined with shunt features (described below).

[0110] In several embodiments, the implant includes a shell. In some embodiments, the shell is tubular and / or elongated. In several embodiments, the shell is formed to have at least a first internal cavity. In some embodiments, the cavity extends the entire length of the shell. In some embodiments, the cavity is subdivided. In those embodiments, additionally serving as a shunt, the shell may have one or more additional cavities within a portion of the device, wherein at least one such cavity serves as a shunt.

[0111] In a preferred embodiment, the outer shell is biodegradable. In a further embodiment, one or more or all of the device's additional components, including but not limited to caps, membranes, clips, and sealing members, are also biodegradable.

[0112] Biodegradable materials suitable for manufacturing implants and their components include, but are not limited to, the following: poly(ester), poly(esteramide) (PEA), poly(carbonate) (PEC), polylactic acid (PLA), poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), poly(DL-lactic acid) (PDLLA), polyglycolic acid (PGA), poly(glycolic acid-co-lactic acid) (PGALA), poly(glycolic acid-co-lactic acid); polycaprolactone (PCL), copolymers such as poly(co-glycolic acid) (PLGA), poly(hydroxyalkanoates), and poly(3-hydroxybutyrate) (PHB). PHB (PHBV) copolymerized with 3-hydroxyvalerate, poly(propylene fumarate) (PPF), poly(acid anhydride) (PAA), poly(butylene succinate) (PBS), poly(vinyl succinate) (PES), poly(hydroxyalkanoate) (PHA), poly(cyanoacrylate) (PCA), polyacetal, polyorthoester (POE), polycarbonate including poly(trimethylene carbonate) (PTMC), polyphosphazene, polyphosphate, and blends, copolymers, and combinations thereof; and natural polymers, including but not limited to modified poly(sugars), such as starch, cellulose, and chitosan.

[0113] The degree, rate, or time of biodegradability can be altered or adjusted for a specific application by any method or combination of methods. For example, reducing the biodegradability time can be achieved by: increasing the surface area to volume ratio of the shell; reducing the wall thickness; modifying the surface geometry through pitting, grooving, or roughening; including pores or micropores in the shell; making the shell more porous; and selecting a material that biodegrades more rapidly. For example, increasing the biodegradability time can be achieved by: decreasing the surface area to volume ratio of the shell; increasing the wall thickness; manufacturing the shell with a smooth surface geometry; preparing the shell to be minimally porous or non-porous; adding an inner and / or outer coating of a relatively slowly dissolving material; and selecting a material that biodegrades more slowly. The degree, rate, or time of biodegradability can also be adjusted based on the placement of the implant. For example, an implant to be placed in the lacrimal punctum of the eye may require a certain rate of implant biodegradation. This rate may or may not differ from the desired biodegradation rate of an implant configured for placement, for example, within the eye (e.g., in the suprachoroidal space). Therefore, although in many embodiments, biodegradation of the punctal implant is required after delivery of all or substantially all of the therapeutic payload, this rate can be specifically tailored to match the implant / patient, etc. According to embodiments, the bio-erosion of the implant is adjusted to begin after delivery of all or substantially all of the drug payload. In some embodiments, the bio-erosion of the implant is adjusted to begin at least partially overlapping with drug elution.

[0114] In several embodiments, the drug (or multiple drugs) is located within the lumen (or cavity) of the implant shell. In several embodiments, the drug is preferably located in the more distal portion of the cavity. In some embodiments, the distal 15 mm of the implant cavity (or multiple cavities) contains the drug (or multiple drugs) to be released. In some embodiments, the distal 10 mm (including 1, 2, 3, 4, 5, 6, 7, 8, and 9 mm) of the lumen contains the drug to be released. In several embodiments, the drug is preferably located in the more proximal portion of the cavity. In some embodiments, the drug is generally uniformly positioned throughout the cavity.

[0115] In some embodiments, the drug diffuses through the shell and enters the intraocular environment. In many embodiments, the shell material is permeable or semi-permeable to the drug (or multiple drugs) located within the lumen, so that at least a portion of the total drug elution occurs through the shell itself, and in addition, through any area such as increased permeability, decreased thickness, orifices. 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 some embodiments, approximately 1% to 15% (including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14%) of the total elution of the drug (or multiple drugs) occurs through the shell. The term "permeable" and related terms (e.g., "impermeable" or "semi-permeable") refer to materials that are permeable (or impermeable) to some extent to one or more drugs or therapeutic agents and / or intraocular fluids. The term "impermeable" does not necessarily mean that the drug has not eluted or spread through the material; rather, it means that such elution or other spread is negligible or very slight, for example, less than approximately 3% of the total elution, including less than approximately 2% or less than approximately 1%.

[0116] In some embodiments, the implant includes a polymer coating on the outer surface of the shell. In other embodiments, the implant includes a polymer coating on the inner surface of the shell. In still other embodiments, the polymer coating is on both the inner and outer surfaces. In yet another embodiment, the polymer coating is biodegradable. Instead of or in addition to the polymer coating, some embodiments include a non-polymer coating (e.g., heparin). Furthermore, in some embodiments, a combination of one or more orifices, a layer covering one or more orifices, and a region of reduced thickness is used to adjust the rate of drug release from the implant.

[0117] In some embodiments, the drug-containing lumen is separated from the proximal portion of the implant by a proximal barrier within the lumen, which prevents the drug from eluting into the anterior part of the eye. In some embodiments, the drug-containing lumen is separated from the proximal portion of the implant by a one-way valve within the lumen, which prevents the drug from eluting into the anterior part of the eye but allows intraocular fluid to reach the drug-containing lumen from the anterior part of the eye.

[0118] In some embodiments, the implant also includes a proximal portion configured to refill / refill the implant with the same or additional therapeutic agent, multiple drugs or adjuvant compounds or multiple compounds.

[0119] In some embodiments including a shunt, after implantation at the implantation site, the shunt portion drains fluid from the ocular cavity into a physiological outflow space to reduce intraocular pressure. In some embodiments, the implant is sized such that when the proximal or distal end of the implant is near the implantation site in the vicinity of the tissue targeted for drug delivery, the outflow port of the implant drains intraocular fluid into a distal area and / or a physiological outflow pathway. For example, the punctal implant disclosed herein (and U.S. Provisional Patent Application No. 62 / 054833, filed September 24, 2014, the entire contents of which are incorporated herein by reference) may also include one or more drainage cavities to drain tears into the nasolacrimal duct. Other implants disclosed herein may be configured to drain intraocular fluid from the anterior chamber to, for example, the suprachoroidal space. Drainage is not included in some embodiments of the punctal implant, and drainage is not included in some embodiments of implants intended for placement within the eye.

[0120] For example, in some embodiments, the implant is sized such that, after implantation, the distal end of the implant is sufficiently close to the macula to allow medication delivered by the implant to reach the macula. In some embodiments that incorporate shunt features, the implant is sized such that, when the distal end of the implant is positioned sufficiently close to the macula, the proximal end of the implant extends into the anterior chamber. In those embodiments, the outflow port in the implant (described in more detail below) is positioned such that aqueous humor is drained into the uveal-scleral outflow pathway or other physiological outflow pathways.

[0121] In other embodiments, the combined drug delivery-shunt implant can be positioned at any physiological location that requires simultaneous drug delivery and fluid transport from a first physiological site to a second site (which may be patient-specific or external). In some embodiments, the shunt feature works in conjunction with the drug delivery function to enhance the therapeutic effect of the delivered medication. In other embodiments, the therapeutic effect of the delivered medication may be associated with undesirable side effects, such as fluid accumulation or swelling. In some embodiments, the shunt feature serves to mitigate the side effects of the delivered medication. It should be understood that the size and features of the implants disclosed herein can be adapted to achieve targeted and / or controlled delivery to various regions of the eye while still allowing connectivity with physiological outflow pathways.

[0122] For example, in some embodiments, the implant is sized such that, after implantation, the distal end of the implant is located in the suprachoroidal space and the proximal end is located in the anterior chamber of the eye. In several embodiments, medication eluted from the implant is eluted from the proximal end of the implant into the anterior chamber. In some embodiments incorporating shunt features, one or more outflow ports in the implant are positioned such that aqueous humor is drained into the uveal-scleral pathway. In several embodiments, aqueous humor is drained from the anterior chamber into the suprachoroidal space.

[0123] The delivery device, described in more detail below, can be used to facilitate the delivery and / or implantation of drug-eluting implants to desired ocular locations. By applying continuous implantation forces, tapping the implant into place using the distal portion of the delivery device, driving a stored energy source within the delivery device, or a combination of these methods, the delivery device can be used to place the implant in a desired location, such as at any length reaching and including the vicinity of the macula, at a location extending from the anterior chamber to the choroidal space, or any other intraocular region. The design of the delivery device can take into account, for example, the implantation angle and the position of the implant relative to the slit. For example, in some embodiments, the delivery device may have a fixed geometry, beveled shape, or actuation. In some embodiments, the delivery device may have an adjunct or auxiliary function, such as injecting dyes and / or viscoelastic fluids, dissecting, or serving as a guidewire. As used herein, the term "slit" should be given in its ordinary sense and may also refer to an incision, opening, slit, notch, perforation, etc.

[0124] In some embodiments, the drug delivery implant may contain one or more drugs, which may or may not be combined with a biodegradable polymer or a biodegradable polymer and at least one additional pharmaceutical agent.

[0125] Drug delivery implant

[0126] This disclosure relates to ophthalmic drug delivery implants that, after implantation at the implantation site, deliver one or more drugs in a controlled manner to a desired target area within the eye, wherein the controlled release is prolonged for a period of time. Various embodiments of the implants are shown in the accompanying drawings and will be referenced herein; however, it should be understood that the invention is not limited to the illustrated embodiments, and as those skilled in the art will understand, features of the illustrated embodiments may be interchanged and / or they may be replaced by or further include features disclosed herein.

[0127] The implant shell can be manufactured by extrusion, stretching, injection molding, micromachining, laser processing, or any combination thereof. Other suitable manufacturing and assembly methods known in the art can also be used. In several embodiments, the shell is an elongated cylindrical or tubular shape and includes at least one inner cavity. In some embodiments, the inner cavity is defined by the shell and a septum. In some embodiments, the septum is impermeable, while in others it is permeable or semi-permeable. In some embodiments, the septum allows for refilling of the implant with a new dose of medication. In several embodiments, the shell thickness is substantially uniform. In other embodiments, the shell thickness varies in certain areas. Depending on the desired implantation site within the eye, thicker areas of the shell are positioned where it is necessary to maintain the structural integrity of the implant. In some embodiments, the implant is made of a flexible material.

[0128] In several embodiments, the housing also has one or more specific or enhanced drug-release regions compared to the rest of the housing. In some embodiments, the drug-release region has a reduced thickness compared to the adjacent and surrounding thickness of the housing. In some embodiments, the reduced-thickness region is formed by one or more of the following techniques: ablation, stretching, etching, grinding, molding, and removal of material from the housing. In other embodiments, the drug-release region has a different thickness compared to the surrounding housing (e.g., thinner in some embodiments and thicker in others), but is manufactured to have increased permeability to one or more of the drug and intraocular fluid. In still other embodiments, the thickness of the housing is uniform or substantially uniform, but is composed of materials with different permeability to intraocular fluid and intracavitary drugs. Thus, these embodiments define an area for drug release from the implant. The drug-release region can have any shape required to achieve adequate delivery of the drug to the specific target tissue of the eye.

[0129] In some embodiments, the implant is self-trephinating. In some embodiments, the distal end of the implant is sharp enough to pierce ocular tissue, such as the cornea, limbus, or vicinity of the scleral spur of the eye. In other embodiments, the distal end is rounded, blunt, or without a sharp tip, but is suitable for blunt dissection of two tissue planes or penetration of some internal ocular tissue, preferably non-invasively. In any case, the distal portion may be blunt enough to substantially avoid penetrating the scleral tissue of the eye.

[0130] In some embodiments, the implant includes fixation or retention features, such as flexible, outwardly extending extensions, like ridges, barbs, barbs, protrusions, threads, or projections, extending from the outer surface of the implant to prevent movement of the implant from its implantation location. In some embodiments, inwardly extending features, such as grooves, help retain the implant. Such features may extend the entire periphery of the implant or only certain portions of the periphery. The extension may be a separate piece attached to the implant, may be integrally formed with the implant, or may be added in a separate manufacturing step. The extension may be located at the proximal or distal end of the implant, or in the near or far zone, or both, to prevent the implant from being extruded or moved from its intended location in the eye. In several embodiments, the extensions are spaced longitudinally along the implant. The spacing between the extensions may be regular or irregular. The flexibility of the retention features can facilitate access through corneal incisions and may also facilitate access through ciliary muscle attachment tissue or other tissues. In some embodiments, surface irregularities serve to prevent host tissue growth into or on the implant (e.g., fibrotic growth), which, depending on the embodiment, may reduce the efficiency of drug elution.

[0131] In some embodiments, the outer diameter of the implant allows it to fit a 23-gauge needle during implantation. The implant may also have a diameter designed for insertion of larger needles. For example, the implant may also be delivered with an 18, 19, or 20-gauge needle. In other embodiments, a smaller applicator, such as a 23-gauge or smaller applicator, is used. In some embodiments, the implant has a substantially constant cross-sectional shape over most of its length. Alternatively, the implant may have portions along its length with decreasing or increasing cross-sectional dimensions (e.g., diameter). In some embodiments, the distal end of the implant has a tapered portion, or a portion with a continuously decreasing radial dimension relative to the cavity axis along its length. In some embodiments, the tapered portion preferably terminates with a smaller radial dimension at the distal end. During implantation, the tapered portion can be manipulated to form, enlarge, and / or increase the size of the puncture or wound created in the tissue. The diameter of the tapered portion can be from about 30 to about 23, preferably about 25. As discussed herein, in many embodiments, the device may be tubular, allowing it to be injected into the vitreous humor via a needle (but other shapes are used in many embodiments). The diameter of such tubular implants can be from about 0.1 to about 0.8 mm, from about 0.2 to about 0.8 mm, from about 0.3 to about 0.8 mm, from about 0.4 to about 0.8 mm, and preferably from about 0.3 to about 0.6 mm. In several embodiments, the length of the device can be from about 1 to about 15 mm, including from about 2 to about 15 mm, from about 4 to about 15 mm, from about 5 to about 15 mm, from about 5 to about 14 mm, from about 5 to about 13 mm, from about 5 to about 12 mm, from about 5 to about 11 mm, from about 2 to about 11 mm, from about 3 to about 11 mm, and preferably 5 to 10 mm. Ranges of diameter and length between those listed are also considered.

[0132] In some embodiments, the drug is formulated or compounded with other compounds. In some embodiments, the drug is in the form of a medicated pill. Some embodiments of therapeutic agents or drugs include drugs compounded with a polymer formulation. In some embodiments, the polymer formulation includes poly(lactic acid-co-glycolic acid) or PLGA copolymers or other biodegradable (e.g., bio-erosive, bioresorbable) polymers.

[0133] Although the medication is typically placed within the cavity of the implant described herein, much of the accompanying drawings have been omitted to clearly illustrate other features of the implant. However, it should be understood that all embodiments described herein may optionally include one or more medications.

[0134] In several embodiments, the implant also includes a coating that may be located at various locations within or on the implant. In some embodiments, the coating is a polymer coating. The coating may optionally be biodegradable. Some other embodiments may comprise an implant made entirely of a biodegradable material, such that the entire implant degrades over time. In some embodiments, the coating is applied to the entire implant (e.g., encapsulates the implant), while in other embodiments, it covers only a portion of the implant. In some embodiments, the coating is located on the outer surface of the implant. In some embodiments, the coating is placed on the cavity wall within the implant, as a replacement or supplement to the exterior of the implant or shell. Similarly, in some embodiments where the coating is located within the implant, the coating covers the entire inner surface of the cavity, while in other embodiments, it covers only a portion of the inner surface.

[0135] In addition to serving as a drug delivery device, various embodiments of the implant may also include a shunt. The term "shunt" as used herein is a broad term and has a common and general meaning to those skilled in the art (and it is not limited to a specific or custom meaning), and non-limitingly refers to a portion of the implant that defines one or more fluid channels for delivering fluid from a first location (typically an undesirable location) to one or more other locations. In some embodiments, the shunt may be configured to provide a fluid flow path for draining aqueous humor from the anterior chamber to an outflow path to reduce intraocular pressure.

[0136] The shunt portion of the implant may have an inflow portion and an outflow portion. The inflow portion, or inlet, may be located at or near the proximal end of the implant. The inlet may include one or more openings. The outflow portion of the shunt may be located at or near the distal end of the implant and may include one or more openings. In some implants, particularly longer implants configured to extend to the macula or other structures at the back of the eye, the outflow portion may be located in the middle segment of the implant or in both the middle and distal segments. In some embodiments, when the implant is deployed, the size and configuration of the inflow portion may be configured to be located in the anterior chamber of the eye, and the size and configuration of the outflow portion may be configured to be located in the supraciliary space or supraendovascular space. In some embodiments, the size and configuration of the outflow portion may be located in the supraciliary region of the uveal-scleral outflow path, the suprachoroidal space, other parts of the eye, or other physiological spaces suitable for fluid deposition.

[0137] In some embodiments, at least one cavity extends through the shunt portion of the implant. In some embodiments, at least one cavity is used to guide fluid through the shunt portion of the implant. In some embodiments, each cavity extends along its axis from the inlet end to the outlet end. In some embodiments, the cavity extends substantially through the longitudinal center of the shunt so that it is coaxial with the drug delivery cavity. In other embodiments, the cavity may be offset from the longitudinal center of the shunt so that it is configured side-by-side with the drug delivery cavity.

[0138] In some embodiments of implants, including those extending to the posterior segment of the eye, the shunt portion and the drug delivery portion of the implant are separate, with the drug delivery portion facing distally and the shunt portion facing proximally. In this embodiment, the nearest outflow orifice on the implant is located proximally or within 10 mm of the proximal end. The outflow orifice can be located anywhere distal to the inflow location. In some embodiments, the shunt portion and the drug delivery portion overlap to some extent and can have a coaxial or side-by-side arrangement as described above.

[0139] Figure 2A An embodiment of a drug-eluting implant 430 is shown, comprising a coaxial shunt operable to drain fluid from the anterior chamber to a naturally occurring outflow path, such as the uveal-scleral outflow path (e.g., the suprachoroidal space). The lumen 436 of the implant 430 may communicate with an inflow portion or inlet 432 and an outflow portion or outlet 434. The drug may reside within the space between the lumen and the outer shell. Walls may be present to separate the drug from the drainage cavity, or they may be in contact with solid drug or drug formulations forming the walls of the lumen. When implanted, the inflow portion 432 is sized and configured to reside in the anterior chamber of the eye, and the outflow portion 434 is sized and configured to reside in the suprachoroidal space. The drug may be eluted directly from the inflow portion or through a cap (not shown) and / or through the walls of the implant. As the drug is eluted from the implant, fluid can be guided through the lumen 436 of the implant.

[0140] The implant 430 may be sized to have an outer diameter that allows it to be fitted into a 21 or 23 gauge needle or hollow instrument during implantation; however, larger or smaller instruments or other specialized delivery devices may also be used. The implant 430 may also have a diameter designed for delivery with a larger needle. For example, the implant 430 may also be delivered with an 18, 19, or 20 gauge needle. The implant 430 may have a constant diameter for most of its length. In some embodiments, the implant 430 includes a retaining feature 446 for mechanically locking or anchoring the implant 430 in place during implantation. In some embodiments, the retaining feature 446 includes a diameter-reducing portion, such as an annular groove, between the proximal end 438 and the distal end 440. In some embodiments, the retaining feature 446 includes barbs or other protrusions extending from the outer surface of the implant to inhibit movement of the implant 430 from its implantation location, as described above.

[0141] like Figure 2B As shown, for example, some embodiments of the implant 430 have a plurality of annular ribs 448 formed on the outer surface of the implant 430. The annular ribs 448 may be spaced longitudinally between the proximal end 438 and the distal end 440 of the implant 430. The spacing between the annular ribs 448 may be regular or irregular.

[0142] The outflow portion 434 of the implant 430 is preferably located at or near the distal end 440 of the implant 430. Figure 2A In the illustrated embodiment, the outflow portion 434 is a tapered distal portion 444; however, it may also have other shapes, including non-tapered or more gently tapered shapes. The tapered distal portion 444 terminates with a smaller radial dimension at the outflow end or outlet 440. During implantation, whether alone or in conjunction with a guidewire, cannula, or part of another delivery device placed flush with or extending beyond the implant tip within the lumen 436, the tapered portion 444 may be manipulated to form, enlarge, and / or increase the size of the puncture or perforation created in the tissue. For example, the distal end 440 may operate as a cannula to puncture or create a perforation in the tissue. After the distal end 440 of the implant 430 has been advanced, the tapered portion 444 may be advanced through the puncture or perforation. The tapered portion 444 will be manipulated to stretch or expand the tissue around the puncture or perforation to accommodate the increased size of the tapered portion 444 as it is advanced through the tissue. Some embodiments of the implant (for placement within the eye or within the lacrimal punctum) do not include drainage.

[0143] The tapered portion 444 can also facilitate proper positioning of the implant 430 into the supraciliary space or suprachoroidal space. For example, during implantation, the implant 430 preferably advances through tissue within the anterior chamber angle. This tissue is typically fibrous or porous and can be relatively easily punctured or cut with a surgical instrument, such as the tip of the implant 430. The implant 430 can advance through this tissue and abut against the sclera once it extends into the uveal-scleral outflow path. As the implant 430 abuts against the sclera, the tapered portion 444 preferably provides a generally rounded edge or surface that facilitates the sliding of the implant 430 along the inner wall of the sclera within the suprachoroidal space. For example, as the implant 430 enters the uveal-scleral outflow path and abuts against the sclera, the implant 430 is likely to be oriented at an angle relative to the inner wall of the sclera. When the tip of the implant 430 engages the sclera, the tip preferably has a radius that allows the implant 430 to slide along the sclera rather than puncture or substantially penetrate it. As the implant 430 slides along the sclera, the tapered portion 444 provides an edge through which the implant 430 can rest against the sclera and reduces the likelihood of the implant 430 puncturing the sclera.

[0144] For clarity, only a few possible implementations of the various retaining protrusions are shown. It should be understood that any implant implementation can be readily combined with any of the retaining protrusions disclosed herein.

[0145] Figures 3A-3D An example of an implant is shown. This implant may include features identical or similar to other implants described herein. As discussed above, the implant may include a housing 54. The housing 54 may include one or more openings. For example, in several embodiments, one or more openings 56a extending through the thickness of the housing 54 provide a communication channel between the external environment of the implant and the internal cavity 58 of the implant. Figures 3A-3D One or more orifices are created through the shell of a particular implant by drilling through the shells or by any other technique known in the art. The orifices can be of any shape, such as spherical, cubic, elliptical, and / or similar. The number, location, size, and shape of the orifices created in a given implant determine the ratio of the orifice to the implant surface area. As described below, this ratio can vary depending on the desired release profile of the drug to be delivered via a particular embodiment of the implant. In some embodiments, the orifice-to-implant surface area ratio is greater than about 1:100. In some embodiments, the orifice-to-implant surface area ratio is about 1:10 to about 1:50, about 1:30 to about 1:90, about 1:20 to about 1:70, about 1:30 to about 1:60, about 1:40 to about 1:50. In some embodiments, the orifice-to-implant surface area ratio is about 1:60 to about 1:100, including about 1:70, 1:80, and 1:90.

[0146] In some implementations, for example, such as Figures 3A-3D As shown, the outer shell may contain one or more apertures 56b in or near the distal tip of the implant. The shape and size of the apertures can be selected according to the desired elution profile. Other embodiments include a combination of distal apertures and multiple apertures positioned closer to the outer shell. Further embodiments include a combination of distal apertures, proximal apertures on the outer shell, and / or drug release regions (and optionally one or more coatings) as described above. Further embodiments have a closed distal end. In this embodiment, the drug release regions (based on shell thickness / permeability, apertures, coatings, drug location, etc.) may be aligned along the long axis of the implant. This configuration helps to reduce the amount of tissue damage caused by the advancing distal end during various embodiments of the implantation procedure disclosed herein.

[0147] In some embodiments, the distal orifice includes a biodegradable or bioeretable plug 61 having a plurality of orifices 56b that retain drug elution from the implant should one or more orifices become blocked by tissue during insertion / implantation. In other embodiments, the orifice may include a permeable or semi-permeable membrane, a porous membrane, or a sheet, etc. In some such embodiments, the permeable or semi-permeable membrane, sheet, or sheet may be located outside the shell and cover the orifice, located inside the shell and cover the orifice, or both. The permeability of the material will partially limit the rate of drug release from the implant, which will be described in further detail below. Such a membrane, sheet, or sheet may be used in those embodiments having elongated orifices in the shell.

[0148] In several embodiments, additional one or more structures within the cavity can at least partially control drug elution from the implant. This supplements or replaces the layer or layers of permeable or semi-permeable material used to encapsulate the aforementioned drug. Figures 3A-3DAn implant is depicted. The implant may have a shell, an inner plug 210, and a drug reservoir at least partially filled with a drug 62. In some embodiments, the inner plug 210 is located between the drug 62 and various openings 56a and 56b of the shell 54. For example, the inner plug 210 does not need to completely surround the drug. However, as described below, in some embodiments, the inner plug 210 at least partially or completely surrounds the drug 62. In some embodiments, the material of the inner plug 210 is different from the material of the shell 54, while in other embodiments, the material of the inner plug 210 is the same as the material of the shell 54. Suitable materials for the inner plug include, but are not limited to, agarose or hydrogel. As described above, the hydrogel may comprise polyacrylamide, polymethyl methacrylate, HEMA (hydroxyethyl methacrylate), polyethylene glycol, polyethylene oxide, polyethylene oxide-co-propylene oxide, copolymers of polyethylene oxide block or random copolymers, polyvinyl alcohol, poly(vinylpyrrolidone), hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, polyvinyl acetate, gelatin, and / or polyvinylpyrrolidone, etc. In some embodiments, the additional materials disclosed herein for other parts of the shell or implant may be suitable for the internal plug.

[0149] In some embodiments, the size, density, porosity, or permeability of the hydrogel plug 210 may differ from that of the shell 54. In some embodiments, the hydrogel plug is formed in a suitable location (i.e., within the cavity of the implant), for example, by polymerization, molding, or in-situ curing of a dispensed liquid, powder, crystal, or gel. In some embodiments, the hydrogel plug is pre-formed outside the shell and placed within the shell prior to implantation. In such embodiments, a tailored implant can be constructed because the selection of the pre-formed inner plug can be optimized based on a specific drug, patient, implant, and / or disease to be treated.

[0150] In some embodiments, the hydrogel stopper may be dehydrated or in a partially shrunken / dehydrated state before being placed into the housing 54 prior to implantation. For example, in a dehydrated state, the hydrogel stopper may shrink to as little as about 10% of its fully hydrated volume, while in other embodiments, it may be 95%, 90%, 85%, 80%, or 75% of its fully hydrated volume in the implant. In some embodiments, the hydrogel may be hydrated and swelled within the housing 54 prior to implantation and / or before being placed into the housing 54. In some embodiments, the hydrogel stopper may include a biocompatible "fugitive" material or solvent, such as a plasticizer or glycerin. After implantation, the short-acting material flows out of the implant and is replaced by intraocular fluid. Therefore, the material can serve as an initiator for drug flow and / or elution from the implant. For example, the outflow of the material may make the stopper more permeable to the drug, thereby allowing the drug to pass through the hydrogel stopper. In some implementations, the material can prevent and / or minimize shrinkage or collapse of the drug when storing and transporting the implant before and / or during elution or before use.

[0151] As discussed above, in several embodiments, the hydrogel stopper may be biodegradable or bioerodible. In some other embodiments, the hydrogel stopper is durable (e.g., non-biodegradable or bioerodible). In some embodiments, the hydrogel stopper is advantageously non-toxic, water-soluble, bioerodible, hydrophilic, highly absorbent, and / or flexible.

[0152] like Figures 3A-3D As shown, the hydrogel stopper 210 can be positioned within the housing 54. In some embodiments, the hydrogel stopper can be positioned adjacent to the drug 62. The hydrogel stopper 210 can be positioned near the farthest end of the housing 54. For example, the drug can be positioned near and / or close to the stopper 210. As discussed herein, the drug 62 can be partially or completely surrounded by the hydrogel stopper. In some embodiments, the stopper 210 can contain a mixture of hydrogel and drug.

[0153] In some embodiments of the implant, various amounts of hydrogel and drug can be incorporated. For example, the volume ratio of drug to hydrogel for elution within the implant is greater than about 1:1. In some embodiments, the volume ratio of drug to hydrogel for elution within the implant is about 1:1 to about 2:1, about 2:1 to about 5:2, about 5:2 to about 3:1, about 3:1 to about 7:2, about 7:2 to about 4:1, about 4:1 to about 9:2, and / or other ranges. In some embodiments, the volume ratio of drug to hydrogel for elution within the implant is about 1:1 to about 1:2, about 1:2 to about 1:3, about 1:3 to about 1:4, and other ranges. As discussed above, the drug can be dispersed in the hydrogel. In this configuration, all or part of the drug can be dispersed in the hydrogel. For example, as described above, at least 50% of the volume of the mixture may include the drug.

[0154] In several embodiments, the inner plug may fit snugly against or adhere to the inner wall of the shell. For example, the hydrogel plug is preferably drug-permeable, allowing the drug to pass through the plug, through the orifice, and into the target tissue. In some embodiments, the hydrogel plug may also be permeable to bodily fluids, allowing fluids from outside the implant to reach the drug. The overall drug release rate from the device can be controlled by various physical characteristics of the implant assembly, including but not limited to the area and volume of the orifice, the surface area of ​​any drug release region, the composition and / or size of the hydrogel or its position relative to the drug and the orifice and / or drug release region, and the permeability of the hydrogel plug to the drug and bodily fluids. Furthermore, in several embodiments, the hydrogel plug increases the path length between the drug and the orifice and / or drug release region, thereby providing additional control over the drug release rate. For example, the drug may be configured to pass through all and / or a portion of the hydrogel plug 210 to reach the target tissue. Drug elution through the hydrogel can occur over periods ranging from two weeks to one year. In some implementations, the drug can be washed with the hydrogel for two weeks to three years, one day to one week, one week to two weeks, two to four weeks, one month to two months, two months to four months, four months to eight months, four to six months, six months to one year, one year to two years, two years to three years, and / or longer.

[0155] In several other embodiments, the hydrogel stopper 210 can fit more loosely into the inner cavity of the shell, which can allow the drug to flow or be delivered around the stopper. (See...) Figure 3BIn other embodiments, the hydrogel stopper may comprise two or more sheets or segments. In some embodiments, the drug can be eluted from the implant by passing through the gap between the hydrogel stopper and the inner wall of the shell. The drug can also be eluted from the implant by passing through the gap between the sheets or segments of the hydrogel stopper. The drug can also be eluted from the implant by passing through a permeable inner plug. Similarly, bodily fluids can enter the implant from the external portion of the implant and reach the drug through any of these or other pathways. Drug elution can occur due to any combination of these pathways or permeability.

[0156] like Figure 3A As shown, the implant may include a proximal barrier 64a. In some embodiments, the proximal barrier 64a is located proximally relative to the drug 62 (see [reference]). Figures 3A-3D The proximal barrier 64a may be positioned adjacent to the drug, hydrogel plug, and / or hydrogel-drug mixture. In some embodiments, the proximal barrier 64a may form the proximal end of the implant. In some embodiments, the proximal barrier 64a is located within the implant. In some embodiments, the proximal barrier 64a may include optional shunt features. Optional shunt features may include an outflow opening 66 communicating with a proximal inflow cavity 68 located in the proximal region 52 of the implant. In some embodiments, optional shunt features may include an outflow opening communicating with a portion of the eye. For example, in some embodiments, the opening 66 may allow drainage of fluid from the implant when it is implanted into the eye. In some embodiments, elution of drug from the implant may cause the formation of a peak and / or increase in intraocular pressure. For example, drainage of fluid from the proximal end of the implant through the opening 66 may help reduce swelling and / or intraocular pressure. In some embodiments, drainage of fluid through the opening 66 may help accelerate the elution of drug 62.

[0157] In several embodiments, one or more eluent membranes 100 are used to cover the orifice 56a (completely or partially), providing a barrier for the release of drug 62 from the lumen 58 of the implant housing 54. In several embodiments, the eluent membrane is permeable to therapeutic agents, bodily fluids, or both. In some embodiments, the membrane is elastic and contains silicone. In other embodiments, the membrane is completely or partially coated with a biodegradable or bioerectable material, allowing control over the initiation of bodily fluid ingress or the expulsion of therapeutic agents from the implant. In some embodiments, the membrane is impregnated with other advantageous agents, such as antifibrotic agents, vasodilators, antithrombotic agents, or permeability control agents. Furthermore, in some embodiments, the membrane comprises one or more layers 100a, 100b, and 100c, for example, which allows for the development of specific permeability.

[0158] In some embodiments, the outer shell 54 may be coated. In some embodiments, the coating is a polymer coating. The coating may optionally be biodegradable. Some other embodiments may comprise an implant made entirely of biodegradable materials, such that the entire implant degrades over time. In some embodiments, the coating is applied to the entire implant (e.g., wrapping the implant), while in other embodiments, it covers only a portion of the implant. In some embodiments, the coating is located on the outer surface of the implant. In some embodiments, the coating is placed on the cavity wall within the implant as an alternative to or supplement to the exterior of the implant or shell, as discussed below. The coating can help control drug elution through the outer shell. In some embodiments, the coating helps extend the lifespan of the implant (e.g., the outer shell). For example, in some embodiments, the coating may undergo bioerosion over time. The coating may undergo bioerosion and / or dissolution at the same or similar rate as drug elution through the outer shell. In some embodiments, the rate of coating bioerosion is faster than the rate of drug elution through the outer shell. In some embodiments, the coating can inhibit and / or prevent bioerosion of the outer shell. For example, in some embodiments, the coating may help prevent or inhibit partial or complete biodegradation of the outer shell until all or part of the drug has been eluted through the outer shell (e.g., after all or part of the treatment has been administered to the patient). For example, in some embodiments, the coating may allow the outer shell 54 to undergo biodegradation or dissolution at a slower rate when the drug is administered to the patient, and / or at a faster rate once the treatment is completed or substantially completed.

[0159] Similar to the hydrogel plugs and drug release regions described herein, the characteristics of the elution membrane at least partially define the rate of release of the therapeutic agent from the implant. Therefore, the overall rate of drug release from the implant can be controlled by the physical properties of the implant, including but not limited to the area and volume of the orifice, the surface area of ​​any drug release region, the size and location of any hydrogel plug relative to the drug and any orifice and / or drug release region, and the permeability of any layer covering any orifice or drug release region to the drug and bodily fluids.

[0160] In some embodiments, the size and shape of the implant described herein can be configured to be implanted into or through various regions of the eye. For example, the implant can be positioned within the supraciliary space, suprachoroidal space, Schlem's canal, anterior chamber, vitreous humor, or capsular pocket. In some embodiments, the implant can be located entirely within the anterior and / or posterior chambers. In some embodiments, the implant is partially located within the anterior and / or posterior chambers. In some embodiments, the implant is positioned within the vitreous humor or a cavity to avoid positioning the implant within the optical or visual axis.

[0161] Some embodiments disclosed herein are sized to be fully contained within the subject's eye and can be obtained on a subject-specific basis using standard ophthalmic techniques. After implantation, in several embodiments, the proximal end of the device may be positioned in or near the anterior chamber of the eye, and the distal end of the implant may be positioned anywhere within the suprachoroidal space. In some embodiments, the distal end of the implant is located near the limbus. In other embodiments, the distal end of the implant is located near the macula in the posterior ocular region. In other embodiments, the proximal end of the device may be positioned in or near other areas of the eye, such as the vitreous cavity or cavities. In some such embodiments, the distal end of the device may also be positioned in or near other areas of the eye. As used herein, the term "near" is sometimes used synonymously with "at," while other uses indicate a sufficiently adjacent distance, depending on the context, to allow drug diffusion from the implant to the target tissue. In yet another embodiment, the implant is sized to span a distance between a first and a second non-ocular physiological space.

[0162] In one embodiment, the drug delivery implant is advanced into the suprachoroidal space via ciliary appendage tissue located posterior to the scleral spur. The ciliary appendage tissue is typically fibrous or porous and can be relatively easily punctured, cut, or separated from the scleral spur using the delivery instruments disclosed herein or other surgical devices. In such embodiments, the implant is advanced through this tissue and approaches or abuts the sclera once it extends into the uveal-scleral outflow path. The implant advances along the inner wall of the sclera within the uveal-scleral outflow path until it reaches the desired implantation site posterior to the uveal-scleral outflow path.

[0163] In some embodiments, the total length of the implant is 1 to 30 mm. In some embodiments, the implant length 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 implant length is about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mm, whereby the delivery device containing the implant can be inserted and advanced through the cornea to the iris, and creates a self-sealing puncture only in the cornea. In some embodiments, the outer diameter of the implant is about 100 to 600 micrometers. In some embodiments, the implant diameter is about 150-500 micrometers, about 125-550 micrometers, or about 175-475 micrometers. 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 micrometers. In some embodiments, the inner diameter of the implant is about 50-500 micrometers. In some embodiments, the inner diameter is about 100-450 micrometers, 150-500 micrometers, or 75-475 micrometers. In some embodiments, the inner diameter is approximately 80, 90, 100, 110, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 410, 420, 425, 430, 440, or 450 micrometers.

[0164] The implant can be sized to have an outer diameter that allows it to fit 23 to 25 gauge needles or hollow instruments during implantation; however, larger or smaller instruments or other specialized delivery devices may also be used. For example, the implant can be sized to have an outer diameter that allows it to fit 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and / or 30 gauge needles. The implant may have a constant diameter for all or part of its length. In some embodiments, the size and shape of the implant can be configured to fit thin-walled needles, such as ultra-thin-walled needles. Embodiments of the implant may have a maximum outer diameter of about 0.1–0.5 mm, including 0.15–0.45 mm, 0.2–0.4 mm, and 0.25–0.35 mm.

[0165] In a further embodiment, the cavity of the implant may be coated with a hydrophilic material to increase the contact rate between the intraocular fluid and the therapeutic agent or drug located within the cavity. In one embodiment, the hydrophilic material is permeable to the intraocular fluid and / or drug. Conversely, the cavity may be coated with a hydrophobic material to synergistically reduce the contact between the intraocular fluid and the therapeutic agent or multiple therapeutic agents located within the cavity. In one embodiment, the hydrophobic material is permeable to the intraocular fluid and / or drug.

[0166] Figures 4A-4C Further embodiments of implant 50 are shown, which may be particularly suitable for direct placement into the vitreous cavity. These embodiments are similar to or identical in many respects to the embodiments discussed above, including but not limited to materials, elution rates, drugs, orifices, configuration, delivery, dimensions, coatings, etc., thus the foregoing description includes, but is not limited to, those described above. Figures 3A-3D The first 21 paragraphs also apply. Figures 4A-4C . Figure 4A A cross-sectional view of another embodiment of the implant 50 is shown.

[0167] Figure 4A The implants shown may include any or any combination of the features described herein. As discussed above, the implants may be bioerodible or bioresorbable. As shown, the implants may be capsule-shaped. For example, the implant may include a distal end 65b and a proximal end 65a. The distal end 65b and proximal end 65a may be rounded. This configuration can help prevent or inhibit harm to the patient when the implant is introduced into the patient's eye. The rounded ends of the implant can facilitate easier insertion into various areas of the patient's eye, such as the supraciliary space, suprachoroidal space, Schlem's canal, anterior chamber, vitreous humor, posterior chamber, and / or capsular bag.

[0168] like Figure 4A As shown, the implant may include a housing 54. The housing 54 may include one or more openings 56a, 56b. The openings 56a, 56b may be located at or near the distal end 65b of the implant. As discussed above, the implant may include an internal or hydrogel plug 210 and a drug 62. In some embodiments, the hydrogel plug 210 is located at the distal end 65b of the implant and / or near the openings 56a, 56b. The drug 62 may be located near the hydrogel plug 210. For example, the drug 62 may be located at or near the proximal end 65a of the implant. In some embodiments, the drug 62 is contained in a drug reservoir.

[0169] In some embodiments, the proximal end 65a of the implant forms a closed end. In some embodiments, the proximal end 65a of the implant includes a cap. For example, the proximal end 65a of the implant may restrict or prevent the elution of drug 62 through the proximal end 65a of the implant. For example, the hydrogel stopper 210 and drug 62 may be positioned within the housing 54 such that drug 62 passes through at least a portion of the distal region of the implant. In several embodiments, drug 62 passes through at least a portion of the hydrogel stopper 210 before passing through the housing 54. Thus, the hydrogel stopper 210 may assist in controlling the elution of drug 62.

[0170] In some embodiments, as discussed above, orifices 56a and 56b may assist in controlling the elution of drug 62 through the hydrogel stopper 210 and the housing 54. As previously mentioned, drug 62 may be positioned within the housing 54 such that drug 62 passes through the hydrogel stopper 210 before elution. In some embodiments, orifices 56a and 56b may allow drug to pass through the housing 54 once drug 62 has passed through at least a portion of the hydrogel stopper 210. In some embodiments, as discussed herein, the size and shape of the orifices may be configured to adjust the elution rate of drug through the hydrogel stopper 210 and / or the housing 54 of the implant.

[0171] As described above, in some embodiments of the implant, the implant may include a hydrogel plug and a drug of various volumes. For example, the volume ratio of the drug 62 for elution within the implant to the volume of the hydrogel may be greater than about 1:1. For example, in some embodiments, at least 50% of the internal volume of the outer shell 54 is filled with the drug 62 before the drug is eluted from the implant. In some embodiments, the volume ratio of the drug for elution within the implant to the hydrogel plug is about 1:1 to about 2:1, about 2:1 to about 5:2, about 5:2 to about 3:1, about 3:1 to about 7:2, about 7:2 to about 4:1, about 4:1 to about 9:2, and / or other ranges. In some embodiments, the volume ratio of the drug for elution within the implant to the volume of the hydrogel is about 1:1 to about 1:2, about 1:2 to about 1:3, about 1:3 to about 1:4, and other ranges.

[0172] Figure 4B A cross-sectional view of another embodiment of the implant 50 is shown. Figure 4B The implants shown are similar to or the same as those discussed in this article in many respects. Figure 4B The implant shown may include any one or any combination of the features of the implant described herein.

[0173] like Figure 4BAs shown, the implant may include a housing 54. The housing 54 may include one or more apertures 56a, 56b. Apertures 56a, 56b may be located at or near the distal end 65b of the implant. In some embodiments, the housing 54 may optionally include one or more apertures 56c located at or near the proximal end 65a of the implant. As discussed above, the implant may include an interior or hydrogel plug 210 and a drug 62. As shown, all or a portion of the drug 62 may be dispersed within and / or mixed with the hydrogel plug 210 to form a hydrogel-drug mixture. The hydrogel-drug mixture may be pre-formed. For example, the hydrogel and drug may be mixed before insertion into the interior space of the housing 54. In some embodiments, as discussed above, at least 50% of the volume of the hydrogel-drug mixture may include the drug. As previously described, apertures 56a, 56b and / or the hydrogel may assist in controlling the elution rate of the drug through the housing 54.

[0174] Figure 4C A cross-sectional view of another embodiment of the implant 50 is shown. Figure 4C The implants shown are similar to or the same as those discussed in this article in many respects. Figure 4C The implant shown may include any one or any combination of the features of the implant described herein.

[0175] like Figure 4C As shown, the implant may include a housing 54. The housing 54 may include one or more apertures 56a, 56b. Apertures 56a, 56b may be located at or near the distal end 65b of the implant. In some embodiments, the housing 54 may optionally include one or more apertures 56c located at or near the proximal end 65a of the implant. As discussed above, the implant may include an inner or hydrogel plug 210 and a drug 62. As shown, the hydrogel plug 210 may surround at least a portion of the drug 62. As previously described, apertures 56a, 56b and / or the hydrogel may assist in controlling the elution rate of the drug through the housing 54. The drug 62 may pass through all or a portion of the hydrogel plug 210 before being eluted through the housing 54.

[0176] like Figure 6A and Figure 6B As illustrated schematically, elongated implants can include several features disclosed herein. For example, Figure 6A An elongated implant with a proximal end 52 and a distal end 50 is depicted, comprising multiple pellets of a therapeutic agent 62. As discussed in more detail herein, depending on the implementation, the therapeutic agent can be in various forms, such as pellets, microspheres, vesicles, micelles or other membrane-bound structures, oils, emulsions, gels, serous fluids, etc. The implant includes a drug release region 56. Furthermore, Figure 6A and Figure 6BThe implementation described includes a fluid inflow path of 38k and an outflow path of 56k, thereby allowing a combination of therapeutic agent delivery and guiding the fluid to an intraocular fluid outflow path (e.g., the suprachoroidal space).

[0177] Figure 6D An eye with one embodiment of an elongated implant positioned according to several embodiments disclosed herein is schematically depicted. As shown, the proximal end of implant 52 resides near the anterior portion of the eye, while the distal end of implant 50 is located further posteriorly. In one embodiment, the implant may be inserted into the suprachoroidal space and positioned such that a drug release region 56 allows a therapeutic agent 58 to be eluted from the implant in the posterior region of the eye. Although not explicitly described herein, it should be understood that the implant may optionally include the fluid inflow and outflow pathways described herein.

[0178] Other embodiments of ocular implants may be configured to be at least partially located in the supraciliary space of the ciliary body and / or the suprachoroidal space, and may include one or more caps or drug delivery elements, as described in the following sections. Figure 18 A perspective view of an exemplary embodiment of an ocular implant 900 having a drug delivery element is shown. Figure 19 A side view of an exemplary embodiment of an eye implant 900 is shown. Figure 20 A cross-sectional view of an exemplary embodiment of an ocular implant 900 is shown. Various features of the ocular implant 900 are related to... Figures 2A-2B The shown or combined Figures 2A-2B The described features are similar or identical, and as discussed above.

[0179] The ocular implant 900 may include a housing 906. The housing and potentially other components of the implant are preferably made of a biodegradable material. The housing 906 may define an inner chamber 908, which may be a drug reservoir for containing one or more drugs as discussed herein. The housing 906 may be configured for implantation into the supraciliary and / or suprachoroidal space of a patient's eye. The housing 906 may have a generally straight configuration, or the implant may be pre-bent to be configured to generally conform to the curvature of the supraciliary and / or suprachoroidal space. In some embodiments, the housing 906 may be flexible, for example, such that the ocular implant has a generally straight configuration when positioned in a delivery device and a curved configuration when implanted in the eye (e.g., in the supraciliary and / or suprachoroidal space). The housing 906 may include a distal end 902, which may be tapered to facilitate insertion into the supraciliary and / or suprachoroidal space.

[0180] The housing 906 may include a proximal portion 904, which may include a drug delivery element 930. In some embodiments, the proximal portion 904 may have an increased outer diameter, such that a step or ridge 905 is formed between the proximal portion 904 and the central portion of the housing 906. In some embodiments, the ocular implant 900 may be inserted into the eye (e.g., into the supraciliary space and / or suprachoroidal space) until the step or ridge 905 abuts against ocular tissue (e.g., ciliary tissue) near the insertion site. The step or ridge 905 may help prevent over-insertion of the ocular implant 900. As discussed herein, the ocular implant 900 may be configured to release (e.g., elute) a drug, such as from the proximal end of the ocular implant 900 into, for example, the anterior chamber 20. The drug delivery site (e.g., proximal end) may be spaced apart from the step or ridge 905 by a distance 907, thereby preventing ocular tissue adjacent to the insertion site from covering or otherwise obstructing the drug delivery site of the ocular implant 900. For example, the distance can be approximately 25 micrometers, approximately 50 micrometers, approximately 75 micrometers, approximately 100 micrometers, approximately 150 micrometers, approximately 200 micrometers, approximately 300 micrometers, approximately 400 micrometers, approximately 500 micrometers, approximately 750 micrometers, approximately 1000 micrometers, approximately 1250 micrometers, approximately 1500 micrometers, or any value between them, including ranges constrained by any of these distances. In some embodiments, the step or ridge 905 can be larger than... Figures 18-20 The step or ridge 905 may extend laterally outward by a distance of approximately 25 micrometers, approximately 50 micrometers, approximately 75 micrometers, approximately 100 micrometers, approximately 150 micrometers, approximately 200 micrometers, approximately 300 micrometers, approximately 400 micrometers, approximately 500 micrometers, approximately 750 micrometers, approximately 1000 micrometers, or any value between these, including ranges constrained by any of these distances.

[0181] The ocular implant 900 may include one or more retaining features 910 configured to anchor the implant in place when implanted into the eye. The one or more retaining features 910 may include one or more annular ribs on the outer surface of the housing 906. The ribs may have angled distal surfaces and / or may be barbed to facilitate insertion of the ocular implant 900 into the eye while preventing unintentional dislodgement of the ocular implant 900 from the ocular tissue. In some embodiments, the outer diameter of the rib may be substantially the same as the outer diameter of the proximal portion 904 to facilitate placement in a delivery device. In some embodiments, the one or more retaining features 910 may be configured to engage ocular tissue adjacent to the insertion site. For example, the one or more retaining features 910 may be located on or near the proximal portion 904, or at or near a step or ridge 905. In some embodiments, the retaining features 910 may be omitted, and the housing 906 may be held in place by friction with the surrounding ocular tissue.

[0182] The ocular implant 900 may include a drug delivery element 930. The drug delivery element will be discussed further in the following sections.

[0183] In several embodiments, the implant includes a punctal plug. In some such embodiments, the physical arrangement of the drug within the implant provides a favorable timing for drug delivery. In several embodiments, this approach is useful, for example, when combining steroids and cyclosporine to treat dry eye. Many current treatments for dry eye use steroid eye drops for an initial treatment period (e.g., two weeks). After the initial phase, cyclosporine eye drops are added to the treatment regimen. Thereafter, steroids are gradually reduced, ending on day 60, and cyclosporine treatment is continued alone as needed. However, according to one embodiment disclosed herein, a punctal implant can deliver steroids and cyclosporine at appropriate times to achieve near-constant zero-order drug administration. This dose profile is generally considered more efficient than bolus delivery (e.g., with eye drops). In several embodiments, as disclosed herein, the punctal plug is configured to be bio-eroded as the drug payload is released, and in some embodiments, the punctal plug is completely eroded when all or substantially all of the drug payload is released.

[0184] In several embodiments employing multiple drugs, a second (or third, etc.) agent produces a synergistic effect when combined with the first agent. In other embodiments, the second agent reduces one or more side effects associated with the first agent.

[0185] Therefore, multiple embodiments provide an implant for insertion into the lacrimal punctum of a subject's eye, comprising: a shell having a proximal end and a distal end, the shell being shaped to define an inner cavity, the shell being sized to be inserted into the lacrimal punctum of a subject's eye, at least a first active drug being located within the inner cavity; at least one drug release region in the proximal portion of the shell; and a distal occlusion member within the inner cavity, the distal occlusion member preventing the first active drug from being washed away from the distal end of the implant.

[0186] In several such embodiments, the first active drug is eluted from the lumen into the tear film of the subject's eye through at least one drug release area. In some embodiments, the implant is sized to be inserted with the distal end of the outer shell positioned within the lacrimal duct. In some embodiments, the implant is sized to be inserted with the distal end of the outer shell positioned within the lacrimal sac. In several embodiments, the implant is sized to be inserted with the distal end of the outer shell positioned within the nasolacrimal duct.

[0187] In several embodiments, a punctal implant is also provided for insertion into the punctum of a subject's eye and configured to deliver two or more active drugs to the subject's eye. The implant includes a housing comprising: (i) a proximal end including at least one drug release area and a flange; (ii) a closed distal end; and (iii) an inner cavity containing at least two active drugs located within the cavity.

[0188] In several embodiments, a punctal implant is also provided for insertion into the punctum of a subject's eye and configured to deliver two or more active pharmaceutical ingredients to the subject's eye. The implant includes a housing comprising: (i) a proximal end including at least one drug release region and a flange; (ii) a closed distal end; and (iii) an inner cavity containing at least two active pharmaceutical ingredients located within the cavity. The drug release region includes an opening through an annular ring located at the proximal portion of the inner cavity. The opening allows elution of the two or more active pharmaceutical ingredients to occur solely through an occlusion member. The size of the opening at least partially defines the elution rate of the two or more active pharmaceutical ingredients. The flange is configured to rest against a surface of the eyelid when the implant is inserted into the punctum. The first and second active pharmaceutical ingredients are eluted from the cavity into the tear film of the subject's eye through the at least one drug release region.

[0189] In several embodiments, at least one drug release region includes at least one opening. Furthermore, in some embodiments, the implant also includes at least one membrane that occludes at least one opening, wherein the membrane is permeable to the at least first active drug, and wherein the membrane allows elution of the at least first active drug to occur solely through the at least one membrane.

[0190] In several embodiments, at least one drug delivery region includes a plurality of openings that pass through the shell and are randomly or patternedly located throughout the proximal portion of the implant. As described above, at least a portion of the plurality of openings is sealed by a membrane that is permeable to the first active drug.

[0191] Some of the implementation methods described herein enable the elution of drugs (or multiple drugs) from the implant to have zero-order or pseudo-zero-order kinetics.

[0192] In some implementations, the intraocular target is the posterior chamber of the eye, the anterior chamber of the eye, the anterior and posterior chambers of the eye, or the macula, retina, optic nerve, ciliary body, and intraocular vascular system.

[0193] In several embodiments, the drug acts on intraocular target tissue to produce a prolonged therapeutic effect. In one embodiment, the drug includes a steroid. In this embodiment, the implant contains a total steroid load 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 nanomolars. In some embodiments, the steroid also produces side effects associated with the accumulation of physiological fluid, and an optional shunt delivers 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 the Schlemm's duct or nasolacrimal duct).

[0194] In several embodiments, at least one drug release region includes an occlusion member permeable to the two or more active pharmaceutical ingredients, and the occlusion member allows elution of the two or more active pharmaceutical ingredients to occur solely through the occlusion member. In several embodiments, the thickness of the occlusion member at least partially defines the elution rate of the active pharmaceutical ingredient (or multiple drugs). In several embodiments, a flange is provided, the flange being configured to rest against the surface of the eyelid when the implant is inserted into the lacrimal punctum. In several embodiments, the active pharmaceutical ingredient (or multiple drugs) is eluted from the cavity into the tear film of the subject's eye by passing through at least one drug release region.

[0195] In several embodiments, the size of the occlusion membrane is determined based on the permeability of the occlusion member to the first active drug (and second or more) and the desired relative timing and duration of elution of the first and second active drugs. In several embodiments, the thickness of the occlusion member is about 0.0001 to 0.0005 inches. In some embodiments, the occlusion member is integrally formed with the outer shell of the implant. In some embodiments, the occlusion member also includes random or patterned perforations through the occlusion membrane.

[0196] In some embodiments, the first active drug is positioned more proximally within the lumen than the second active drug. In some embodiments, a third active drug is included, and in some such embodiments, the first and second active drugs are positioned adjacent to each other, and both the first and second active drugs are positioned more proximally within the lumen than the third active drug.

[0197] In several embodiments, the active pharmaceutical ingredient (or multiple pharmaceutical ingredients) is formulated into tablets, nanodispersions, or combinations thereof. In some embodiments, the first active pharmaceutical ingredient is formed as a discontinuous first phase, and the second active pharmaceutical ingredient is formulated into a solid dispersion of liquid particles, wherein the first active pharmaceutical ingredient is dispersed in the liquid particles.

[0198] In several embodiments, the device may be filled with a protein drug in the form of an amorphous solid, powder, or crystalline solid; or in the form of a suspension of these; or in the form of a solution. If the device is filled with a suspension or solution, the initial concentration of the protein drug may optionally be in the range of about 100 to about 500 mg / mL, including concentrations between about 100 to about 150 mg / mL, about 150 to about 200 mg / mL, about 200 to about 250 mg / mL, about 250 to about 300 mg / mL, about 300 to about 350 mg / mL, about 350 to about 400 mg / mL, about 400 to about 450 mg / mL, and about 450 to about 500 mg / mL. In some preferred embodiments, the concentration is about 200 to about 300 mg / mL.

[0199] In several embodiments, the drug may include excipients such as trehalose to stabilize the protein drug during preprocessing (e.g., lyophilization) or during its use in the eye. Depending on the concentration of trehalose, an osmotic gradient may be created from the inside to the outside of the device, causing water from the vitreous humor to tend to enter the device and expel some of the drug. If an initial burst of elution is desired, this event can be intentional. Otherwise, the concentration of trehalose can be reduced to an isotonic level, or a polymer with multiple hydroxyl residues can be used to reduce osmotic pressure and slow elution loss.

[0200] Other excipients may contain buffers to maintain a neutral pH during the hydrolysis of bioabsorbable materials. Such buffers may also be polymerized to mitigate their elution loss.

[0201] In several embodiments, the outer shell of the implant includes a protrusion in the distal region to anchor the implant in the tear punctum.

[0202] In several embodiments, the first active drug is eluted from the implant over a period of 1 to 75 days, and the second active drug is eluted over a period of approximately 1 to approximately 24 months after the first active drug is eluted.

[0203] In several embodiments, the implant disclosed herein has a length of about 0.5 mm to about 2.5 mm. In some embodiments, the implant has a length of about 1.4 mm to about 1.6 mm. In some embodiments, the implant has a diameter of about 0.2 mm to about 1.5 mm. In some embodiments, the implant has a diameter of about 0.2 mm to about 0.6 mm.

[0204] Depending on the implementation, the first active pharmaceutical ingredient may be a steroid. In some such implementations, the steroid is selected from the group consisting of cloprednisolone ethyl carbonate, dexamethasone, and triamcinolone acetonide. In some implementations, the second active pharmaceutical ingredient is cyclosporine and is optionally formulated as a nanodispersion. In many implementations, the first active pharmaceutical ingredient is cyclosporine A. In many implementations, the first active pharmaceutical ingredient contributes to tear production.

[0205] Multiple embodiments may optionally include a retaining protrusion configured to anchor the implant at an implantation site (e.g., the lacrimal punctum). Such a retaining protrusion may optionally include one or more of the following: a protrusion, a ridge, a claw, a thread, a flexible rib, a rivet-like shape, a flexible barb, a barb tip, an expanding material (e.g., hydrogel), and a biocompatible adhesive. In some embodiments, the expanding material is placed on the outer surface of the implant shell and expands upon contact with a solvent (e.g., intraocular fluid or tear film).

[0206] In several embodiments, the shell of the punctal plug implant comprises a bioerodible material. As discussed in more detail elsewhere in this disclosure, in several embodiments, the bioerodible material is configured to allow the entire implant (including those for punctal insertion and other implantation sites) to be eroded at a rate of complete or substantially bioerosion. This may optionally be configured to simulate the timing of drug release such that the implant itself is also completely or substantially eroded when all or substantially all of the drug payload has been eluted from the implant (including the punctal implant). However, in some embodiments, the bioerosion of the implant is adjusted to begin only after all or substantially all of the drug payload has been delivered.

[0207] It should be understood that any device described herein (including) Figure 2A and Figure 2B or Figure 5A and Figure 5B The device may be equipped with any cap including a drug delivery element, as discussed below and shown. Figures 5A-5B and Figures 12-17 The cap in the middle, and Figures 18 to 20 The drug delivery implant shown can be equipped with, for example, Figure 5A and Figure 5BThe cap shown may or may not include any cap. Furthermore, any embodiment disclosed and described herein may include a cap at the distal end as an alternative to the proximal end, the cap comprising a drug delivery element, or they may include caps at both ends. If the implant includes caps at both ends, the type of cap at each end may be the same or may be different, and each may deliver the same drug from the same cavity, the same drug from the same cavity (where the cavity is divided into two compartments by an intracavitary barrier), the same drug from different cavities, different drugs from a cavity containing a barrier separating the two drugs, or different drugs from different cavities. In the case of two caps, the timing and / or rate of drug delivery may be the same or different, and if the timing is different, they may overlap or differ. Similarly, similar to... Figure 5A and Figure 5B or Figures 18 to 20 Implants can include similar Figure 2A and Figure 2B The drainage cavity, or as otherwise described in this article.

[0208] It should also be understood that, Figure 2A and 2B , Figure 5A and Figure 5B as well as Figures 18 to 20 The possible characteristics and materials of the implant (including, but not limited to, biodegradable materials, size, length, diameter, retention features, shunts, orifices, coatings, distal shape, etc.) are the same as those discussed throughout this specification (including this section and previous sections). As those skilled in the art will understand, the physical separations in this specification are not intended and should not be construed as meaning that these concepts are separate and cannot be applied to the various device implementations described herein.

[0209] Cap, including drug release element

[0210] In several embodiments, the implant may include one or more caps. In this embodiment, one or more parts of the implant are manufactured separately and then assembled into a final implant (e.g., an assembled cap and implant shell) ready for insertion into a target site. For example, as Figure 5A As shown, in several embodiments, the implant 53 includes an implant shell 54 and a separate cap 54a (shown in different shades for clarity, but optionally made of the same or different materials than the implant shell). Any of the various cap configurations can be used with any implant shell, of course, the dimensions need to be adjusted to allow interaction between the components.

[0211] like Figure 5AAs shown, the cap 54a includes a central opening, thereby forming a drug release region 56. In several embodiments, the assembly of certain embodiments utilizes the elastic or semi-elastic properties of the membrane 60 through which the drug (or multiple drugs) contained in the implant will be eluted. Advantageously, in several embodiments, the elastic properties of the membrane 60 allow the cap of the implant to press-fit onto the implant shell and then be held in place by the elastic rebound of the membrane against the pressure provided by the cap (e.g., a "self-locking" feature). Thus, in several embodiments, the membrane 60 serves not only to define the release rate of the drug (or multiple drugs) but also as a gasket to seal the internal portion of the implant from the external environment, thereby limiting fluid communication between the internal and external portions to occur through the membrane 60. The membrane 60 can be made of any or multiple materials suitable for drug elution. For example, in one embodiment, membrane 60 comprises ethylene-vinyl acetate, while in another embodiment, the membrane comprises silicone or other partially or semi-permeable materials, homopolymers, polymer blends and copolymers, such as random copolymers and block copolymers, polyethylene, polyurethane, polyethersulfone, polyamide, poly(ethyl carbonate), poly(ethyl ether carbamate), silicone poly(ethyl carbonate), silicone poly(ethyl ether carbamate), PurSil TM Elasthane TM CarboSil TM and / or Bionate TM The biodegradable materials discussed above regarding the outer shell can also be used for membranes, caps, and other components. The selection of membrane materials and their dimensions (e.g., their thickness) can be determined at least in part by the following: the drug selected, its form in which it is placed in the implant (free acid, prodrug, oil, solid, micelles, etc.), and whether intraocular fluid needs to be removed from the device, etc.

[0212] Figure 5B An exploded view of one embodiment of the implant disclosed herein is depicted. The implant 53 includes at least one lumen 58 for containing a therapeutic agent (or multiple agents). As discussed above, the implant also includes a cap 54a and a membrane 60, which, when assembled together, create a drug release region 56, which is adjusted (based on the membrane) to accommodate a specific target therapeutic agent (or multiple agents).

[0213] In various embodiments, the thickness of the membrane 60 (together with the selected specific therapeutic agent or multiple therapeutic agents) is from about 30 to about 200 μm, including 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 their overlapping ranges. In several embodiments, the thickness of the membrane 60 also at least partially defines the elution rate of the target drug (or multiple drugs). The opening size of the cap also contributes to the elution rate.

[0214] Many alternatives and variations are possible. For example, in some cases, Figure 5A and Figure 5B Assembly of the embodiments shown may include providing a housing 54 filled with a drug reservoir. A cap 54a having a membrane 60 may be applied to the proximal end of the housing 54. In some embodiments, the cap 54a may be advanced distally until the desired membrane compression is achieved (e.g., 30 micrometers or any other suitable amount as discussed herein), after which the cap 54a may be reversibly or irreversibly rolled up or otherwise secured to the body 54. In some embodiments, a micrometer may be used to determine the membrane compression.

[0215] A particular type of cap is referred to in this paper as a drug-release element. Figure 13A A distal exploded perspective view of the drug delivery element 530 is shown. Figure 13B An exploded perspective view of the proximal end of the drug delivery element 530 is shown. As described herein, the drug delivery element 530 can be configured to slowly elute a drug. The drug delivery element 530 can be positioned at or near the proximal end 504 of the implant 500. In other embodiments, it can be positioned at or near the distal end of the implant or at both ends. The shell 506 may include a shelf 548. The proximal portion of the interior of the shell 506 near the shelf 548 may have a larger diameter than the portion farther from the shelf 548. In some embodiments, the shelf 548 may include a uniform annular dimension around its circumference. In some embodiments, the shelf 548 does not have a uniform annular dimension around its circumference, and in some cases, as discussed herein, the shelf 548 may be one or more protrusions that create a stop for the distal sealing member. The shell 506 may include one or more slots 550, as described herein, which can be configured to receive the retainer 532. In some embodiments, the shell 506 may include two slots 550 that are generally positioned opposite each other.

[0216] The drug delivery element 530 may include a distal sealing member 552, a membrane 554, and a proximal sealing member 556. The distal sealing member 552 may be positioned abutting against a shelf 548 on the housing 506. The distal sealing member 552 may have an outer diameter larger than the distal portion of the housing interior (the distal end of the shelf 548) and smaller than the proximal portion of the housing interior (the proximal end of the shelf 548). The distal sealing member 552 may have a generally annular shape and / or may have an opening 558 extending therethrough. The proximal sealing member 556 may have an outer diameter larger than the distal portion of the housing interior (the distal end of the shelf 548) and smaller than the proximal portion of the housing interior (the proximal end of the shelf 548). The proximal sealing member 556 may be inserted into the proximal end 504 of the housing 506. The proximal sealing member 556 may typically be disc-shaped. The proximal sealing member 556 may include at least one opening 560 extending therethrough. In the illustrated embodiment, the proximal sealing member 556 includes two openings 560. A membrane 554 may be positioned between the distal sealing member 552 and the proximal sealing member 556, and in some embodiments, the membrane 554 may be compressed between the distal sealing member 552 and the proximal sealing member 556. As discussed herein, a retainer 532 may hold the drug delivery element 530 in a compressed state (e.g., using a compressed membrane 554). The distal sealing member 552 may include a step 562. Figure 14 The membrane 554 is shown in its undeformed state. When compressed, the membrane 554 can deform to fill the space of the step 562.

[0217] As discussed herein, distal sealing member 552 and / or proximal sealing member 556 may be made of a variety of biocompatible materials, such as ceramics or metals (e.g., titanium). In some embodiments, forming members 552 and / or 556 with ceramic materials is advantageous for creating fine details on the components. In some embodiments, one or both of sealing members 552 and 556 may be made of an elastic biocompatible material that is impermeable or substantially impermeable to drugs (e.g., silicone). Membrane 554 may be made of a variety of suitable materials that allow drugs to be eluted from implant 500. In some embodiments, the membrane may be made of ethylene-vinyl acetate (EVA). The elution rate of the drug may depend at least in part on the percentage concentration of vinyl acetate in the EVA material. The vinyl acetate concentration may be less than or equal to about 40%, less than or equal to about 30%, less than or equal to about 25%, at least about 10%, at least about 20%, at least about 25%, and / or at least about 30%, but values ​​outside these ranges may be used in some embodiments. The concentration of vinyl acetate can be from about 10% to about 30%, from about 20% to about 30%, or from about 25% to about 30% of the EVA material. In some embodiments, the concentration of vinyl acetate can be about 25% or about 28% of the EVA material.

[0218] As discussed herein, a membrane 554 can be compressed between a distal sealing member 552 and a proximal sealing member 556. The proximal sealing member 556 can be pressed distally to compress the membrane 554, and a retainer 532 can be inserted through a slot 550 such that the retainer is located proximal to the proximal sealing member 556. The retainer 532 may have a length greater than the inner diameter of the proximal portion of the housing interior and less than or equal to the outer diameter of the housing 506 at the slot 550. When inserted, the retainer 532 can extend into two opposing slots 550. Force from compressing the membrane 554 can press the retainer 532 proximally, and the slots 550 can hold the retainer in place to maintain the membrane 554 in a compressed configuration. The retainer 532 may have a generally hourglass shape, but other shapes may be used in some embodiments. The retainer may include one or more tabs 564 that can be folded downwards to secure the retainer 532. Figure 14 This is a partial view showing the inserted retainer 532, with the tab 564 facing upwards. Figure 15 This is a partial cross-sectional view showing the inserted retainer 532, wherein the tab 564 is folded downward to engage the proximal sealing member 556. When folded downward, the tab 564 can enter one or more openings 560 and engage the proximal sealing member 556, which can prevent or stop the retainer 532 from moving (e.g., sliding out of the groove 550). In some embodiments, when the membrane 554 is compressed, a portion of the membrane 554 can be pushed proximally into one or more openings 560, and the folded tab 564 can engage the membrane 554, which facilitates the retention of the membrane 554.

[0219] The drug can be eluted from the proximal end of the implant 500. The drug can pass from the inner chamber 508 through at least one opening 558 in the distal sealing member 552 to the membrane 554. The membrane 554 can be configured to allow the drug to pass through the membrane 554 at a desired elution rate. The drug can pass through at least one hole 560 in the proximal sealing member 556, through the retainer 532, and exit from the proximal end 504 of the implant 500. Figure 15In the diagram, two arrows indicate drug elution. In some embodiments, the thickness and / or compression of membrane 554 can at least partially affect the drug elution rate. In some embodiments, the compressed thickness of membrane 554 can be at least about 50 micrometers, at least about 75 micrometers, at least about 80 micrometers, at least about 90 micrometers, at least about 95 micrometers, at least about 100 micrometers, less than or equal to about 200 micrometers, less than or equal to about 150 micrometers, less than or equal to about 125 micrometers, less than or equal to about 110 micrometers, less than or equal to about 105 micrometers, less than or equal to about 100 micrometers, less than or equal to about 95 micrometers, and / or less than or equal to about 90 micrometers, but values ​​outside these ranges may be used in some embodiments. The compressed thickness 566 of membrane 554 can be from about 75 micrometers to about 125 micrometers, from about 85 micrometers to about 105 micrometers, or from about 90 micrometers to about 100 micrometers. In some embodiments, the compressed thickness 566 of membrane 554 can be about 95 micrometers. The membrane can be compressed to at least about 10 micrometers, at least about 20 micrometers, at least about 30 micrometers, at least about 40 micrometers, less than about 50 micrometers, less than about 40 micrometers, less than about 30 micrometers, and / or less than about 20 micrometers, but values ​​outside these ranges may be used in some embodiments. Membrane 554 can be compressed to about 20 micrometers to about 40 micrometers or about 25 micrometers to about 35 micrometers. In some embodiments, membrane 554 can be compressed to about 30 micrometers. Compression of membrane 554 can improve its long-term operation over several years.

[0220] The amount of compression applied to membrane 554 can be reliably applied without human determination because the amount of compression applied to membrane 554 is determined by the dimensions of the implant 500 components, not by a human determination during assembly. For example, the longitudinal distance 568 between the proximal end of shelf 548 and slot 550 can be approximately 235 micrometers. Distal sealing member 558 can have a longitudinal thickness 570 of approximately 65 micrometers. Proximal sealing member 556 can have a longitudinal thickness 572 of approximately 50 micrometers. Retainer 532 can have a longitudinal thickness of approximately 25 micrometers. Membrane 554 with a longitudinal thickness of approximately 125 micrometers can be compressed to a longitudinal thickness of approximately 95 micrometers (or less) 566, and retainer 532 with a longitudinal thickness of approximately 25 micrometers 574 can be inserted to keep membrane 554 in a compressed form. Therefore, the dimensions of the individual components determine that membrane 554 will be compressed by 30 micrometers, from a thickness of 125 micrometers to a thickness of 95 micrometers.

[0221] Many changes are possible. For example, Figure 16A perspective view of an exemplary embodiment of an alternative seal 576 is shown, which in some embodiments may be used in place of seal 528. Seal 576 may be a single integral piece and may be formed of an elastic material (e.g., silicone) that is impermeable or substantially impermeable to drugs. Seal 576 may include a distal protrusion 578 and a proximal protrusion 580, both of which may be configured to seal the inner wall of chamber 508. Figure 17 This is a perspective view of an exemplary embodiment of an alternative top sealing member 582, which can be used in place of the top sealing member 556 discussed herein. The top sealing member 582 is typically annular or ring-shaped. The top sealing member 582 includes a single, relatively large aperture 584, instead of the two relatively small apertures 560 of the top sealing member 556 described herein. The larger aperture 584 can produce a faster elution rate than the two smaller apertures 560. Similarly, the size and number of apertures in the distal sealing member 552 can at least partially affect the elution rate of the drug. The implant 500 can be configured to have elution rates less than or equal to about 100 nanograms / day, less than or equal to about 75 nanograms / day, less than or equal to about 50 nanograms / day, less than or equal to about 40 nanograms / day, less than or equal to about 30 nanograms / day, less than or equal to about 25 nanograms / day, less than or equal to about 20 nanograms / day, at least about 10 nanograms / day, at least about 15 nanograms / day, at least about 20 nanograms / day, at least about 25 nanograms / day, at least about 30 nanograms / day, and / or at least about 40 nanograms / day, but values ​​outside these ranges may be used in some embodiments. The elution rate can be from about 15 nanograms / day to about 35 nanograms / day or from about 20 nanograms / day to about 30 nanograms / day. In some cases, the elution rate can be about 25 nanograms / day. The drug delivery time provided by the elution rate and volume of the drug can be at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, at least about 10 years, less than or equal to about 15 years, less than or equal to about 12 years, less than or equal to about 10 years, less than or equal to about 8 years, less than or equal to about 6 years, and / or less than or equal to about 4 years, but values ​​outside these ranges may be used in some embodiments.

[0222] Drug delivery ocular implants can be manufactured to accommodate a variety of different drug volumes. Implants can accommodate at least about 30 nanoliters, at least about 40 nanoliters, at least about 50 nanoliters, at least about 60 nanoliters, at least about 70 nanoliters, at least about 80 nanoliters, at least about 90 nanoliters, at least about 100 nanoliters, at least about 110 nanoliters, at least about 120 nanoliters, at least about 130 nanoliters, at least about 140 nanoliters, at least about 150 nanoliters, less than or equal to about 200 nanoliters, less than or equal to about 175 nanoliters, less than or equal to about 150 nanoliters, less than or equal to about 130 nanoliters, less than or equal to about 120 nanoliters, less than or equal to about 110 nanoliters, less than or equal to about 100 nanoliters, less than or equal to about 90 nanoliters, less than or equal to about 80 nanoliters, less than or equal to about 70 nanoliters, less than or equal to about 60 nanoliters, and / or less than about 50 nanoliters, but values ​​outside these ranges may be used in some embodiments. The implant can hold a drug volume of approximately 40 nanoliters to approximately 150 nanoliters or approximately 50 nanoliters to approximately 120 nanoliters.

[0223] Various other embodiments disclosed herein may include drug-release elements that may be similar to or identical to drug-release elements 530 and / or 730 or other drug-release elements described and discussed herein. For example, in some embodiments, an ocular implant may be configured to be at least partially located in the supraciliary space and / or suprachoroidal space and may include a drug-release element having features similar to or identical to those of the drug-release elements disclosed herein (e.g., drug-release elements 530 and / or 730). Figure 18 A perspective view of an exemplary embodiment of an eye implant 900 is shown. Figure 19 A side view of an exemplary embodiment of an eye implant 900 is shown. Figure 20 A cross-sectional view of an exemplary embodiment of an ocular implant 900 is shown. Various features of the ocular implant 900 are related to... Figures 2A-2B The shown or combined Figures 2A-2B The described features are similar or identical, and as discussed above.

[0224] The ocular implant 900 may include a housing 906. The housing and potentially other components of the implant are preferably made of a biodegradable material. The housing 906 may define an inner chamber 908, which may be a drug reservoir for containing one or more drugs as discussed herein. The housing 906 may be configured for implantation into the supraciliary space and / or suprachoroidal space of a patient's eye. The housing 906 may have a generally straight configuration, or the implant may be pre-bent to be configured to generally conform to the curvature of the supraciliary space and / or suprachoroidal space. In some embodiments, the housing 906 may be flexible, for example, such that the ocular implant has a generally straight configuration when positioned in a delivery device and a curved configuration when implanted in the eye (e.g., into the supraciliary space and / or suprachoroidal space). The housing 906 may include a distal end 902, which may be tapered to facilitate insertion into the supraciliary space and / or suprachoroidal space.

[0225] The housing 906 may include a proximal portion 904, which may include a drug delivery element 930. In some embodiments, the proximal portion 904 may have an increased outer diameter, forming a step or ridge 905 between the proximal portion 904 and the central portion of the housing 906. In some embodiments, the ocular implant 900 may be inserted into the eye (e.g., into the supraciliary space and / or suprachoroidal space) until the step or ridge 905 abuts against ocular tissue (e.g., ciliary tissue) near the insertion site. The step or ridge 905 may help prevent over-insertion of the ocular implant 900. As discussed herein, the ocular implant 900 may be configured to release (e.g., elute) a drug, such as from the proximal end of the ocular implant 900 into, for example, the anterior chamber 20. The drug delivery site (e.g., proximal end) may be spaced 907 from the step or ridge 905 to prevent ocular tissue adjacent to the insertion site from covering or otherwise obstructing the drug delivery site of the ocular implant 900. For example, the distance can be about 25 micrometers, about 50 micrometers, about 75 micrometers, about 100 micrometers, about 150 micrometers, about 200 micrometers, about 300 micrometers, about 400 micrometers, about 500 micrometers, about 750 micrometers, about 1000 micrometers, about 1250 micrometers, about 1500 micrometers, or any value between them, including ranges constrained by any of these distances. In some embodiments, the step or ridge 905 can be larger than... Figures 18-20 The step or ridge 905 extends laterally outward. The distance by which the step or ridge extends laterally outward can be approximately 25 micrometers, approximately 50 micrometers, approximately 75 micrometers, approximately 100 micrometers, approximately 150 micrometers, approximately 200 micrometers, approximately 300 micrometers, approximately 400 micrometers, approximately 500 micrometers, approximately 750 micrometers, approximately 1000 micrometers, or any value in between, including ranges constrained by any of these distances.

[0226] The ocular implant 900 may include one or more retaining features 910 configured to anchor the implant in place when implanted into the eye. The one or more retaining features 910 may include one or more annular ribs on the outer surface of the housing 906. The ribs may have angled distal surfaces and / or may be barbed to facilitate insertion of the ocular implant 900 into the eye while preventing unintentional dislodgement of the ocular implant 900 from the ocular tissue. In some embodiments, the outer diameter of the rib may be substantially the same as the outer diameter of the proximal portion 904 to facilitate placement in a delivery device. In some embodiments, the one or more retaining features 910 may be configured to engage ocular tissue adjacent to the insertion site. For example, the one or more retaining features 910 may be located on or near the proximal portion 904 or at or near a step or ridge 905. In some embodiments, the retaining features 910 may be omitted, and the housing 906 may be held in place by friction with the surrounding ocular tissue.

[0227] The ocular implant 900 may include a drug delivery element 930. The drug delivery element may include a distal sealing member 952, a membrane 954, and a proximal sealing member 956, which may be the same as or similar to other distal sealing members, membranes, and proximal sealing members discussed and described herein. The disclosure of other embodiments including drug delivery elements provided herein can be applied to the ocular implant 900 and will not be repeated here. As discussed herein, the membrane 954 may be compressed between the distal sealing member 952 and the proximal sealing member 956. As discussed herein, a retainer 932 may hold the drug delivery element 930 in place. The housing 906 may include one or more slots 950, and the retainer 932 may engage one or more slots 950 proximal to the proximal side of the proximal sealing member 956. Two slots 950 may be positioned on opposite sides of the housing 906, and the retainer 930 may be inserted through one of the slots 950, through the inner chamber 908, and into the other slot 950. The distal sealing member 952 can be mounted against a shelf in the inner chamber 908. The compression diaphragm 954 can apply a force to press the distal sealing member 952 against the shelf and the proximal sealing member 956 against the retainer 932.

[0228] It should be understood that the elements discussed above should not be construed as limiting the implant to the specific combinations or implementations described. Rather, the features discussed are freely interchangeable to allow for flexible construction of drug delivery implants according to this disclosure.

[0229] Delivery instrument

[0230] Another aspect of the systems and methods described herein relates to a delivery device for implanting an implant used to deliver medication to the eye and optionally drain fluid from the anterior chamber to a physiological outflow space. In some embodiments, the implant is inserted into the eye from a transocular site located at the implantation site. The delivery device is long enough to advance the implant transocularly from the insertion site through the anterior chamber into the implantation site. At least a portion of the device may be flexible. The device may comprise a plurality of components longitudinally movable relative to each other. In some embodiments, the plurality of components include one or more slidable conduits. In some embodiments, at least a portion of the delivery device is curved. In some embodiments, a portion of the delivery device is rigid while another portion of the device is flexible.

[0231] In some embodiments, the delivery device has a distal curvature. In some embodiments, the distal curvature of the delivery device can be characterized as a radius of approximately 10 to 30 mm. In some embodiments, the distal curvature has a radius of approximately 20 mm.

[0232] In some embodiments, the delivery device has a distal angle 88 (measured as χ in Figure 22). The angle measurement χ can be characterized as approximately 90 to 180 degrees relative to the proximal segment 94 of the delivery device. In some embodiments, the angle measurement χ can be characterized as approximately 145 degrees and approximately 170 degrees. In some embodiments, the angle measurement is approximately 150 to approximately 170 degrees or approximately 155 to approximately 165 degrees. This angle can incorporate a small radius of curvature at the “elbow” to allow for a smooth transition from the proximal segment to the distal segment of the delivery device. In some embodiments, the length of the distal segment can be approximately 0.5 to 7 mm, while in some other embodiments, the length of the distal segment is approximately 2 to 3 mm.

[0233] In other embodiments, a curved distal end is generally preferred. In this embodiment, the height of the delivery device / shunt assembly ( Figure 8 The size (90) is less than about 3 mm, in some embodiments, and less than 2 mm in other embodiments.

[0234] In some embodiments, the instrument has a sharp tip and is self-trepanning (i.e., self-penetrating) to penetrate tissue without pre-forming a cut, hole, or opening. In some embodiments, the self-trepanning instrument is configured to penetrate only the corneal and / or limbal tissue. In other embodiments, the self-trepanning instrument is configured to penetrate internal ocular tissue, such as the anterior chamber angle, to deliver the implant. Alternatively, a separate cannula, scalpel, scraper, or similar instrument may be used to pre-form a cut in such tissue before inserting the implant into the ocular tissue (cornea / sclera or more internal tissue). In some embodiments, the implant is blunt at the distal end to facilitate blunt dissection of the ocular tissue (and thus reduce the risk of tissue trauma). However, in other embodiments, the implant is also sharp, conical, or otherwise configured to pierce the ocular tissue to assist in implantation.

[0235] In some embodiments for delivering drug-eluting ocular implants, the device has a sufficiently small cross-section such that the insertion site self-seales without sutures when the device is removed from the eye. The external dimensions of the delivery device are preferably no greater than about 18 and no less than about 27 or 30.

[0236] In some implementations of drug-eluting ocular implant delivery, a slit is created in the corneal tissue using a hollow needle, through which the implant is delivered. The needle has a small diameter (e.g., 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27 gauge) such that the slit can be self-sealing and implantation occurs in a closed chamber, with or without viscoelasticity. A self-sealing incision can also be created using a conventional “tunneling” procedure, where a roughly inverted V-shaped slit is formed through the cornea using a scraper-shaped scalpel. In a preferred mode, the instrument used to create the slit through the cornea remains in place during the procedure (i.e., extending through the corneal slit) until after implantation. This slit-creating instrument can either be used to place the ocular implant or can be used in conjunction with a delivery instrument to allow implantation through the same slit without requiring withdrawal of the slit-creating instrument. Of course, in other modes, various surgical instruments can pass through one or more corneal slits multiple times.

[0237] Some implementations include a spring-loaded actuator system. In some implementations, the spring-loaded actuator includes a button operably connected to a hinged actuator assembly. The lever of the hinged actuator engages a recess in the surface of the actuator, holding the spring of the actuator in a compressed configuration. When the user presses the button, the lever disengages from the recess, allowing the spring to depress, thereby advancing the actuator forward.

[0238] In some implementations, an over-the-wire system is used to deliver the implant. The implant can be delivered via the wire. In some implementations, the wire is self-trepanning. The wire can also be used as a cannula. The wire can be hyperelastic, flexible, or relatively inflexible relative to the implant. The wire can be pre-formed with a specific shape. The wire can be curved. The wire can have shape memory or be elastic. In some implementations, the wire is a pull cord. The wire can also be a maneuverable catheter.

[0239] In some embodiments, the wire is located within a cavity of the implant. The wire can move axially within the cavity. The cavity may or may not include valves or other flow control devices.

[0240] In some embodiments, the delivery instrument is a cannula. The cannula may be angled or curved. In some embodiments, the cannula is flexible. In other embodiments, the cannula is relatively rigid. In other embodiments, the cannula is rigid. In embodiments where the cannula is rigid, the implant is relatively flexible. The diameter of the cannula is about 0.001 inches to about 0.01 inches. In some embodiments, the diameter of the cannula is 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, or 0.01 inches.

[0241] In some implementations, implant delivery is achieved by applying a driving force at or near the proximal end of the implant. The driving force can be a tensile or pushing force applied to the distal end of the implant.

[0242] The device may include a seal or coating to prevent aqueous humor from flowing between the delivery device and / or its components when the device is in the eye. The seal helps prevent backflow. In some embodiments, the device is coated with a coating and a hydrophilic or hydrophobic agent. In some embodiments, one area of ​​the device is coated with a coating and a hydrophilic agent, and another area of ​​the device is coated with a coating and a hydrophobic agent. The delivery device may additionally include a seal between the various components constituting the device. The seal may contain a hydrophobic or hydrophilic coating between the sliding mating surfaces of the device components. When carried by the delivery device, the seal may be positioned near the implant. In some embodiments, the seal is present on at least one section of each of two devices machined to fit tightly against each other.

[0243] The delivery device can be configured to deliver multiple implants. In some such embodiments, the implants can be arranged in series within the device (or, for a number of implants greater than two, arranged in sequence).

[0244] In some embodiments, the delivery device has a substantially straight needle or cannula with a sharp tip and measured to be about 21-30 gauge (inclusive 23-25) and / or having an inner diameter of about 0.15-0.45 mm (inclusive 0.25-0.35 mm). The needle or cannula is operatively connected to a handpiece having an initiator, plunger, or actuator that, when operated, causes the implant to be ejected from the distal end of the delivery device. The implant is preferably pre-loaded into the delivery device by the manufacturer.

[0245] Procedure

[0246] In some implementations of delivering ocular implants, the implantation takes place in a closed chamber, which may or may not be viscoelastic.

[0247] Implants can be placed using an applicator such as a push rod, or they can be placed using a delivery device with energy stored in the device, such as the delivery device disclosed in U.S. Patent 7,331,984, issued February 19, 2008, the entire contents of which are incorporated herein by reference and form part of this specification and disclosure. In some embodiments, fluid can be injected via the applicator to create elevated fluid pressure at the tip of the implant, thereby facilitating implantation.

[0248] In one embodiment of the invention, the delivery device (or “applier”) used is similar to that used for placing a trabecular shunt through the trabecular mesh of the eye. Certain embodiments of such delivery devices are disclosed in U.S. Patent 7,331,984, issued February 19, 2008; U.S. Publication No. 2002 / 0133168, entitled “APPLICATOR AND METHODS FOR PLACING A TRABECULAR SHUNT FOR GLAUCOMA TREATMENT”; and U.S. Provisional Application No. 60 / 276,609, filed March 16, 2001, entitled “APPLICATOR AND METHODS FOR PLACING A TRABECULAR SHUNT FOR GLAUCOMA TREATMENT”, the entire contents of each of which are incorporated herein by reference and constitute a part of this specification and disclosure.

[0249] In one embodiment, the delivery device 2000 includes a handheld component, an elongated tip, a retainer, and an actuator, which are schematically shown in... Figure 6CThe handpiece 1000 has a distal end 1002 and a proximal end 1004. An elongated tip 1010 is attached to the distal end of the handpiece. The elongated tip has a distal portion and is configured to be placed through a corneal incision and into the anterior chamber of the eye. A retainer 1020 (e.g., an insertion cannula) is attached to the distal portion of the elongated tip. The retainer is configured to retain and release a drug delivery implant. An actuator 1040 is on the handpiece and actuates the retainer to release the drug delivery implant from the retainer. In one embodiment, the deployment mechanism within the delivery device includes a push-pull plunger.

[0250] In some embodiments, the retainer includes a clamp. In some embodiments, the device further includes a spring within a handheld component, configured to be loaded when the retainer holds the drug delivery implant, the spring being at least partially unloaded upon actuation of an actuator, allowing release of the drug delivery implant from the retainer. In various embodiments, the clamp includes a plurality of claws configured to apply a clamping force to at least a proximal portion of the drug delivery implant. The retainer may also include a plurality of flanges.

[0251] In some embodiments, the distal portion of the elongated tip is made of a flexible material. This could be a flexible wire. The distal portion may have a deflection range, preferably at approximately 45 degrees to the long axis of the handpiece. The delivery device may also include a flushing port in the elongated tip.

[0252] In some embodiments, the method includes using a delivery device comprising a handpiece having a distal and a proximal end, and an elongated tip attached to the distal end of the handpiece. The elongated tip has a distal portion and is configured to be placed through a corneal incision and into the anterior chamber of the eye. The device also includes a retainer attached to the distal portion of the elongated tip and an actuator on the handpiece, the retainer being configured to retain and release a drug delivery implant, the actuator actuating the retainer to release the drug delivery implant from the retainer.

[0253] The delivery instrument can be advanced through the insertion site in the cornea and forward, either anterior or posterior, to the anterior chamber angle and positioned at its base. Using the anterior chamber angle as a reference point, the delivery instrument can be further advanced in a generally posterior direction to drive the implant into the iris, medial to the anterior chamber angle.

[0254] Alternatively, based on the structure of the implant, the implant can be placed within the anterior chamber angle, presenting a curved shape to match the annular shape of the anterior chamber angle.

[0255] In some implementations, the implant can be positioned adjacent to tissue in the anterior chamber angle or iris tissue, with the advancement tube axially advanced toward the distal end of the delivery device. As the advancement tube advances, the implant is also advanced. Once the implant has been advanced through the tissue and is no longer within the lumen of the delivery device, the delivery device is retracted, leaving the implant in the ocular tissue.

[0256] Implant placement and implantation can be performed using a gonioscope or other conventional imaging equipment. In some implementations, the implant is advanced to the desired location using a delivery device by applying a continuous implantation force, tapping the implant into place with the distal portion of the delivery device, or a combination of these methods. Once the implant is in the desired position, it can be further secured by tapping with the distal portion of the delivery device.

[0257] Figure 9 An embodiment of a surgical method for implanting a drug delivery implant into the eye is shown, as described in the embodiments herein. A first incision or cut is formed through the conjunctiva and sclera 11 at a location posterior to the limbus 21 (i.e., posterior to the region of the sclera 11, where the opaque white sclera 11 begins to become the transparent cornea 12). In some embodiments, the first incision is located posterior to the limbus 21, including approximately 3 mm posterior to the limbus. In some embodiments, such as... Figure 9 As shown, the fracture is made so that surgical instruments can be inserted into the anterior chamber at a smaller angle (relative to the anterior-posterior axis). In other embodiments, the first fracture can be made to allow for instrument insertion at a larger angle (see, for example...). Figures 10-12 Furthermore, the first incision is made slightly larger than the width of the drug delivery implant. In one embodiment, a conventional ciliary body dissecting scraper can be inserted through the first incision into the supraciliary space to confirm the correct anatomical location.

[0258] A portion of the upper and lower surfaces of the drug delivery implant can be firmly grasped by a surgical tool (e.g., forceps) so that the tip of the implant can be properly oriented. The implant can also be secured by viscoelastic or mechanical interlocking with the walls of the delivery tube or implant delivery device. In one embodiment, the implant is oriented by making its longitudinal axis substantially coaxial with the longitudinal axis of the grasping end of the surgical tool. The drug delivery implant is positioned via a first slit.

[0259] The delivery instrument can be advanced from the insertion site across the eye to the anterior chamber angle and positioned near the scleral spur. Using the scleral spur as a reference point, the delivery instrument can be advanced further in a generally posterior direction to drive the implant into the ocular tissue just inside the scleral spur towards the iris.

[0260] Alternatively, depending on the structure of the implant, the shear edge of the implant insertion head can pass between the scleral spur and the ciliary body 16 at the posterior part of the trabecular meshwork.

[0261] The drug delivery implant can be continuously advanced posteriorly until a portion of its insertion tip and the first end of the catheter are positioned within the anterior chamber 20 of the eye. Thus, the first end of the catheter is placed in fluid communication with the anterior chamber 20 of the eye. 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 catheter is placed in fluid communication with the suprachoroidal space. Alternatively, the implant can be positioned near the tissue in the anterior chamber angle, and the advancement tube is axially advanced toward the distal end of the delivery device. As the advancement tube advances, the implant is also advanced. When the implant has been advanced through the tissue and is no longer within the lumen of the delivery device, the delivery device is retracted, leaving the implant in the ocular tissue.

[0262] Implant placement and implantation can be performed using a gonioscope or other conventional imaging equipment. In some embodiments, the implant is advanced to the desired location by applying a delivery instrument, tapping it into place using the distal portion of the delivery instrument, or a combination of these methods. Once the implant is in the desired position, it can be further secured by tapping with the distal portion of the delivery instrument.

[0263] In one embodiment, the drug delivery implant is sutured to a portion of the sclera 11 to assist in implant fixation. In another embodiment, the first break is subsequently sutured closed. It is understood that the sutures used to fix the drug delivery implant can also be used to close the first break. In another embodiment, the drug delivery implant is substantially held in place by the interaction of the outer surface of the implant with the tissues of the sclera 11 and ciliary body 16 and / or choroid 12 without sutures being made to the sclera 11. Furthermore, in one embodiment, the first break is small enough that it self-seals upon withdrawal of the surgical instrument after implantation of the drug delivery implant without the need for sutures.

[0264] As discussed herein, in some embodiments, the drug delivery implant additionally includes a shunt comprising a cavity configured to provide drainage between the anterior chamber 20 and the suprachoroidal space. After implantation, this drainage device can detach from the implant to form the ciliary body, providing permanent open communication of aqueous humor along the length of the shunt. Thus, aqueous humor is delivered to the suprachoroidal space, where it can be absorbed, and further reduction of intraocular pressure can be achieved.

[0265] In some implementations, it is desirable to deliver a drug delivery implant through the eye into the eye via a small incision at or near the limbus (ab interno).Figure 10 The overall geometry of the system allows the delivery device to incorporate distal curvature (e.g., Figure 8 (as shown) or distal angle (e.g. Figure 7 (As shown) is advantageous. In the former case, the drug delivery implant can be flexible to facilitate delivery along curvature or can be held more loosely to easily move along a precise path. In the latter case, the implant can be relatively rigid. The delivery device may include an implant actuation element (e.g., a push rod) that is flexible enough to pass through the distal angle.

[0266] In some embodiments, the implant and delivery device are advanced together through the anterior chamber 20 from the limbus 21 or nearby, across the iris 13, and through the ciliary muscle appendages until the drug delivery implant exit portion is located in the uveal-scleral outflow path (e.g., exposed to the suprachoroidal space defined between the sclera 11 and the choroid 12). Figure 10 A transocular implantation method is shown that can be used with a delivery device inserted above the corneal rim 21. In other embodiments (see, for example...) Figure 11 The break point can be positioned further posteriorly and closer to the limbus 21. In one embodiment, the break point is placed on the nasal side of the eye, with the drug delivery implant 40 implanted on the temporal side of the eye. In another embodiment, the break point can be on the temporal side, allowing the drug delivery implant to be implanted on the nasal side of the eye. In some embodiments, the operator simultaneously pushes the push rod while pulling the delivery device backward, maintaining the exit portion of the drug delivery implant in its position in the posterior region of the suprachoroidal space near the macula 34, such as... Figure 12 As shown. The implant is released from the delivery device and the delivery device is retrieved from the proximal end. The delivery device is removed from the anterior chamber through the rupture.

[0267] In some embodiments, it is preferable to implant a drug delivery implant through a fiber attachment area with continuous water outflow, thereby connecting the anterior chamber 20 to the uveal-scleral outflow path to reduce intraocular pressure in glaucoma patients. In some embodiments, a drug delivery implant may be delivered through a small opening in the limbus 21 using an internally penetrating device.

[0268] In several embodiments, a minimally invasive method for implanting a drug delivery implant is provided. In several such embodiments, external techniques are utilized. In some embodiments, the techniques are 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, this implant facilitates the removal of fluid from a first location while providing drug delivery. In some embodiments, the implant delivers fluid from the anterior chamber to the suprachoroidal space, which facilitates the removal of fluid (e.g., aqueous humor) from the anterior chamber and reduces pressure increases within the anterior chamber.

[0269] Figure 8 A meridional section of the anterior segment of the human eye is shown, and another embodiment of the delivery device 38 is schematically illustrated, which can be used in conjunction with embodiments of the drug delivery implant described herein. Figure 8 Arrow 82 shows the fibrous attachment area of ​​the ciliary muscle 84 to the sclera 11. The ciliary muscle 84 extends together with the choroid 28. The suprachoroidal space is the interface between the choroid 28 and the sclera 11. Other structures in the eye include the lens 26, cornea 12, anterior chamber 20, iris 13, and Schlem's canal 22.

[0270] The delivery device / implant assembly can pass between the iris 13 and the cornea 12 to reach the iridocorneal angle. Therefore, in some embodiments, the height of the delivery device / shunt assembly ( Figure 8 The dimension 90 in the middle is less than about 3 mm, and in other embodiments it is less than 2 mm.

[0271] The suprachoroidal space between the choroid 28 and the sclera 11 typically forms an angle 96 of approximately 55° with the optical axis 98 of the eye. In addition to the height requirements described in the preceding paragraph, this angle is a feature that must be considered in the geometric design of the delivery device / implant assembly.

[0272] The overall geometry of the drug delivery implant system results in the delivery device 38 including a distal curvature of 86 (e.g., Figure 8 As shown), distal angles or combinations thereof are advantageous. Expected distal curvature ( Figure 9 This allows for a smoother passage through the cornea or the scleral tear at the limbus. In this embodiment, the drug delivery implant can be curved or flexible. Alternatively, the drug delivery implant can be mounted on the straight segment of the delivery device, at the distal end of the "elbow" or angle. In this case, the drug delivery implant can be straight and relatively non-flexible, and the delivery device can include a delivery mechanism that is flexible enough to advance through the angle. In some embodiments, the drug delivery implant can be a rigid tube, provided that the implant is not longer than the length of the distal segment.

[0273] In some embodiments, the distal curvature 86 of the delivery device 38 may be characterized as a radius between about 10 and 30 mm, and in some embodiments about 20 mm. In one embodiment, the distal angle of the delivery device, having a straight portion and a single angle near the distal end, may be characterized as about 90 to 170 degrees relative to the axis of the proximal segment 94 of the delivery device. In other embodiments, the angle may be from about 145 to about 170 degrees. The angle includes a smaller radius of curvature at the "elbow" to allow a smooth transition from the proximal segment 94 to the distal segment 92 of the delivery device. In some embodiments, the length of the distal segment 92 may be about 0.5 to 7 mm, and in some embodiments about 2 to 3 mm.

[0274] In some embodiments, a viscoelastic or other fluid is injected into the suprachoroidal space to form a chamber or pouch between the choroid and sclera, into which a drug delivery implant can enter. This pouch exposes more of the choroidal and scleral tissue, providing lubrication and protection to the tissue during implantation, and in embodiments where the drug delivery implant includes a shunt, it increases uveal-scleral outflow, resulting in lower intraocular pressure (IOP). In some embodiments, a 25 or 27G cannula is used to inject the viscoelastic material, for example, through a slit in the ciliary muscle appendage or through the sclera (e.g., from the lateral aspect of the eye). The viscoelastic material can also be injected through the implant itself before, during, or after implantation.

[0275] In some implementations, a hypertonic agent is injected into the suprachoroidal space. This injection can delay IOP deterioration. Therefore, by temporarily reducing choroidal absorption, low intraocular pressure can be avoided in the acute postoperative period. Hypertonic agents can be, for example, glucose, albumin, or hypaque. TM Mediators, glycerin, or poly(ethylene glycol). As the patient heals, the hyperosmolar agent can break down or wash out, resulting in a stable and acceptable low IOP and avoiding transient low intraocular pressure.

[0276] In some embodiments, the distal portion of the delivery device is needle-like, allowing it to create an opening in the sclera of the eye and permitting the implant to be ejected from the distal end of the device by pushing or pressing the plunger or actuator on the handpiece, thereby removing the implant (e.g.) Figures 4A-4C The implant is placed directly into the vitreous cavity of the eye. In this embodiment, a straight needle or cannula is preferably used to deliver the implant.

[0277] Controlled drug release

[0278] The drug delivery implants described herein are designed to contain drugs and to deliver drug elution from the implant in a controlled manner over a prolonged period, based on the design of the various components of the implant. The various components of the implant, the physical properties of the implant, the location of the implant in the eye, and the composition of the drug work together to produce the desired drug release profile.

[0279] As described above, in various embodiments, the drug delivery implant is made of one or more biodegradable materials that degrade after implantation into the eye and delivery of all or substantially all of the drug, for example, through bio-erosion, bioreabsorption, or bioabsorption. Such materials can be permeable, semi-permeable, or impermeable for the drug delivered from the device. The material can be formulated or manufactured to be porous or substantially non-porous. Suitable biodegradable materials may optionally possess one or more other physical properties, such as flexibility, hydrophilicity, hydrophobicity, elasticity, etc.

[0280] In some embodiments, the implant is designed to control the rate at which a drug is released from the device. In some such embodiments, the outer shell of the device substantially entirely controls the rate of drug delivery. In other such embodiments, the outer shell controls a portion of the drug delivery rate, with the remainder controlled by a drug-permeable membrane, which may be part of one or more membrane-cap systems (such as drug delivery elements as described above). In other embodiments, one or more membrane-cap systems substantially or entirely control the rate of drug delivery.

[0281] Biodegradable materials suitable for manufacturing implants and their components include, but are not limited to, the following substances: poly(ester), poly(ester amide) (PEA), poly(ester carbonate) (PEC), polylactic acid (PLA), poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), poly(DL-lactic acid) (PDLLA), polyglycolic acid (PGA), polycaprolactone (PCL), copolymers such as polylactic acid-glycolic acid (PLGA), poly(hydroxyalkyl ester), poly(3-hydroxybutyrate) (PHB), and PH copolymers with 3-hydroxyvalerate. B(PHBV), poly(propylene fumarate) (PPF), poly(acid anhydride) (PAA), poly(butylene succinate) (PBS), poly(vinyl succinate) (PES), poly(hydroxyalkanoate) (PHA), poly(cyanoacrylate) (PCA), polyacetal, polyorthoester (POE), polycarbonate including poly(trimethylene carbonate) (PTMC), polyphosphazene, polyphosphate, and blends, copolymers and combinations thereof; and natural polymers, including but not limited to modified poly(sugars), such as starch, cellulose and chitosan.

[0282] The material may be coated on the inner and / or outer sides, on all or part of either side. The coating can be used for any and all purposes, including but not limited to: altering the elution rate of a drug through the material (accelerating or decelerating the elution rate), altering the degradation rate of the material (accelerating or decelerating the degradation rate), altering water resistance or permeability (increasing or decreasing water resistance or permeability), or other properties. The coating is preferably biodegradable.

[0283] The coating can be any suitable material, including but not limited to: poly(lactic acid), polyvinyl acetate, poly(lactic acid-co-glycolic acid), poly(D,L-lactic acid), poly(D,L-lactic acid-co-trimethylene carbonate), collagen, heparinized collagen, poly(caprolactone), poly(glycolic acid), and / or other polymers or copolymers. Suitable atomic or inorganic materials may also be used. As described above, the various materials, coatings, and mechanisms used to adjust the elution profile of the drug from the device can be applied to any type of implant disclosed herein, including those for intraocular placement and those for placement within the lacrimal punctum. Similarly, bioerodible materials for the body of the implant can be used for implants for intraocular placement and implants for placement within the lacrimal punctum. In many embodiments, the ability of the implant to be substantially or completely erodible, whether placed intraocularly or within the lacrimal punctum, is advantageous. In some embodiments, implant erosion occurs only after all or substantially all of the drug has been released from the implant. In some embodiments, implant erosion overlaps with at least a portion of the drug release. In some implementations, implant erosion occurs simultaneously with drug release, such that the implant is substantially eroded when all or substantially all of the drug has been released from the implant.

[0284] In some ocular conditions, treatment may require a defined kinetic profile for drug delivery to the eye, such as zero-order release or pseudo-zero-order release. As can be understood from the discussion of the various embodiments above, the ability to adjust the rate of drug release from the implant can be similarly used to achieve the desired kinetic profile. For example, the composition of the shell and any polymer coating can be manipulated to provide a specific kinetic profile for drug release. Furthermore, the design of the implant itself (including the thickness of the shell material) and the presence and composition of any caps (including drug-release elements) are ways to provide means of creating a specific drug release profile. Similarly, the use of PLGA copolymers and / or other controlled-release materials and excipients can provide a specific kinetic profile for complex drug release. In some embodiments, zero-order release of the drug can be achieved by manipulating any of the above features and / or variables, individually or in combination.

[0285] In some embodiments, in conjunction with controlled release of the drug to the target tissue, a dose of drug (or multiple drugs) over time is desirable. Therefore, in some embodiments, the total drug load delivered to the target tissue over the lifetime of the implant is about 10 to about 1000 μg. In some embodiments, the total drug load is about 100 to about 900 μg, about 200 to about 800 μg, about 300 to about 700 μg, or about 400 to about 600 μg. In some embodiments, the total drug load is about 10 to about 300 μg, about 10 to about 500 μg, or about 10 to about 700 μg. In other embodiments, the total drug load is about 200 to about 500 μg, 400 to about 700 μg, or about 600 to about 1000 μg. In still other embodiments, the total drug load is 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 load is about 500 to about 700 μg, about 550 to about 700 μg, or about 550 to about 650 μg, including 575, 590, 600, 610, and 625 μg. It should be understood that in some embodiments, other ranges of drugs that are close to, overlap with, or include the ranges listed above are also used.

[0286] Similarly, in other embodiments, controlled drug delivery is calculated based on the elution rate of the drug from the implant. In some such embodiments, the achieved drug elution rate is about 0.05 μg / day to about 10 μg / day. In other embodiments, the achieved elution rate is about 0.05 μg / day to about 5 μg / day, about 0.05 μg / day to about 3 μg / day, or about 0.05 μg / day to about 2 μg / day. In other embodiments, the achieved elution rate is about 2 μg / day to about 5 μg / day, about 4 μg / day to about 7 μg / day, or about 6 μg / day to about 10 μg / day. In other embodiments, the achieved elution rate is about 1 μg / day to about 4 μg / day, about 3 μg / day to about 6 μg / day, or about 7 μg / day to about 10 μg / day. In other embodiments, the achieved elution rate is from about 0.05 μg / day to about 1 μg / day, including 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or μg / day. It should be understood that in some embodiments, other ranges of drugs that are close to, overlap with, or include the ranges listed above are also used.

[0287] Alternatively, or in addition to one or more of the parameters described above, drug release from the implant can be controlled based on the desired drug concentration at the target tissue. In some embodiments, the desired drug concentration at the target tissue is about 1 nM to about 100 nM. In other embodiments, the desired drug concentration at the site of action is about 10 nM to about 90 nM, about 20 nM to about 80 nM, about 30 nM to about 70 nM, or about 40 nM to about 60 nM. In still other embodiments, the desired drug concentration at the site of action is about 1 nM to about 40 nM, about 20 nM to about 60 nM, about 50 nM to about 70 nM, or about 60 nM to about 90 nM. In still other embodiments, the desired drug concentration at the site of action is about 1 nM to about 30 nM, about 10 nM to about 50 nM, about 30 nM to about 70 nM, or about 60 nM to about 100 nM. In some embodiments, the required drug concentration at the site of action is from about 45 nM to about 55 nM, including 46, 47, 48, 49, 50, 51, 52, 53, and 54 nM. It should be understood that in some embodiments, other ranges of drugs that are close to, overlap with, or include the ranges listed above are also used.

[0288] Drug

[0289] Therapeutic agents used in conjunction with drug delivery implants may include, alone or in combination, one or more of the drugs provided below. The drugs used may also be prodrugs, equivalents, derivatives, or analogs of one or more of the drugs provided below. Drugs may include, but are not limited to, pharmaceutical agents, including antiglaucoma drugs, ocular agents, antibacterial agents (e.g., antibiotics, antiviral agents, antiparasitic agents, antifungal agents), anti-inflammatory agents (including steroids or nonsteroidal anti-inflammatory drugs), biological agents (including hormones, enzymes, or enzyme-related components), antibodies or antibody-related components, oligonucleotides (including DNA, RNA, short interfering RNA, antisense oligonucleotides, etc.), DNA / RNA vectors, viruses (wild-type or genetically modified) or viral vectors, peptides, proteins, enzymes, extracellular matrix components, and living cells configured to produce one or more biological components. The use of any particular drug is not limited to its primary action or the therapeutic indication or manner of use approved by a regulatory agency. Drugs may also include compounds or other materials that reduce or treat one or more side effects of another drug or therapeutic agent. Because many drugs have more than one mode of action, any particular drug listed under any one therapeutic category represents only one possible use of the drug and is not intended to limit its use to use with ophthalmic implant systems.

[0290] As described above, the therapeutic agent can be combined with any number of excipients known in the art. In addition to the biodegradable polymeric excipients discussed above, other excipients may be used, including but not limited to benzyl alcohol, ethyl cellulose, methyl cellulose, hydroxymethyl cellulose, cetyl alcohol, croscarmellose sodium, dextran, glucose, fructose, gelatin, glycerol, monoglycerides, diglycerides, kaolin, calcium chloride, lactose, lactose monohydrate, maltodextrin, polysorbate, pregelatinized starch, calcium stearate, magnesium stearate, silica, corn starch, talc, etc. The total content of one or more excipients may be as low as about 1%, 5%, or 10%, and in other embodiments, the total content may be as high as 50%, 70%, or 90%.

[0291] Examples of drugs can include various antisecretory agents; antimitotic agents and other antiproliferative agents, particularly antiangiogenic agents such as angiostatin, anecoxitol acetate, thromboretin, VEGF receptor tyrosine kinase inhibitors, and anti-vascular endothelial growth factor (anti-VEGF) drugs, such as ranibizumab (e.g.) ) and bevacizumab (e.g. ), phenagatanib (e.g.) ), Apsiber (e.g.) ), anti-PDGF (e.g.) ), latanosprotene bunod (e.g.) ), netasurdil AR-11324 (e.g.) The following are prohibited: olopatadine, sunitinib, and sorafenib, as well as any of the known small molecules and transcription inhibitors with anti-angiogenic effects; known ophthalmic drugs, including: glaucoma agents such as adrenergic antagonists, including, for example, β-blockers such as atenolol, propranolol, metenolol, betalol, carteolol, levobetaolol, levobenoolol, and timolol; adrenergic agonists or sympathomimetic agents such as adrenaline, dipiformin, clonidine, adaloride, and brimonidine; parasympathomimetic agents or cholinergic agonists such as pilucarpine, carbadylcholine, diethoxyphosphatidylcholine iodine, and physostigmine, salicylates, acetylcholine chloride, physostigmine, diisopropyl fluorophosphate, and demecarium bromide. bromide; muscarinic alkaloids; carbonic acid dehydratase inhibitors, including local and / or systemic agents such as acetazolamide, brinzolamide, dazolamide and metronidazole, esoxazolamide, sulfadiazine and diclofenac; mydriatic-cycloplegic agents such as atropine, cyclopenton, succinylcholine, homatropine, phenformin, scopolamine and tropicamide; prostaglandins such as prostaglandin F2α, antiprostaglandins, prostaglandin precursors or prostaglandin analogs such as bimatoprost, latanoprost, travoprost and unoprostone.

[0292] Other examples of medications may include anti-inflammatory agents, including, for example, glucocorticoids and corticosteroids, such as betamethasone, cortisone, dexamethasone, dexamethasone 21-phosphate, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, prednisolone, fluocinolone, clotiprednisolone, medroxyprogesterone acetate, fluocinolone acetonide, triamcinolone acetonide, fluocinolone acetonide, beclomethasone, budesonide, flunisolone, fluocinolone acetonide, fluticasone, hydrocortisone, hydrocortisone acetate, clotiprednisolone, limexole. Nonsteroidal anti-inflammatory agents, including, for example, diclofenac, flurbiprofen, ibuprofen, bromofenac, naprofen, and ketorolac, salicylates, indomethacin, ibuprofen, naxopren, piroxicam, and nabuprofen; anti-infective or antibacterial agents, such as antibiotics, including, for example, tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, brevicin, cephalexin, oxytetracycline, chloramphenicol, rifampin, ciprofloxacin, tobramycin, gentamicin, erythromycin, penicillin, sulfonamides, sulfadiazine, and sulfacetamide. Sulfadiazine, sulfamethoxazole, furacilin, sodium propionate, aminoglycosides such as gentamicin and tobramycin; fluoroquinolones such as ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin; bacitracin, erythromycin, closporine, neomycin, polymyxin B, bacitracin, trimethoprim, and sulfacetamide; antifungal drugs such as amphotericin B and miconazole; antiviral drugs such as idoxuridine, triflumuline, acyclovir, ganciclovir, and interferon; antifungal drugs; immunomodulators. Drugs such as antihistamines, including sodium cromoglycate, azoline, dexamethasone, chlorpheniramine, cetirizine, pyramine, and propiramide; antihistamines such as azelastine, emestraline, and levocabastine; immunomodulatory drugs (e.g., vaccines, immunostimulants, and / or immunosuppressants); MAST cell stabilizers such as sodium cromoglycate, ketotifen, lodoxa, nedocrimil, olopatadine, and pemirolast; and ciliary body ablation agents. Body ablative agents, such as gentamicin and cidofovir; and other ophthalmic agents, such as verteporfen, promecaine, tetracaine, cyclosporine, and pilocarpine; inhibitors of cell surface glycoprotein receptors; decongestants such as phenylephrine, naphazoline, and tetrahydrohydrazine; lipids or hypotensive lipids; dopaminergic agonists and / or antagonists, such as quinpyrrole, fenodopam, and isopause; vasodilators; antihypertensive agents; angiotensin-converting enzyme (ACE) inhibitors; angiotensin-1 receptor antagonists, such as olmesartan; microtubule inhibitors; molecular motor (dynein and / or kinase) inhibitors; actin cytoskeleton regulators, such as cytochalasin, latrunculin, swinholide A, ethacrylic acid, H-7, and Rho kinase (ROCK) inhibitors; remodeling inhibitors; extracellular matrix regulators, such as tert-butylhydroquinolones and AL-3037A;Adenosine receptor agonists and / or antagonists, such as N-6-cyclohexyladenosine and (R)-phenylisopropyladenosine; serotonin agonists; hormones, such as estrogens, estradiol, progesters, progesterone, insulin, calcitonin, parathyroid hormone, peptides, and vasopressin-hypothalamic releasing factor; growth factor antagonists or growth factors, including, for example, epidermal growth factor, fibroblast growth factor, platelet-derived growth factor or their antagonists (such as those disclosed in U.S. Patent 7,759,472 or U.S. Patent Applications Nos. 12 / 465,051, 12 / 564,863 or 12 / 641,270, the entire contents of which are incorporated herein by reference), β-transforming growth factor, growth hormone, fibronectin, connective tissue growth factor, bone morphogenetic protein (BMP); cytokines, such as interleukins, CD44, cocrine, and serum amyloid proteins, such as serum amyloid A.

[0293] Other therapeutic agents may include neuroprotective agents such as lubezole, nimodipine, and related compounds, and include flow enhancers such as dazolamide or betalol; compounds that promote blood oxygenation such as erythropoietin; sodium channel blockers; calcium channel blockers such as nivardipine or lomerizine; glutamate inhibitors such as memantine, nitromemantine, riluzole, dextromethorphan, or guanidine; acetylcholinesterase inhibitors such as galantamine; hydroxylamine or its derivatives, such as the water-soluble hydroxylamine derivative OT-440; synaptic modulators such as hydrogen sulfide compounds containing flavonoid glycosides and / or terpenoids, such as ginkgo; and neurotrophic factors. Examples of cytokines include glial cell-derived neurotrophic factor (GGF) and brain-derived neurotrophic factor (BDNF); IL-6 protein family cytokines, such as ciliary neurotrophic factor (CNF) or leukemia inhibitory factor (LEF); compounds or factors affecting nitric oxide levels, such as nitric oxide, nitroglycerin, or nitric oxide synthase inhibitors; cannabinoid receptor agonists, such as WIN55-212-2; free radical scavengers, such as methoxy polyethylene glycol thioester (MPDTE) or methoxy polyethylene glycol thiolate coupled with EDTA methyltriester (MPSEDE); and antioxidants, such as astaxanthin, dithiolethione, vitamin E, or metallocarboxylic acid (MCCA). Locorrole (e.g., iron, manganese, or gallium); compounds or factors involved in oxygen homeostasis, such as neuroglobin or cytoglobin; inhibitors or factors affecting mitochondrial division or fission, such as Mdivi-1 (a selective inhibitor of dynein-associated protein 1 (Drp1)); kinase inhibitors or modulators, such as the Rho-kinase inhibitor H-1152 or the tyrosine kinase inhibitor AG1478; compounds or factors affecting integrin function, such as the β1-integrin activation antibody HUTS-21; N-acyl-ethanolamine and its precursors, N-acyl-ethanolamine phospholipids; glucagon-like peptide-1 receptor Stimulants (e.g., glucagon-like peptide-1); polyphenol-containing compounds, such as resveratrol; chelating compounds; apoptosis-associated protease inhibitors; compounds that reduce the synthesis of new proteins; radiotherapy agents; photodynamic therapy agents; gene therapy agents; genetic modulators; autoimmune modulators that prevent nerve or partial nerve damage (e.g., demyelination), such as glatimir; myelin inhibitors, such as anti-NgR blocking protein, NgR(310)ecto-Fc; other immunomodulators, such as FK506 binding protein (e.g., FKBP51); and dry eye medications, such as cyclosporine, cyclosporine A, analgesics, and sodium hyaluronate.

[0294] Other treatment options include: other beta-blockers such as acebutolol, atenolol, bisoprolol, carvedilol, esmolol, labetalol, nadolol, pentbuprofen, and indrolol; other corticosteroids and nonsteroidal anti-inflammatory drugs such as pirin, betamethasone, cortisone, diflunisal, ethdoleacetic acid, fenprofen, fludrocortisone, flurbiprofen, hydrocortisone, ibuprofen, indomethacin, ketoprofen, meclofenlinoline, mefenamic acid, meloxicam, methylprednisolone, nabumetone, naproxen, oxapazol, prednisolone, piroxicam, disalicylate, sulindac, and tometetin; COX-2 inhibitors such as celecoxib, rofecoxib, and vardicoxib; and other immunomodulators such as interleukin and adalimumab. Azathioprine, baribizumab, dalizumab, etanercept Hydroxychloroquine, infliximab Leflunomide, methotrexate, mycophenolate mofetil, and sulfasalazine; other antihistamines, such as loratadine, desloratadine, cetirizine, diphenhydramine, chlorpheniramine, dextromethorphan, chlormastine, cyproheptadine, fexofenadine, hydroxyzine, and promethazine; other anti-infectives, such as aminoglycosides, such as amikacin and streptomycin; antifungal agents, such as amphotericin B, caspofungin, clotrimazole, fluconazole, itraconazole, ketoconazole, voriconazole, terbinafine, and nystatin; antimalarial agents, such as chloroquine, atovaquine, mefloquine, primaquine, quinidine, and quinine; antimycobacterial agents, such as ethambutol, isoniazid, pyrazinamide, rifampin, and rifabutin; antiparasitic agents, such as albendazole, mebendazole, and thiobenzimidazole. Metronidazole, fenvalerate, atorvaquinone, iodoquinolone, ivermectin, paromomycin, praziquantel, and trimethoprim; other antiviral agents, including anti-CMV or anti-herpes agents, such as acyclovir, cidofovir, famciclovir, ganciclovir, valacyclovir, valganciclovir, vidarabine, trifluorouracil, and sodium phosphonate; protease inhibitors, such as ritonavir, saquinavir, lopinavir, indinavir, atazanavir, ampravir, and nelfinavir; nucleotide / nucleoside / non-nucleoside reverse transcriptase inhibitors, such as abacavir, ddI, 3TC, d4T, ddC, tenofovir, emtricitabine, delavudine, efavirenz, and nevirapine; other antiviral agents, such as interferon, ribavirin, and trifluorouracil; other antibacterial agents, This includes carbapenems, such as ertapenem, imipenem, and meropenem; cephalosporins, such as cefadroxil, cefazolin, cefdinir, cefotaxime, cefalexin, cefaclor, cefepime, cefoperazone, cefotaxime, cefotetan, cefoxitin, cefpodoxime, cefprozil, cefpodoxime, cefbutan, cefazolin, ceftriaxone, cefuroxime, and loracapar; other macrolides and ketolides, such as azithromycin, clarithromycin, erythromycin, and telithromycin; penicillins (with and without clavulanate), including amoxicillin, ampicillin, piamphocycillin, dicloxacillin, nafcillin, oxacillin, piperacillin, and ticarcillin; tetracyclines, such as doxycycline, minocycline, and tetracycline; and other antibacterial drugs, such as ammonia. Triamcinolone, chloramphenicol, clindamycin, linezolid, nitrofurantoin, and vancomycin; alpha-blockers such as doxazosin, prazosin, and terazosin; calcium channel blockers such as amlodipine, benprodil, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, and verapamil; other antihypertensive drugs such as clonidine, diazoxide, fenodoprine, hydralazine, minoxidil, sodium nitroprusside, phenoxybenzamine, eprostol, tolazoline, treprostol, and nitrates; anticoagulants, including heparin and heparin-like substances such as heparin, dalteparin, enoxaparin, tinzaparin, and fondaparinux; other anticoagulants such as hirudin, aprotinin, argatroban, bivalirudin, disiludin, lepirudine, warfarin, and cimetidine;Antiplatelet agents, such as abciximab, clopidogrel, dipyridamole, optifibatide, ticlopidine, and tirofiban; prostaglandin PDE-5 inhibitors and other prostaglandin agents, such as alprostadil, carboprost, sildenafil, tadalafil, and vardenafil; thrombin inhibitors; antithrombotic agents; antiplatelet aggregation agents; thrombolytic and / or fibrinolytic agents, such as alteplase, compound plasminogen activator, reteplase, streptokinase, tenecteplase, and urokinase; antiproliferative agents, such as sirolimus, tacrolimus, everolimus, zotamoxetine, paclitaxel, and mycophenolate mofetil; hormone-related agents, including levothyroxine, fluorometholone, methyltestosterone, nandrolone, oxandrolone, testosterone, estradiol, estrone, piperazine estradiol thioester, clomiphene, gonadotropins, hydroxyprogesterone, levonorgestrel, medroxyprogesterone, and methylprogesterone acetate. Pregnancy-progesterone, mifepristone, norethindrone, oxytocin, progesterone, raloxifene, and tamoxifen; antineoplastic drugs, including alkylating agents such as carmustine, lomustine, melphalan, cisplatin, fluorouracil, and procarbazine; antibiotic-like agents such as bleomycin, daunorubicin, doxorubicin, idarubicin, mitomycin, and procainoxine; antiproliferative agents (such as 1,3-cis-retinoic acid, 5-fluorouracil, paclitaxel, and rapamycin). Mitomycin C and cisplatin); antimetabolites such as cytarabine, fludarabine, hydroxyurea, mercaptopurine, and 5-fluorouracil (5-FU); immunomodulators such as interleukin, imatinib, rituximab, and tosimomab; mitotic inhibitors such as docetaxel, etoposide, vincristine, and vinblastine; radioactive agents such as strontium-89; and other antitumor agents such as irinotecan, topotecan, and mitotane.

[0295] The drug delivery plant-borne drug can be in any form that can be reasonably retained within the device, resulting in controlled elution of resident drugs or multiple drugs over a period of several years. Some embodiments use drugs readily soluble in intraocular fluid, while others use drugs partially or slightly soluble in intraocular fluid. It should be emphasized again that the term "drug" as used herein includes active drugs, their prodrugs and salts, and drugs otherwise modified for storage, membrane permeability, stability, etc. Drugs stored in the device may include excipients, stabilizers, agents that alter elution or dissolution rates, and any other materials or agents that contribute to long-term drug stability and desired elution.

[0296] For example, the therapeutic agent can be in any form, including but not limited to compressed pellets, solids, capsules, various granules, liquids, oils, gels, suspensions, slurries, emulsions, etc. In some embodiments, the drug particles are in the form of microcapsules (e.g., microtablets), fine powders, or slurries, each having fluid-like properties, which allows for reloading by injecting into the lumen in the same manner as liquids or oils. In some embodiments, loading and / or reloading of the device is performed using a syringe / needle, through which the therapeutic agent is delivered. In some embodiments, they are delivered using needles of about 23 to about 32 gauge, including 23-25, 25-27, 27-29, 29-30, 30-32 gauges, and their overlapping ranges. In some embodiments, the needles are 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32 gauge.

[0297] When more than one drug is needed to treat a specific pathology or when a second drug is administered to counteract the side effects of the first drug, some implementations may use two identical forms of the drug. In other implementations, different forms of the drug may be used. Similarly, if one or more drugs use adjuvants, excipients, or auxiliary compounds, for example to enhance stability or adjust elution profiles, these compounds or compounds may be in any form compatible with the drug and may be reasonably retained in the implant.

[0298] In some embodiments, treating a specific pathology with medication delivered by an implant may not only cure the pathology but may also cause undesirable side effects. In some cases, the delivery of certain medications may treat the pathological condition but indirectly increase intraocular pressure. For example, steroids may have such an effect. In some embodiments, a drug delivery implant that delivers steroids to target tissues of the eye may cause an undesirable increase in intraocular pressure. In such embodiments, the drug delivery implant may include a shunt feature that reduces the undesirable increase in intraocular pressure by draining excess aqueous humor from the anterior chamber. Thus, in some embodiments, an implant that serves as both a drug delivery device and a shunt can be used to deliver therapeutic agents while draining accumulated fluid, thereby mitigating the side effects of the medication.

[0299] It is understood that the embodiments described herein may include drugs mixed or compounded with biodegradable materials, excipients, or other agents that alter drug release characteristics. Preferred biodegradable materials include those mentioned above, including copolymers of lactic acid and glycolic acid, also known as poly(lactic-co-glycolic acid) or PLGA. Those skilled in the art will understand that while some disclosures herein specifically describe the use of PLGA, other suitable biodegradable materials may be used in place of or in combination with PLGA in these embodiments. It is also understood that in some embodiments described herein, the drug positioned in the implant cavity is not compounded or mixed with any other compound or material to maximize the drug volume within the cavity.

[0300] In some embodiments, it may be necessary to provide a specific drug release rate from the PLGA copolymer or other polymeric material. Since the rate of drug release from a polymer is related to the degradation rate of that polymer, controlling the degradation rate provides a means of controlling the drug delivery rate. Variations in the average molecular weight of the polymer or copolymer chains constituting the PLGA copolymer or other polymer can be used to control the degradation rate of the copolymer, thereby achieving the desired duration of therapeutic delivery to the eye or other release profiles. In some other embodiments employing copolymers, the biodegradation rate of the copolymer can be controlled by changing the proportion of monomers or oligomers in the copolymer. Other embodiments utilize a combination of changing the average molecular weight of the copolymer components and changing the copolymer composition to obtain the desired biodegradation rate.

[0301] Example

[0302] In many configurations of the bioresorbable implants disclosed herein, the concentration of the protein drug within the device will decrease over time during use. Since the elution rate is proportional to the concentration gradient between the inside and outside of the device, the elution rate will also decrease over time. In several embodiments, to regulate this event, elution characteristics and initial protein drug concentrations are selected such that the therapeutic elution rate will still be delivered over an extended period of time (e.g., 3, 6, 9 months or longer).

[0303] Figure 21A and Figure 21B Predicted elution data related to implant elution were depicted according to several embodiments, wherein the initial protein concentration in the device was 300 mg / mL, the initial effective protein load was 300 μg, the total elution feature area and wall thickness were adjusted to achieve an initial elution rate of 14 μg / week through the elution feature, and the size of the elution feature was fixed. Under this assumption, as the drug eluted through the elution feature, the drug-protein concentration in the device decreased by approximately nine-fold over six months. Figure 21AAnd the rate also decreases over time. Figure 21B ).

[0304] 21B The erosion rate can be determined by selecting the chemical structure of the bioresorbable material. The bioresorbable material can be determined to be absorbable over a number of days, weeks, or months. The chemical bonds in the bioresorbable material can be water-degradable (polymers, copolymers, and oligomers of glycolide, dl-lactic acid, l-lactic acid, dioxane, esters, carbonates, and trimethylene carbonate); or enzyme-degradable (e.g., peptides, amides, and polyetheramides); or poly(alkyd), poly(orthocarbonate), poly(anhydride), poly(lactone), poly(amino acid), poly(carbonate), and poly(phosphonate), or any combination thereof.

[0305] Figures 22A-22B Drug elution data according to several embodiments described herein are presented. Figure 21A The rate of drug elution from the implant was depicted over time, in which the tube was an approximately 1-inch long LDPE segment with a 0.040-inch (1 mm) ID, the hydrogel stopper was polymerized from 5% acrylamide and 0.14% methylenebisacrylamide, the length of the hydrogel stopper was trimmed to approximately 1-3 mm, the protein solution was bovine serum albumin (e.g., an alternative to ranibizumab) initially at 150 mg / ml, and approximately 1 cm of each tube was filled with a BSA solution with an effective load of approximately 1200 μg.

[0306] Figure 22B The rate of drug elution from the implant was depicted over time, in which the tube was a 350×500 μm PLG 8523 segment approximately 1 inch long, the hydrogel stopper was polymerized from 7.5% acrylamide and 0.21% methylenebisacrylamide, the length of the hydrogel stopper was trimmed to approximately 1-3 mm, the protein solution was an initial 40 kD FITC-glucan (e.g., an alternative to ranibizumab) at 200 mg / ml, and approximately 1.5 cm of each tube was filled with an effective load of approximately 300 μg of FITC-glucan solution.

[0307] While certain embodiments of this disclosure have been described, these embodiments are presented by way of example only and are not intended to limit the scope of this disclosure. In fact, the novel methods, systems, and devices described herein can be embodied in a variety of other forms. For example, an embodiment of an implant shown or described may be combined with an embodiment of another shunt shown or described. Furthermore, the aforementioned implants can be used for other purposes. For example, the implants can be used to drain fluid from the anterior chamber to other locations of the eye or outside the eye. Additionally, various omissions, substitutions, and changes can be made to the form of the methods, systems, and devices described herein, without departing from the spirit of this disclosure.

[0308] One or more of the features shown in the accompanying drawings and / or described herein may be rearranged and / or combined into a single component or embodied in multiple components. Additional components may also be added. While certain exemplary embodiments have been described and illustrated in the accompanying drawings, it should be understood that these embodiments are merely illustrative and not restrictive. Therefore, the invention is not limited to the specific structures and arrangements shown and described, as various other modifications will be conceived by those skilled in the art based on this disclosure.

[0309] The various operations described above can be performed by any suitable device capable of performing the operations, such as various hardware and / or software components, circuits and / or modules. Typically, any operation shown in the figure can be performed by a corresponding functional device capable of performing the operation.

[0310] The methods disclosed herein include one or more steps or actions for implementing the methods. The method steps and / or actions may be interchanged with each other without departing from the scope of the claims. In other words, unless a specific order of steps or actions is specifically specified, the order and / or use of specific steps and / or actions may be modified without departing from the scope of the claims. The method steps and / or actions disclosed herein may be performed in combination with each other, and the steps and / or actions may be further divided into additional steps and / or actions.

[0311] It should be understood that the claims are not limited to the precise configurations and components described above. Various modifications, alterations, and variations can be made to the arrangement, operation, and details of the methods and apparatus described above.

Claims

1. An ocular implant configured for implantation into an eye of a subject, comprising: an elongated shell comprising a bioerodible material and shaped to define a single continuous lumen extending from a proximal end to a distal end; a plug-drug mixture positioned within the lumen, the mixture comprising a drug at least partially dispersed or mixed within an inner plug, wherein the plug-drug mixture fills the entire lumen, a first orifice and a second orifice positioned generally opposite the first orifice; wherein the drug is configured to pass through the inner plug to control elution of the drug through at least one of the orifices; and wherein the implant is positioned in a vitreous chamber.

2. The ocular implant of claim 1, wherein, the orifices are positioned near the distal end of the shell, wherein the orifices are configured to control elution of the drug through the inner plug and out of the implant.

3. The ocular implant of claim 1, further comprising a coating around at least a portion of the shell.

4. The ocular implant of claim 1, wherein, the proximal end comprises a cap.

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

6. The ocular implant of claim 1, wherein, the shell is configured to begin bioeroding while at least a portion of the drug to be eluted from the lumen of the implant remains in the lumen.

7. The ocular implant of claim 1, wherein, the implant is configured for implantation into an eye of a subject.

8. The ocular implant of claim 1, wherein, the implant is within a lumen of a 23-25 gauge needle or cannula of a delivery device.

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

10. The ocular implant of claim 1, wherein, the implant is capsule-shaped.

11. The ocular implant of claim 1, wherein, the proximal end and the distal end are each circular.

12. The ocular implant of claim 1, wherein, the drug is completely dispersed or mixed within the inner plug.

13. The ocular implant of claim 1, wherein, the drug comprises at least 50% of the inner plug and drug mixture.

14. The ocular implant of claim 1, wherein, the plug-drug mixture is pre-formed.

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