Bio-erodible ocular implants for treatment of conditions of the eye

Abstract

Cyclosporine-eluting implants for treating a condition of the eye, and methods for their use, are disclosed herein. Also disclosed herein are methods for treating a condition of an eye of a subject. Also disclosed herein are methods of forming a system for treating a condition of an eye of a subject.

Description

BIO-ERODIBLE OCULAR IMPLANTS FOR TREATMENT OF CONDITIONS OF THE EYECROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 653,199 filed on May 29, 2024, the content of which is incorporated herein by reference in its entirety for all purposes.TECHNICAL FIELD

[0002] This invention relates generally to bio-erodible ocular implants (e.g., drug-eluting implants) for treating conditions of the eye, and associated methods and systems for treating such conditions of the eye.BACKGROUND

[0003] Glaucoma is a group of optic neuropathies associated with specific structural changes to the optic nerve ultimately leading to irreversible visual field loss. In many cases, this loss of vision is progressive and leads to blindness if untreated. According to the National Eye Institute at the United States National Institutes of Health, glaucoma is the leading cause of irreversible blindness worldwide. In 2020, approximately three million people in the United States carry a diagnosis of glaucoma. Worldwide, that number is 80 million people. By 2040, it is expected that over 110 million people will be living with this potentially blinding condition ("Global Prevalence of Glaucoma and Projections of Glaucoma Burden through 2040", Ophthalmology 2014; 121 :2081-2090). Glaucoma generally falls into two categories: open angle glaucoma and closed angle glaucoma. Open angle glaucoma is approximately seven times more common than the closed angle form in both the U.S. and Europe (Quigley HA, Broman AT. Br. J. Ophthalmol. 2006; 90(3):262-267). The course of both forms of the disease is, typically, a chronic and progressive loss of vision, leading to constriction of the visual field. The ultimate result is permanent blindness. Because it is typically asymptomatic until the disease is significantly advanced, early diagnosis through regular eye exams and early treatment are critical. While the prevalence of glaucoma increases with age, the majority of patients with undiagnosed glaucoma are under 60 years of age (Shaikh Y, Yu F, Coleman AL. Am. J. Ophthalmol. 2014; 158(6): 1121- 1129).

[0004] Risk factors associated with glaucoma include family history, ethnic origin, and age. Having a first degree relative with glaucoma is associated with a significantly increased risk (Wolfs RC, Klaver CC, Ramrattan RS, van Duijn CM, Hofman A, de Jong PT. Arch Ophthalmol. 1998; 116(12): 1640-1645). Black and Hispanic individuals have increased prevalence of open angle glaucoma. Additionally, they are often diagnosed with more severe disease. Asian, Southeast Asian, Asian Indian, and Inuit individuals are more often diagnosed with closed angle glaucoma (see e.g., Varma R, Ying-Lai M, Francis BA, et al.; Los Angeles Latino Eye Study Group. Ophthalmology 2004;l 11(8): 1439-1448; Tielsch JM, Sommer A, Katz J, Royall RM, Quigley HA, Javitt J. JAMA. 1991;266(3):369-374; Wormaid RP, Basauri E, Wright LA, Evans JR. Eye (Lond). 1994;8(Pt 3):315-320; and Arkell SM, Lightman DA, Sommer A, Taylor HR, Korshin OM, Tielsch JM. Arch. Ophthalmol. 1987;105(4):482-485).

[0005] Closed angle glaucoma typically results from anatomic obstruction of the anterior chamber angle and its associated drainage channels. The anatomic obstruction prevents aqueous humor from efficiently reaching the drainage channels, thereby resulting in increased intraocular pressure. Surgical iridectomy, laser iridotomy, or lensectomy are often considered more definitive surgical options versus more palliative medical therapy such as cholinergic drugs (e.g., pilocarpine eyedrops) to relive obstruction by pupil constriction.

[0006] Open angle glaucoma (OAG) is much more common in the U.S., and it accounts for significantly more loss of vision that its closed counterpart. While the exact pathophysiology of OAG is not completely understood, it has been demonstrated that increased intraocular pressure (IOP) correlates with retinal ganglion cell death. There is a relationship between secretion of aqueous humor by the ciliary body and its egress from the eye via conventional trabecular meshwork pathways and the unconventional uveoscleral pathway. This relationship and any resultant imbalances determine IOP. It is felt that an increased resistance to outflow in the trabecular meshwork or more distal aqueous collector channels are associated with increased IOP in OAG. Increased IOP may cause mechanical stress on the lamina cribrosa, where retinal ganglion cell axons exit the eye to coalesce into the optic nerve. lOP-induced stress at the lamina cribrosa can deform, damage, and interfere with the retinal axons leading to irreversible injury and vision loss. While such IOP associated damage typically occurs when the pressure is above the population average pressures, it can occur at lower or “normal” pressure depending on an individual’s vulnerability. Conversely, many people with higher-than-average IOP neverdevelop glaucoma. A growing number of studies are identifying genomic loci associated with glaucoma susceptibility. Thus, glaucoma may develop in patients with an intraocular pressure relatively high for their individual susceptibility (see e.g., Thorleifsson G, Walters GB, Hewitt AW, et al. Nat Genet. 2010;42( 10): 906-909; and Wiggs JL, Yaspan BL, Hauser MA, et al. PLoS Genet. 2012;8(4):el002654). When ganglion cell death does occur in glaucoma, characteristic changes in the optic nerve head and the nerve fiber layer become evident. This eventually is associated with characteristic visual field loss patterns. Prompt referral to an eye care specialist is critical to treat the glaucoma and slow the progression of irreversible damage and subsequent loss of vision. There is no single gold standard test for diagnosing glaucoma. Typically, several criteria are taken into consideration in making the diagnosis of glaucoma. These include age, family history, ethnic background, IOP, corneal thickness, optical coherence tomographic analysis of various retinal tissues, optic nerve head appearance, and peripheral visual field testing.

[0007] The primary goal of treatment is to slow progressive optic nerve damage in order to preserve vision and quality of life. Early diagnosis and intervention are critical given that visual loss is irreversible. Reduction of IOP with treatment combined with continuous diagnostic assessments of treatment efficacy are part of the mainstay of glaucoma care.

[0008] Initially, treatment is typically comprised of the least number of medications required to adequately reduce IOP. Medications include drugs from the following families of compounds: prostaglandins, prostaglandin analogs, beta-adrenergic blockers, alpha-adrenergic agonists, carbonic anhydrase inhibitors, Rho-kinase (ROCK) inhibitors, and cholinergic drugs.

[0009] Should medical therapy fail, not be tolerated, or not be possible, other forms of therapy may be added or substitute to medical therapy. For example, laser therapy to the eye in the form of trabeculoplasty, cycloablation (endoscopic or transscleral) may be performed. In more advanced cases or under some circumstances, incisional surgery can be considered.Trabeculectomy, valves, or shunts can be used to help control IOP. Recently, minimally invasive glaucoma surgery or MIGS has become a popular surgical approach to the treatment of glaucoma. Various technologies are being employed to reduce IOP while reducing exposure to surgical risks posed by more invasive treatments like trabeculectomy or valve placement. In 2017, nearly 175,000 surgical procedures were performed. The surgeries included over 20,000trabeculectomies, 20,000 glaucoma drainage implants, and over 130,000 MIGS procedures (Ma AK, Lee JH, Warren JL, Teng CC. Clin Ophthalmol. 2020;14:2551-2560).

[0010] While medical therapy is the preferred initial treatment of OAG in the U.S., it does have many problems. Drops can be cost prohibitive for patients, and patients can forget to regularly use them. Additionally, proper instillation into the conjunctival cul-de-sac may be more difficult, especially in the hands of the elderly or arthritic. Excessive instillation, such as instilling multiple drops, and subsequent wasting of medication is also an issue. However, even with proper instillation of the eyedrops, medication is wasted. For instance, a typical eyedrop may be 60-90 microliters, but the ocular surface can typically hold no more than 10 microliters. The therapeutic ingredients and the preservatives with which they are often combined can lead to ocular surface disease, discomfort, inflammation, dry eye, and reduced corneal sensitivity, all of which can irritate the eye and further reduce compliance. Multiple eyedrop medications can also lead to confusion and misuse of the medications. All of these factors combine to create problems with the mainstay of glaucoma therapy-drugs. However, medications do avoid a lot of the more serious complications that can occur with surgery.

[0011] Surgical therapy of glaucoma is typically reserved as a second line therapy in the U.S. That is gradually changing with microinvasive glaucoma surgery (MIGS) becoming more mainstream. Nonetheless, glaucoma surgery carries its own risks. One of the more problematic complications is bacterial endophthalmitis, which is a potentially visually devastating ocular infection. However, there are many other complications of glaucoma surgery, including failure, hypotony, hemorrhage, malignant glaucoma, progression, hyphema, retinal detachment, and many others. Moreover, there are long term complications with trabeculectomy plus antimetabolite and glaucoma drainage devices.

[0012] While glaucoma has been covered in more detail here, many other ocular diseases are being successfully treated with drugs. In addition to being used to medically treat various ocular diseases, drugs are also often used as an adjunct in the surgical treatment of ocular diseases. They are used to treat ocular surface disease, corneal disease, scleral disease, uveal disease, vitreous disease, and chorioretinal disease.

[0013] Age-related macular degeneration (AMD) is a common cause of vision loss in the U.S., and it is globally the third leading cause of blindness. It is associated with degeneration ofthe retinal pigment epithelium and Bruch’s membrane. This itself can lead to overlying retinal damage and visual loss. Unlike the aforementioned “dry” degeneration, further degeneration and resulting in growth of neovascularization from the underlying choriocapillaris can lead to significant visual loss. This latter process is called “wet” macular degeneration. One of the more common forms of treatment is regular intravitreal injections of antibodies or drugs targeting vascular endothelial-derived growth factor (VEGF). Patients often need to receive such injections with anti- VEGF drugs, typically antibody-derived therapeutics, including ranibizumab, aflibercept, or bevacizumab every 4-8 weeks to control their wet macular degeneration. There are significant issues with cost, complications, and associated morbidity with this mainstay of treatment.

[0014] Other retinal diseases require drug treatment, including macular edema, vascular occlusions, diabetic retinopathy, retinal degenerations, and retinal dystrophies. Uveal diseases can affect the choroid, ciliary body, and iris. Examples include iritis and other forms of uveitis which can respond well to various drugs such as steroids. Steroids are often given as oral treatments or as topical therapy. More aggressive cytotoxic agents and chemotherapy can be employed for more severe cases like Behcet’s disease.

[0015] The vitreous can also be a location for ocular disease. It may harbor vision obstructing opacities or hemorrhage. In other instances, it may accumulate inflammatory cells in the setting of vitritis which can also lead to visual loss.

[0016] The lens in the eye is subject to a number of diseases. The most common are age related. Lens opacity or cataract often requires surgical correction in the form of cataract surgery. While many drugs have been used to slow cataract formation, none have so far proven to be significantly effective. After cataract surgery, a variety of drugs are often used to reduce likelihood of infection or inflammation.

[0017] The cornea can become opaque, scarred, or deformed because of diseases such as herpes zoster or simplex infection, keratitis, keratoconus, various infectious diseases, or other corneal degenerations. Additionally, transplanted corneas can suffer from immune mediated rejection or recurrence of a primary ocular disease.

[0018] Scleral disease can result from immune processes or infections. In fact, one of the most common ocular diseases is myopia or nearsightedness, and it is believed that the sclera plays a critical role in axial length and refractive state of the eye. Dilute topical atropine which may work by inducing cycloplegia, or paralysis of the ciliary body, has been shown to reduce development of axial myopia in children. Complex pathways likely account for the development of myopia in children. There is great interest in this area given the large percentage of the world’s population that is affected.

[0019] Dry eye disease (DED) encompasses a number of disease states, defined by the TFOS DEWS II (Ocul. Surf., 2017, 15(3), 269-650) as “a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.” DED can be generally divided into two classes: aqueous tear-deficient dry eye (ADDE) and evaporative dry eye (EDE), each of which can be divided further into subclasses. One of the leading conditions associated with DED, and in particular EDE, is meibomian gland dysfunction (MGD), which is itself an umbrella term encompassing several disorders, wherein disruption and obstruction of the meibomian gland negatively impacts the quality and quantity of meibum, a lipid-rich secretion that protects the ocular surface from damage and premature evaporation of tears (Chhadva, et al., Ophthalmology, 2017, 124(11 Suppl), S20-S26). There are approximately 20-40 meibomian glands in each eyelid and they are responsible for producing meibum that coats the tears and prevents premature tear evaporation. When the meibomian glands are healthy and functioning properly, meibum assumes a liquid, olive-oil like consistency. Every blink applies an expression force to the meibomian glands and some clear liquid meibum is expressed from the gland orifice and fortifies the tear’s outermost lipid layer. With MGD-based EDE, the development of an imbalance in natural lipids and lipid chemistry results in a higher meibum melting temperature, which ultimately leads to meibum transitioning from a healthy, clear, liquid state to a cloudy, semi-hardened state to an advanced, diseased, hardened state. Eventually as the disease progresses and the lipid chemistry of meibum worsens, the hardened meibum becomes unavailable and inexpressible resulting in a low-quality tear lipid layer and premature tear evaporation. In obstructive MGD, the blink results in little to no expression of meibum due to its hardened physiochemical state and inexpressibility, a compromised lipid layer, and accelerated tear evaporation.

[0020] Globally, the prevalence of dry eye disease (DED) is estimated to be between 5 to 20 percent, and approximately 16 million Americans have been diagnosed. It is estimated that 86% of these DED sufferers have MGD-associated EDE (Lemp, et al., Cornea, 2012, 472-478). Those with DED suffer from either inadequate tear production, poor quality of tears, or both, which results in redness, stinging, burning, itching, light sensitivity, watery eyes, blurry vision, irregularities of the ocular surface, and damage to corneal or conjunctival epithelium and tissues. It is believed that a majority of dry eye patients have at least some degree of both aqueous deficiency and lipid deficiency. Symptoms of DED includes dryness, redness, burning or stinging, itching, grittiness, foreign body sensation, sensitivity to light, blurred vision, eye fatigue, excessive tearing, and mucus discharge. Treatment is largely palliative, and no broad cure for DED has been developed.

[0021] Drugs can be administered for these, and other, ocular diseases in various ways. While there are systemic routes of administration such as oral or intravenous drug administration, the eye is particularly well suited to local administration because of its location on the surface of the body. Thus, local routes of drug administration are preferred in the majority of cases. This allows limited exposure of the rest of the body to drug and reduces the amount of drug needed. Currently, the most common route of drug administration for glaucoma is a topical eyedrop approach. Such topically administered drugs typically diffuse across the cornea and into the eye. For retinal diseases, drug injection is a common route.

[0022] Given the above-described difficulty in treating diseases such as, for example, glaucoma, age-related macular degeneration, and dry eye disease, there is a need for safer, more effective, and convenient treatments which address the shortcomings of the current standards of care.SUMMARY

[0023] Cyclosporine-eluting implants for treating a condition of the eye, and methods for their use, are disclosed herein. In some variations, implant comprises a drug-eluting matrix comprising a bio-erodible polymer and a cyclosporine, and the drug-eluting implant is configured to release a sufficient amount of the cyclosporine to reduce a symptom of the condition of the eye, and at 1 month post-implantation maintains a concentration of the cyclosporine of 40 ng / g or greater in conjunctiva of the eye.

[0024] Also disclosed herein are methods for treating a condition of an eye of a subject. These methods may comprise implanting at least one drug-eluting implant in an eye of the subject, wherein the drug-eluting implant comprises a drug-eluting matrix comprising a bio-erodible polymer and cyclosporine, wherein a sufficient amount of the cyclosporine is delivered from the at least one drug-eluting implant to the eye to reduce a symptom of the dry eye disease of the subject, and wherein at 1 month post-implantation, a concentration of the cyclosporine is 40 ng / g or greater in conjunctiva of the eye.

[0025] Also disclosed herein are methods of forming a system for treating a condition of an eye of a subject. In some variations, the method comprises inserting an implant formulation comprising a plurality of drug-eluting microparticles and a liquid carrier into a lumen of a cannula, wherein the cannula is configured for insertion into a target location in an eye, and freezing the implant formulation.BRIEF DESCRIPTION OF THE DRAWINGS

[0026] FIG. 1 shows a cross-sectional view of the anatomy of a normal human eye.

[0027] FIG. 2 shows exemplary drug-eluting implants.

[0028] FIGS. 3A-3D shows an exemplary implantation system.

[0029] FIG 3E shows an alternative drive assembly comprised in an implantation system.

[0030] FIG. 4 shows a flowchart of a method for loading a dry implant formulation into an embodiment of a cannula of an implantation system.

[0031] FIGS. 5A-5B show an exemplary method of dry implant formulation into an embodiment of a cannula of an implantation system.

[0032] FIG. 6 shows a flowchart of a method for implanting a dry implant formulation.

[0033] FIG. 7 shows an exemplary method of implanting a dry implant formulation in the eye to treat an ocular condition.

[0034] FIGS. 8A-8C shows plots indicating in vitro elution of cyclosporine from exemplary cyclosporine-eluting implants of different formulations.

[0035] FIG. 9 shows a chart summarizing the quantification of cyclosporine in various portions of eyes of rabbit subjects with one or more implanted exemplary cyclosporine-eluting implants in the subconjunctival space, one month after implantation.DETAILED DESCRIPTIONOverview

[0036] Described herein are devices, systems, and methods for treating conditions of the eye (e.g., glaucoma, dry eye disease, and others as described herein). Generally, such devices are intended to be implanted in the eye (e.g., within one or more of the sulcus, posterior chamber, anterior chamber, vitreous, suprachoroidal space, subretinal space, retrobulbar space, peribulbar space, intracapsular space, Tenon’s capsule, sub-Tenon’s space, intrascleral space, juxta- choroidal space, suprachoroidal space, subconjunctival space, intra-lenticular capsule space, Berger’s space) to release one or more drugs to one or more regions impacted by a disease or condition of the eye. For instance, the devices described herein may be intraocular implants.

[0037] The devices described herein may generally comprise intraocular, drug-eluting implants for treating one or more conditions of the eye. The drug-eluting implants may comprise a drug-eluting matrix configured to release one or more drugs into the eye. The implants and / or drug-eluting matrices of the implants may comprise a bio-erodible material (e.g., a bio-erodible polymer) that degrades over a predetermined period of days, weeks, months, or years, delivering the drug or drugs over a portion or the entirety of that same time period. Additionally or alternatively, the drug-eluting implants and / or drug-eluting matrices of the implants may comprise a material that preferentially release the drug or drugs when in an aqueous environment, such as in tear, humor, or serum, for example when in the eye or a portion thereof, as compared to a dry environment. In some variations, the drug-eluting implants may be spherical (e.g., microspheres), spheroidal, ellipsoid, ovoid, or spherocylindrical. In some variations, the drug-eluting implants may be roughly spherical. In some variations, the drugeluting implants may comprise an elongate shape, and may be, for example, a cylinder, a spherocylinder, an ovoid, a needle-shape, an ellipsoid or the like. In some variations, the drugeluting implants may be a cuboid. In some variations, the drug-eluting implants may be a pellet or a particle. In some variations, the drug-eluting implants may be irregular in shape. The drugeluting implants may be a sub -millimeter (“sub-mm”) drug-eluting implant, which isdimensioned so that the maximum linear dimension of the implant (e.g. diameter if spherical, major axis if ovoid, space diagonal if cuboid) is less than a millimeter. As used herein, a submm, drug-eluting implant may be referred to as a “microparticle implant”. The drug-eluting implants may be a sub-micron drug-eluting implant, which is dimensioned so that the maximum linear dimension is less than a micron. As used herein, a sub-micron drug-eluting implant may be referred to as a “nanoparticle implant”.

[0038] Also described herein are implant formulations that may comprise a plurality of microparticle implants as well as implantation systems configured to deliver an implant formulation to an eye of a subject. In some variations, the implant formulation may be a dry implant formulation without a liquid carrier, and the implantation system may be configured to deliver to an eye of a subject the dry implant formulation without a liquid carrier, In some variations, one or more microparticle implants, optionally in the form of an implant formulation (e.g. a dry implant formulation as described herein), and one or more implantation devices or systems (e.g., two, three, four, or more) may be packaged as a kit. In some instances, one or more drug-eluting implants or an implant formulation (e.g. a dry implant formulation as described herein), may be preloaded in a corresponding implantation system, while in other variations, one or more implants may be provided separately from an implantation system, and the one or more implants may be loaded into or otherwise positioned within an implantation system (e.g., within a cannula of an implantation system) by a user. In some of these variations, the one or more implants may be provided separately and may be prepared as an implant formulation (e.g. a dry implant formulation), and the implant formulation may be loaded into or otherwise positioned within an implantation system (e.g., within a cannula of an implantation system). In some variations, multiple implants, or multiple implant formulations, may be delivered sequentially. In some variations, multiple implants, or multiple implant formulations, may be delivered simultaneously. For instance, 2, 3, 4, 5, 6, 7, 8, 9, 10, 50, 100 or more implants or implant formulations may be delivered sequentially or simultaneously.

[0039] Methods for treating conditions of the eye may generally comprise advancing one or more drug-eluting implants (e.g., microspheres), or an implant formulation comprising a plurality of implants (e.g., a dry implant formulation as disclosed herein), to a target location (e.g., an implantation site) in the eye, positioning the one or more drug-eluting implants or implant formulations in one or more target locations in the eye, and delivering one or more drugs fromthe implant(s) to the target location(s), and / or to other locations in the eye to treat the condition of the eye and / or reduce one or more symptoms associated with the condition of the eye. For example, in some variations, the target location may be the subconjunctival space, and the methods may generally comprise advancing one or more drug-eluting implants or implant formulations through the conjunctiva, positioning the one or more implants or implant formulations, in the subconjunctival space, and delivering one or more drugs from the implant(s) to the subconjunctival space or the conjunctiva to treat the condition of the eye and / or to reduce one or more symptoms of the condition of the eye. In some variations, the target location may be the anterior chamber, and the methods may generally comprise advancing a drug-eluting implant or an implant formulation through the conjunctiva and the cornea of the eye, positioning the implant or implant formulation in the anterior chamber, and delivering a drug from the implant to the anterior chamber to treat the condition of the eye and / or to reduce one or more symptoms of the condition of the eye. In some variations, the target location may be the vitreous, and the methods may generally comprise advancing and positioning a drug-eluting implant or implant formulation into the vitreous to treat the condition of the eye and / or to reduce one or more symptoms of the condition of the eye. In some variations, the target location may be the suprachoroidal space, and the methods may generally comprise advancing and positioning a drug-eluting implant or implant formulation into the suprachoroidal space, optionally via an ab externo approach or ab interno approach through the anterior chamber angle, to treat the condition of the eye and / or to reduce one or more symptoms of the condition of the eye. Additionally or alternatively, such implants or implant formulations may be advanced using an implantation system. Conditions of the eye may include, but are not limited to, ocular surface diseases, corneal diseases, scleral diseases, uveal diseases, vitreous diseases, optic nerve diseases, choroidal diseases, and retinal diseases. Implantation of the drug-eluting implants or implant formulations may be performed in a doctor’s office by general ophthalmologists and thus do not require costly surgery performed by a specialist. Additionally or alternatively, implantation of the drug-eluting implants or implant formulations may be done in an operating room as a standalone procedure or combined with other procedures (e.g., cataract surgery).

[0040] Implants or implant formulations that reside in the posterior chamber (e.g., within the sulcus, within the sulcus and partially extending into the remainder of the posterior chamber) may utilize naturally occurring currents (e.g., anterior flowing currents, posteriorly flowing currents), that may deliver one or more drugs to different portions of the eye. For example, it hasbeen shown that aqueous humor produced at the ciliary body and released into the ciliary sulcus and / or posterior chamber can travel anteriorly into the anterior chamber where it travels via convection currents. Additionally, posterior aqueous currents may reach the retina and thus deliver drugs to the retina and choroid (e.g. anti-vascular endothelial growth factor antibodies for exudative macular degeneration).

[0041] Accordingly, the devices, systems, and methods described herein may provide effective treatment for many conditions of the eye while avoiding the costs and consequences of utilizing formal operating rooms, decreasing the total amount of drug needed, reducing or eliminating systemic drug exposure through spatially targeted implantation, decreasing or eliminating the need for frequent injections or daily eyedrops, and increasing patient compliance with suggested treatment regimens by eliminating repeated administration of eye drops or injections used in conventional treatments. The devices, systems, and methods described herein may deliver a much smaller amount of drug to target tissue without compromising on efficacy, and thus drug and preservative side effects may be reduced. For example, whereas timolol is potentially effective in treating elevated ocular pressure, systemically available timolol is known in the art to cause cardiac and pulmonary complications. This safety issue imposes a limitation on the dosage and frequency of administration when using timolol eye drops for treating elevated ocular pressure. Dry delivery of timolol-eluting implants in the eye (e.g. in the subconjunctival space or sub-Tenon’s space) would make it possible to deliver a timolol, when compared to eye drops, at a higher concentration in the eye and a lower concentration systemically (e.g., in serum). Dry delivery in the eye would also make available for use other beta-adrenergic blockers such as propranolol and pindolol that have low solubility in aqueous environments (in contradistinction to timolol, in particular timolol maleate, which has high solubility in water). Also for example, dorzolamide hydrochloride eye drops typically cause pain and discomfort due to the low pH that is typically required to dissolve the dorzolamide into solution. Dry delivery of dorzolamide hydrochloride, dorzolamide base, or brinzolamide-eluting implants would eliminate pH or solubility issues seen with topical administration, and reduce the pain and / or discomfort associated with dorzolamide or brinzolamide eye drops.Anatomy

[0042] For context, FIG. 1 shows a partial cross-sectional view of the anatomy of a normal human eye. The eye can be conceptualized as a fluid filled sphere. Anteriorly, it is bounded bythe cornea (100), a three-layered clear tissue that allows entry of light, and functions like a protective window allowing for entry of light into the eye. The periphery of the cornea (100) is known as the corneal limbus (“limbus”) (102) which defines the junction with the sclera (104). The limbus (102) contains stem cells for the ocular surface, contains numerous aqueous outflow pathways, and is highly vascularized.

[0043] The sclera (104) is the opaque, tough, protective, outer layer of the eye. Like the cornea it is essentially avascular. Overlying the sclera (104) is the conjunctiva (106), the thin, clear tissue that overlies the sclera (104) and the inside of the eyelids. By contributing mucus and tears, it helps lubricate the ocular surface. In addition, it is vascularized, and it helps contribute to ocular immune responses. The space below the conjunctiva is the subconjunctival space (122). Tenon's capsule (124) is a membrane that covers the outside of the eyeball between the conjunctiva and the sclera. Tenon's capsule contributes to the structural integrity of the eye, and provides another layer of protection for the eyeball. Sub-Tenon’s space (125), which may also be referred to as episcleral space, is a space between the Tenon’s capsule and the sclera. SubTenon’s space contains loose connective tissue, blood vessels, and fat, and allows for smooth movements of the eyeball by providing a cushioning effect. The sub-Tenon’s space may be divided into an anterior sub-Tenon’s space and a posterior sub-Tenon’s space. Typically, the anterior sub-Tenon space extends from the corneal limbus (the location where the cornea meets the sclera) to approximately 2 mm to 10 mm posteriorly along the surface of the human eye. Further than about 10 mm from the corneal limbus one encounters the posterior sub-Tenon’s space. Juxta-choroidal space (126) is a potential space that may be created in the sclera adjacent to choroid. For example, a partial thickness scleral puncture extending 90 percent depth into the sclera would reach the juxta-choroidal space. Suprachoroidal space (127) is a potential space that may be created between the choroid and the sclera.

[0044] Posterior to the cornea, is the iris (108), or the colored part of the eye. It is an annular structure which can adjust its aperture (pupil) to regulate the amount of light entering the eye. Bright light causes constriction of the pupil thereby limiting exposure to excessive light or resulting glare. Under dim lighting, the pupil opens to capture more of the available light.

[0045] The anterior chamber angle (110), which is filled with aqueous humor, resides between the iris and cornea. At its periphery, there is the anterior chamber angle (110), where aqueous drains out of the eye through the trabecular meshwork and Schlemm’s canal. A circular band ofthe ciliary body is seen on gonioscopy. This area provides intracameral access to the suprachoroidal space.

[0046] Behind the iris (108) is the lens (112). The normal lens is transparent, and it focuses light on the retina to create a clear image. With age or disease, the lens (112) may cloud, and this is known as cataract. The lens (112) is suspended in the eye by fibers known as lens zonules. One end of the zonules attach around the equator of the lens (112). The other end of the zonules attaches to the ciliary body (114). Contraction and relaxation of the ciliary body alter load on the zonules thereby resulting in increased curving of the lens or flattening of the lens (112). This is the primary mechanism our eyes use for focusing.

[0047] The ciliary body (114) not only contains muscles that apply load to the zonules, but it is also responsible for secreting aqueous humor which travels through the ciliary sulcus (116), the peripheral part of the posterior chamber. Implants or devices residing in the ciliary sulcus or peripheral posterior chamber avoid the visual axis and thus do not interfere with vision. Aqueous humor flows into the ciliary sulcus and posterior chamber into the pupil and ultimately into the anterior chamber (110). Research has also shown that aqueous humor currents can also drive fluid and substances through the vitreous and through the retina. In other words, the currents are bidirectional. The posterior chamber is the space in the eye behind the iris and in front of the lens. At its periphery, it is bounded by the ciliary sulcus (116). The ciliary sulcus (116) is the space between the front of the ciliary body (114) and the posterior surface of the iris. This part of the posterior chamber is typically 12 mm in diameter.

[0048] The vitreous humor (118) is the gelatinous substance filling the central cavity of the eye. Its volume is approximately 4-4.5 mL (milliliters). It is bounded by the retina peripherally and posteriorly. Anteriorly, it is bounded by Berger’s space, which separates the vitreous cavity from the lens centrally and by the canal of Petit, also known as spatia zonularis, which separates it from the lens peripherally. The retina is the photosensitive nerve layer lining the back of the eye. In humans, the retina has ten layers, with the outermost, or closest to the sclera (104), being the retinal pigment epithelium. This layer has been implicated in macular degeneration.

[0049] Between the sclera and the retina is a part of the uvea known as the choroid (120). It is a high flow, low resistance vascular layer that nourishes and oxygenates the outer two thirds of the retina. It has also been implicated in macular degeneration. The macula is a region of theretina that accounts for high contrast, crisp vision. It is the functional center of the retina and gives humans their central vision. For example, the ability to read or recognize faces clearly is dependent on the macula. Macular degeneration affects this area, and thus can have a devastating impact on vision. The optic nerve is the coalescence of approximately 1 million retinal axons carrying visual information from the eye to vision centers in the brain.Drug-eluting Implants

[0050] In general, the devices, systems, and formulations described herein comprise drugeluting implants for treating one or more conditions of the eye by delivering one or more drugs to the eye. The implants may comprise a round shape (e.g., spherical, generally spherical, spheroidal, spherocylindrical, ovoid, ellipsoid), and / or an irregular shape, and may be configured to be implanted within one or more structures and / or cavities of the eye. For instance, the drugeluting implant(s) may be configured to reside partially or entirely within one or more of the subconjunctival space, the anterior chamber, the sulcus, the posterior chamber, the suprachoroidal space, the sub-retinal space, or the vitreous of one or both eyes. In some variations, the implants may be microparticle implants, such as, for example, in the form of microspheres.

[0051] In some variations, as will be discussed in more detail herein, the implants may be configured to be delivered with or without a carrier (e.g., vehicles and the like). As used herein, a carrier is defined as a substance (e.g., a fluid) used as a medium for administration of a pharmaceutical compound or pharmaceutical device. For instance, an implant could be delivered without a carrier (i.e., dry), or it could be delivered with a carrier (e.g., one or more implants suspended in a fluid). It will be appreciated that delivering implants with non-fluid additives or compositions, for example binding agents (e.g. sucrose, gelatin or cellulose) would be considered dry delivery in accordance with the disclosure.

[0052] The implants may comprise one or more drugs, and may be configured to release or elute the one or more drugs over time (e.g., a predetermined period of time). In certain variations, the implants may be configured or formulated to preferentially release the one or more drugs when in an aqueous environment, such as in tear, humor, interstitial fluid, or serum, for example when in the eye or a portion thereof, as compared to a dry environment. In some variations, the implant may comprise the one or more drugs, such as within a drug-eluting matrixforming the implant and / or in a coating on an exterior surface thereof. Regardless, the implants may be drug-eluting or otherwise configured to deliver, administer, and / or provide one or more drugs to the eye.

[0053] FIG. 2 depicts exemplary drug-eluting implants described herein, where a plurality of the drug-eluting implants (202) reside intramurally in the sclera, where a plurality of the drugeluting implants (204) reside within the subconjunctival space, where a plurality of the drugeluting implants (206) reside within the sulcus, and where a plurality of the drug-eluting implants (208) reside within the sub-Tenon’s space.

[0054] As shown in FIG. 2, the drug-eluting implant may comprise a rounded shape, and may be, for example, a sphere, a spheroid, an ovoid, or an ellipsoid. In some variations, the drugeluting implants comprising a rounded shape may additionally be microparticle implants, such as, for example, microspheres, microspheroids, microovoids, microellipsoids, or the like. In some variations, the drug-eluting implant may comprise an elongate shape, and may be, for example, a cylinder, a spherocylinder, an ovoid, a needle-shape, an ellipsoid or the like. The drug-eluting implants comprising an elongate shape may additionally be microparticle implants, such as, for example, microcylinders, microspherocylinders, microovioids, microellipsoids, needle-shaped, or the like. Thus, the drug-eluting implants described herein may have a variety of cross-sectional shapes, including, for example, circular, rectangular, oval, elliptical, or the like. In some variations, the drug-eluting implant may be any other shape as discussed above, e.g., cuboid, or an irregular shape. In the variations where the implant has an elongate shape, the implant may have a first end and a second end.

[0055] In general, the implant, or a portion of the implant, may be solid. In some variations, all or a portion of the implant may be a drug-eluting matrix. For example, in some variations, the entire external surface of the implant may be coated with the drug-eluting matrix or only a portion (e.g., one third, one half, two-thirds, or the like) of the implant may be coated. In some variations, the drug-eluting implant may consist essentially of the drug-eluting matrix. In some variations, the drug-eluting implant may comprise the drug-eluting matrix and one or more additional substances that control elution rate, control degradation rate or provide biocompatibility. The one or more additional substances may be mixed with the drug-eluting matrix, or coat a surface of the drug-eluting implant. In some variations, the drug-eluting matrix may comprise a mixture, optionally an evenly dispersed mixture, of one or more drugs and oneor more bio-erodible polymers. In certain variations, the implant may comprise at least one anchoring element, which may, e.g., be formed from, or coupled to, the drug-eluting matrix.

[0056] In some variations, the implants described herein may be characterized by a maximum linear dimension (e.g., a diameter if spherical or a major axis if ovoid or other elongate shape). In some variations, the drug-eluting implants described herein may comprise a length (or major axis) or width (or minor axis) of between about 10 pm and about 20 mm. For example, the implants described herein may comprise a length (or major axis) or width (or minor axis) of between about 0.1 mm and about 20 mm, between about 0.1 mm and about 5 mm, between about 0.1 mm and about 4 mm, between about 0.1 mm and about 3 mm, between about 0.1 mm and about 2 mm, between about 0.1 mm and about 1.5 mm, between about 0.1 mm and about 1 mm, between about 0.1 mm and about 0.5 mm, between about 0.5 mm and about 5 mm, between about 0.5 mm and about 4 mm, between about 0.5 mm and about 3 mm, between about 0.5 mm and about 2 mm, between about 0.5 mm and about 1 mm, between about 1.0 mm and about 5.0 mm, between about 1.0 mm and about 4.0 mm, between about 1 mm and about 3 mm, between about 1 mm and about 2 mm, between about 1 mm and about 1.5 mm, between about 1 mm and about 20 mm, between about 2 mm and about 20 mm, between about 2 mm and about 18 mm, between about 2 mm and about 16 mm, between about 2 mm and about 14 mm, between about 2 mm and about 12 mm, between about 2 mm and about 10 mm, between about 2 mm and about 8 mm, between about 2 mm and about 6 mm, between about 2 mm and 4 mm, between about 4 mm and about 20 mm, between about 4 mm and about 18 mm, between about 4 mm and about 16 mm, between about 4 mm and about 14 mm, between about 4 mm and about 12 mm, between about 4 mm and about 10 mm, between about 4 mm and about 8 mm, between about 4 mm and about 6 mm, between about 6 mm and about 20 mm, between about 6 mm and about 18 mm, between about 6 mm and about 16 mm, between about 6 mm and about 14 mm, between about 6 mm and about 12 mm, between about 6 mm and about 10 mm, between about 6 mm and about 8 mm, between about 8 mm and about 20 mm, between about 8 mm and about 18 mm, between about 8 mm and about 16 mm, between about 8 mm and about 14 mm, between about 8 mm and about 12 mm, between about 8 mm and about 10 mm, between about 10 mm and about 20 mm, between about 10 mm and about 18 mm, between about 10 mm and about 16 mm, between about 10 mm and about 14 mm, between about 10 mm and about 12 mm, between about 12 mm and about 20 mm, between about 12 mm and about 18 mm, between about 12 mm and about 16 mm, between about 12 mm and about 14 mm, between about 14 mm and about 20 mm, betweenabout 14 mm and about 18 mm, between about 14 mm and about 16 mm, between about 16 mm and about 20 mm, between about 16 mm and about 18 mm, or between about 18 mm and about 20 mm (including all sub-ranges and values therein). In some variations, the length or width described herein may be about 1 mm, about 1.5 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, about 10 mm, about 11 mm, about 12 mm, about 13 mm, about 14 mm, about 15 mm, about 16 mm, about 17 mm, about 18 mm, about 19 mm, or about 20 mm (including all sub-ranges and values therein).

[0057] In certain variations, the implants described herein may have a width (or minor axis) of about 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 1.0 mm, 2.0 mm, or 3.0 mm. In certain variations, the implant may have a width (or minor axis) of between about 0.1 mm and about 2 mm, between about 0.1 mm and about 1.5 mm, between about 0.1 mm and about 1.0 mm, between about 0.1 mm and about 0.5 mm, between about 0.5 mm and about 2 mm, between about 0.5 mm and about 1.5 mm, between about 0.5 mm and about 1.0 mm, between about 1.0 mm and about 2.0 mm, between about 1.0 mm and about 1.5 mm, between about 1.5 mm and about 2.0 mm, between about 0.25 mm and about 1.0 mm, between about 0.1 mm and about 0.5 mm, or between about 0.2 mm and about 0.3 mm (including all sub-ranges and values therein). In certain variations, the implants described herein may have a widths of about 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, or 0.5 mm.

[0058] In certain variations, the implants described herein may be spheres, spheroids, or ovoids, and may have a diameter (or minor axis) of about 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 1.0 mm, 2.0 mm, or 3.0 mm. In certain variations, the implants may have a diameter (or minor axis) of between about 0.1 mm and about 2 mm, between about 0.1 mm and about 1.5 mm, between about 0.1 mm and about 1.0 mm, between about 0.1 mm and about 0.5 mm, between about 0.5 mm and about 2 mm, between about 0.5 mm and about 1.5 mm, between about 0.5 mm and about 1.0 mm, between about 1.0 mm and about 2.0 mm, between about 1.0 mm and about 1.5 mm, between about 1.5 mm and about 2.0 mm, between about 0.25 mm and about 1.0 mm, between about 0.1 mm and about 0.5 mm, or between about 0.2 mm and about 0.3 mm (including all sub-ranges and values therein). In certain variations, the implants described herein may have a diameter (or minor axis) of about 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, or 0.5 mm.

[0059] In certain variations where the implants are microparticle implants, the maximum linear dimension may be between about 0.1 pm and about 500 pm. In some variations, the implants may, independently, have a maximum linear dimension of between about 0.1 pm and about 40 pm, between about 0.1 pm and about 30 pm, between about 0.1 pm and about 20 pm, between about 0.1 pm and about 10 pm, between about 0.1 pm and about 1 pm, between about 0.1 pm and about 400 pm, between about 0.1 pm and about 300 pm, between about 0.1 pm and about 200 pm, between about 0.1 pm and about 100 pm, between about 0.1 pm and about 10 pm, between about 0.5 pm and about 40 pm, between about 0.5 pm and about 30 pm, between about 0.5 pm and about 20 pm, between about 0.5 pm and about 10 pm, between about 1 pm and about 400 pm, between about 1 pm and about 300 pm, between about 1 pm and about 200 pm, between about 1 pm and about 100 pm, between about 1 pm and about 10 pm, between about 1 pm and about 5 pm, between about 5 pm and about 100 pm, between about 10 pm and about 100 pm, between about 10 pm and about 90 pm, between about 10 pm and about 80 pm, between about 10 pm and about 70 pm, between about 10 pm and about 60 pm, between about 10 pm and about 50 pm, between about 10 pm and about 40 pm, between about 10 pm and about 30 pm, between about 10 pm and about 20 pm, between about 20 pm and about 100 pm, between about 20 pm and about 90 pm, between about 20 pm and about 80 pm, between about 20 pm and about 70 pm, between about 20 pm and about 60 pm, between about 20 pm and about 50 pm, between about 20 pm and about 40 pm, between about 20 pm and about 30 pm, between about 40 pm and about 100 pm, between about 30 pm and about 90 pm, between about 30 pm and about 80 pm, between about 30 pm and about 70 pm, between about 30 pm and about 60 pm, between about 30 pm and about 50 pm, between about 30 pm and about 40 pm, between about 40 pm and about 100 pm, between about 40 pm and about 90 pm, between about 40 pm and about 80 pm, between about 40 pm and about 70 pm, between about 40 pm and about 60 pm, between about 40 pm and about 50 pm, between about 50 pm and about 100 pm, between about 50 pm and about 90 pm, between about 50 pm and about 80 pm, between about 50 pm and about 70 pm, between about 50 pm and about 60 pm, between about 60 pm and about 100 pm, between about 60 pm and about 90 pm, between about 60 pm and about 80 pm, between about 60 pm and about 70 pm, between about 70 pm and about 100 pm, between about 70 pm and about 90 pm, between about 70 pm and about 80 pm, between about 80 pm and about 100 pm, between about 80 pm and about 90 pm; or between about 90 pm and about 100 pm, (including all sub-ranges and values therein). In some variations, an implant may have amaximum linear dimension of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, or 500 pm.

[0060] In some variations, a mixture of implants (e.g., different sized implants, different shaped implants, implants with different drugs) described herein may be delivered. In some instances, it may be beneficial to administer a mixture of the implants described herein, in which the mixture contains implants of a similar size (e.g., a majority of the implants have a maximum linear dimension, which may be a diameter in the case of microsphere implants, within 5%, 10%, 15%, or 20% of the mean maximum linear dimension of the implants in the mixture). Without being bound by theory, using implants of a similar size, for example, in a dry implant formulation, may aid in preventing formation of a lattice between individual implants, and this prevention of lattice formation may reduce or prevent clogging of an implantation system loaded with a plurality of implants or a dry implant formulation.

[0061] When two or more implants are delivered (for example as an implant formulation), they may collectively have a mean maximum linear dimension. For instance, in some variations, when two or more microparticle implants are delivered, the two or more microparticle implants may have a mean maximum linear dimension of between about 0.1 pm and about 500 pm. In some variations, the implants may, collectively, have a mean maximum linear dimension of between about 0.1 pm and about 40 pm, between about 0.1 pm and about 30 pm, between about 0.1 pm and about 20 pm, between about 0.1 pm and about 10 pm, between about 0.1 pm and about 1 pm, between about 0.1 pm and about 400 pm, between about 0.1 pm and about 300 pm, between about 0.1 pm and about 200 pm, between about 0.1 pm and about 100 pm, between about 0.1 pm and about 10 pm, between about 0.5 pm and about 40 pm, between about 0.5 pm and about 30 pm, between about 0.5 pm and about 20 pm, between about 0.5 pm and about 10 pm, between about 1 pm and about 400 pm, between about 1 pm and about 300 pm, between about 1 pm and about 200 pm, between about 1 pm and about 100 pm, between about 1 pm and about 10 pm, between about 1 pm and about 5 pm, between about 5 pm and about 100 pm, between about 10 pm and about 100 pm, between about 10 pm and about 90 pm, between about 10 pm and about 80 pm, between about 10 pm and about 70 pm, between about 10 pm and about 60 pm, between about 10 pm and about 50 pm, between about 10 pm and about 40 pm, between about 10 pm and about 30 pm, between about 10 pm and about 20 pm, between about 20 pm and about 100 pm, between about 20 pm and about 90 pm, between about 20 pm andabout 80 pm, between about 20 pm and about 70 pm, between about 20 pm and about 60 pm, between about 20 pm and about 50 pm, between about 20 pm and about 40 pm, between about 20 pm and about 30 pm, between about 40 pm and about 100 pm, between about 30 pm and about 90 pm, between about 30 pm and about 80 pm, between about 30 pm and about 70 pm, between about 30 pm and about 60 pm, between about 30 pm and about 50 pm, between about 30 pm and about 40 pm, between about 40 pm and about 100 pm, between about 40 pm and about 90 pm, between about 40 pm and about 80 pm, between about 40 pm and about 70 pm, between about 40 pm and about 60 pm, between about 40 pm and about 50 pm, between about 50 pm and about 100 pm, between about 50 pm and about 90 pm, between about 50 pm and about 80 pm, between about 50 pm and about 70 pm, between about 50 pm and about 60 pm, between about 60 pm and about 100 pm, between about 60 pm and about 90 pm, between about 60 pm and about 80 pm, between about 60 pm and about 70 pm, between about 70 pm and about 100 pm, between about 70 pm and about 90 pm, between about 70 pm and about 80 pm, between about 80 pm and about 100 pm, between about 80 pm and about 90 pm; or between about 90 pm and about 100 pm, (including all sub-ranges and values therein). In some variations, implants may have, collectively, an average maximum linear dimension of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, or 500 pm.

[0062] The implants (e.g., microparticles such as microspheres) described herein may comprise a drug-eluting matrix. As used herein, a “drug-eluting matrix” refers to a material impregnated with a drug, where the drug is released from the material when positioned within the eye. In some variations, the drug may be released slowly from the material over a set period of time. The drug-eluting matrix may, for instance, comprise a polymer impregnated with the drug, where the drug is released from the polymer while implanted within the eye. In some variations, the drug-eluting matrix may be erodible such that it dissolves or disintegrates within a predetermined period of time inside the subject, safely, into non-toxic or biocompatible components. In some variations, the entire microsphere is comprised of the drug-eluting matrix. The drug-eluting matrices described herein may form a coating on, or a filler within, a structure of the drug-eluting implants described herein. For instance, in some variations, the microsphere may comprise a hollow interior chamber containing the drug-eluting matrix and the microsphere may further comprise fenestrations (e.g., openings) through a wall of the microsphere to deliver the drug from the drug-eluting matrix in the interior chamber to the eye. Additionally oralternatively, all or a portion of the implant may comprise a drug-eluting matrix in the form of a coating.

[0063] The implants (e.g., microparticles such as microspheres) described herein may comprise, in part or in whole, a variety of materials suitable for use in a human subject, such as one or more biocompatible polymers or plastics or polymer composites. Examples of biocompatible polymers include poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly-epsilon-caprolactone (PCL), high density polyethylene (HDPE), poly(styrene-Z> / oc^-isobutylene-Z> / oc&-styrene) (SIBS), polyurethane, polycarbonate, polypropylene, polymethylmethacrylate (PMMA), polybutylmethacrylate, polyesters, polytetrafluoroethylene (PTFE), silicone, acrylic polymers, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl chloride, ethyl vinyl acetate, collagen, collagen derivatives, flexible fused silica, polyolefins, NYLON® polymers, polyimide, polyacrylamide, fluorinated elastomers, and copolymers and blends thereof. In some variations, the biocompatible polymer may be a thermoresponsive polymer, such as Poly(N-isopropylacrylamide) (PNIPAM). The implant (e.g., microsphere) may be fully or partially bio-erodible (e.g., biodegradable), and may, for instance, comprise poly(D,L-lactide), poly(D,L-lactide-co-glycolide), poly(D,L-lactide)acid, and polyethylene glycol 3350. Put another way, in some variations, the entire drug-eluting implant (e.g., entire microsphere) may be fully bio-erodible (e.g., biodegradable). The rate of elution of a drug from an erodible implant (e.g., microsphere) described herein may be controlled by selecting an appropriate erodible material (e.g., a polymer) with predictable release characteristics (e.g., rate of release). In some variations, the implant (e.g., microsphere) may comprise an erodible drug-eluting matrix with variable erosion rates. For example, in some variations, a first portion of the implant may have a first erosion rate (e.g., the rate at which the drug-eluting matrix is degraded or absorbed) and a second portion of the implant may have a second, different erosion rate. Thus, elution of a drug from an implant (e.g., microsphere) described herein may have a constant or variable rate. In some variations, the first erosion rate may be higher than the second erosion rate, or vice versa. In some variations, the implant may comprise one or more layers, each layer comprising an erodible drug-eluting matrix. The layers may have the same erosion rates, or one or more layers may have different erosion rates. In some variations, the implant may contain a drug or erodible drug-eluting matrix. In some variations, the implant may comprise an erodible material (e.g., polymer), the erosion rate of which can be tuned by selecting an appropriate material (e.g., polymer). In some variations, the implant mayhave a first erosion rate (e.g., the rate at which outer portion of the implant is degraded or absorbed), and a drug-eluting matrix contained within may have a second erosion rate (e.g., the rate at which the drug-eluting matrix is degraded or absorbed). In some variations, the second erosion rate may be higher than the first erosion rate. Thus, the drug-eluting matrix may elute faster than the outer portion erodes.

[0064] In some variations, the implant may further comprise at least one anchoring element coupled to, or formed from, the drug-eluting matrix. The anchoring element may be any structural feature suitable for holding the implant in place and / or preventing the implant from becoming dislodged from a portion of the eye (e.g., from the sclera, subconjunctival space, subTenon’s space, intrascleral space, suprachoroidal space, juxta-choroidal space, etc.). Anchoring elements may be present on any portion of the implant. Suitable anchoring elements may comprise knots, beads, barbs, crossbars, heads, enlarged (e.g., rounded) or extended portions of an implant, or any other feature configured to maintain placement and / or orientation of an implant within the eye.

[0065] Anchoring elements may be expandable such that they remain folded or stowed prior to implantation and / or during removal of the implant from the eye and deploy upon implantation. For example, one or more anchoring elements may have a first compressed or low-profile, undeployed configuration or position and a second expanded, deployed configuration or position. The anchoring elements may be in the first, undeployed, position during advancement of the intraocular implants into the desired position in the eye, and the anchor elements may transition to the deployed position during or after implantation (e.g., during or after release of the implants from a delivery device). Upon proper positioning of the implant, the anchoring elements may be in the expanded, deployed configuration and may assist in securing the implant in the appropriate location, position and orientation. In some variations, expandable anchoring elements may comprise barbs (e.g., with sharpened distal tips) or crossbars, which may extend from the elongate implant when in the expanded configuration. The barbs and / or crossbars may extend from a surface of the implant at any suitable angle relative to a longitudinal axis of the implant, such as, for example, between 20 degrees and 160 degrees, including all values and sub-ranges therein. In some variations, the barbs and / or crossbars may extend at about a 45 degree, about a 90 degree, or between about a 45 degree and about a 90-degree angle relative to the longitudinal axis of the implant surface. Anchoring elements may be comprised of shape-memory metal, shape-memory alloys, or shape-memory polymers which may change shape upon delivery (e.g., expand to secure the position of the implant). An anchoring element may expand upon delivery due to fluid absorption. Anchoring elements may additionally be erodible. In some variation comprising erodible anchoring elements, the erodible anchoring elements may erode at a different rate (e.g., faster, slower) than another erodible element of the intraocular implant (e.g., a housing).

[0066] In some variations, the implant may not comprise an anchoring element and the entire implant may be used to anchor the intraocular implant. For example, in some variations, the entire implant may expand (e.g., by gaining moisture) to secure the implant in place. Additionally or alternatively, the implant may be secured by positioning the implant within a channel or cavity created in a tissue prior to implantation that has a smaller diameter or width than the diameter or implant positioned therein after implantation.

[0067] In some variations, an implant may comprise a plurality of anchoring elements. For example, in some variations, the implant may comprise two, three, four, five, six, or more anchoring elements, each of which may assist in retaining the implant in the appropriate position and orientation within the eye. In these variations, the plurality of anchoring elements may be the same, or one or more of the anchoring elements may be different from one or more of the remaining anchoring elements. Each anchoring element may be independently positioned on any portion of the implant in order to prevent the implant from becoming dislodged. Utilizing multiple anchoring elements may, for instance, allow for precisely controlling the depth or location of implantation of the implant. Suitable positions for the anchoring elements include, for instance, at a first end of the implant, at a second end of the implant body, on a distal portion of the implant body, between the first and second ends of the implant (e.g., equally or unequally spaced along a length of the implant).Implant Formulation

[0068] As described herein, a plurality of microparticle implants may be formulated for implantation, e.g., into the eye , as an implant formulation. In some variations, the implant formulation may be a wet implant formulation that comprises the plurality of implants and a liquid carrier. The liquid carrier may, for example, comprise water, saline, glycerin, or other non-toxic aqueous media, e.g., aqueous solution comprising hyaluronate, chondroitin sulfate,gelatin, carboxymethylcellulose, polyethylene glycol, or combinations thereof. In some variations, the liquid carrier may be a high viscosity fluid. For example, the liquid carrier may have a viscosity of about 5,000 mPa seconds to about 40,000 mPa seconds, about 5,000 mPa seconds to about 30,000 mPa seconds, about 5,000 mPa seconds to about 20,000 mPa seconds, about 10,000 mPa seconds to about 30,000 mPa seconds, about 10,000 mPa seconds to about 25,000 mPa seconds, about 10,000 mPa seconds to about 20,000 mPa seconds, about 15,000 mPa seconds to about 30,000 mPa seconds, about 15,000 mPa seconds to about 25,000 mPa seconds, about 15,000 mPa seconds to about 20,000 mPa seconds, about 20,000 mPa seconds to about 30,000 mPa seconds, about 20,000 mPa seconds to about 25,000 mPa seconds, or about 25,000 mPa seconds to about 30,000 mPa seconds, including all subranges and values therein. The liquid carrier may have a viscosity of about 5,000 mPa seconds, 10,000 mPa seconds, 15,000 mPa seconds, 17,500 mPa seconds, 20,000 mPa seconds, 22,500 mPa seconds, 25,000 mPa seconds, 30,000 mPa seconds, or about 40,000 mPa seconds, including all subranges and values therein. In some variations, the fluid may be a non-Newtonian fluid to assist in ejecting the microparticles.

[0069] In some variations, the wet implant formulation may be a microsuspension with a relatively low dry implant liquid carrier volume ratio, e.g., of about 1 : 10 or below. In some variations, the implant formulation may be a dry implant formulation, that comprises the plurality of implants without a liquid carrier.

[0070] In some variations, the dry implant formulation may be formulated as a semi-solid mass that is malleable, but does not readily dissociate into individual implants, and may be delivered together as a unit. Utilizing a dry implant formulation or a microsuspension formulation, which have consistency of a a semi-solid mass, may be advantageous for a number of reasons. By way of example, a dry implant formulation formulated as a semi-solid mass may facilitate loading and / or delivery of the dry implant formulation using an implantation system (e.g., a cannula of an implantation system). In some variations, the formulation may be sufficiently malleable so as not to get clogged inside a lumen of the implantation system (e.g., the cannula). Additionally or alternatively, utilizing such a dry implant formulation may also prevent unintended or premature ejection from the implantation system (e.g., a cannula of the implantation system), due to, for example, gravity or during advancement of the cannula through tissue towards a target location.

[0071] The dry implant formulation may be endowed with a semi-solid property without use of a liquid carrier. The presence of the semi-solid property may be based, in certain variations, on a property of a component material of the implants, e.g., a property of a bio-erodible polymer. In some embodiments, the semi-solid property of the dry implant formation or the microsuspension formulation may at least in part be due to a coalescence of the plurality of implants comprised in a formulation, for example through a presence of adhesion between individual implants (inter-implant adhesion). In some variations, a majority (e.g., about 51%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) of the implants of a dry implant formulation may be adhered to at least one other implant. The basis for interimplant adhesion may be electrostatic adhesion, adhesion through a molecular intermediary, and / or through malleability of individual implants and partial deformation of the surface of one implant against one or more other implants. In certain variations, the coalescence of the implants may occur due to hydrophobic interactions within the predominantly aqueous environment of the eye after implantation. For instance, if the bio-erodible polymer of the implants is hydrophobic, the implants will naturally coalesce to minimize direct contact with the surrounding aqueous medium.

[0072] In some variations, the dry implant formulation may exhibit a longer elution duration compared to a wet implant formulation with the same implants. Elution duration may be measured in various ways. Exemplary measures of elution duration include: a time from implantation at which the implant formulation no longer contains detectable amount of drug; or a time from implantation at which drug levels in surrounding tissue is not below detectable levels. The longer elution duration of a dry implant formulation compared to an equivalent wet implant formulation may be, e.g., between about 2 times (“2x”) and about lOx longer, between about 3x and about lOx longer, between about 4x and about lOx longer, between about 5x and about lOx longer, between about 6x and about lOx longer, between about 8x and about lOx longer, between about 2x and 8x longer, between about 3x and 7x longer, between about 4x and about 6x longer, about 2x longer, about 3x longer, about 4x longer, about 5x longer, about 6x longer, about 7x longer, about 8x longer, about 9x longer, and about lOx longer, including all values and sub-ranges therein.

[0073] In some variations, a dry implant formulation may comprise a plurality of drug-eluting implants and one or more binding agents that serve as an adhesive molecular intermediarybetween individual implants. In some variations, the binding agent may be selected from a sugar, a gelatin, a collagen, polyethylene glycol (PEG), a starch, a cellulose, an alginate, a chitosan, or a combination thereof.

[0074] In some variations, at least a majority of the implants may be heated above respective a glass transition temperature of the polymer or polymers comprised in the individual implants, and optionally compressed (during or shortly after heating, before the temperature of the majority of the implants fall below the respective glass transition temperatures). Glass transition temperature is the temperature at which an amorphous polymer changes from a hard / glassy state to a soft / leathery state, or vice versa Without being bound by theory, heating above the glass transition temperature, optionally combined with compression during or shortly after heating, while at least a majority of the implants are above the glass transition temperature, which may be about 1 minute, about 2 minutes, about 5 minutes, or about 10 minutes, may induce the surface of individual implants to be partially deformed against neighboring implants. In some variations, the inter-implant adhesion may be weakened in an aqueous environment, e.g., in the eye, so that individual implants may be more susceptible to dispersion after implantation.

[0075] A dose of an implant formulation for a single implantation into the eye may be referred to herein as an “implantation dose” or “implantation unit” of the implant formulation. An implantation unit of an implant formulation may comprise between about 1 and about 100, between about 100 and about 1000, between about 1000 and about 10000 or greater implants. In some variations, an implantation unit of an implant formulation may comprise between about 100 and about 200, between about 100 and about 300, between about 100 and about 400, between about 100 and about 500, between about 100 and about 600, between about 100 and about 700; between about 100 and about 800, between about 100 and about 900, between about 100 and about 1000, between about 200 and about 300, between about 200 and about 400, between about 200 and about 500, between about 200 and about 600, between about 200 and about 700; between about 200 and about 800, between about 200 and about 900, between about 200 and about 1000, between about 300 and about 400, between about 300 and about 500, between about 300 and about 600, between about 300 and about 700; between about 300 and about 800, between about 300 and about 900, between about 300 and about 1000, between about 400 and about 500, between about 400 and about 600, between about 400 and about 700; between about 400 and about 800, between about 400 and about 900, between about 400 andabout 1000, between about 500 and about 600, between about 500 and about 700; between about 500 and about 800, between about 500 and about 900, between about 500 and about 1000, between about 600 and about 700; between about 600 and about 800, between about 600 and about 900, between about 600 and about 1000, between about 700 and about 800, between about 700 and about 900, between about 700 and about 1000, between about 800 and about 900, between about 800 and about 1000, between about 900 and about 1000, implants. In some variations, an implantation unit of an implant formulation may comprise between about 1000 and about 2000, between about 1000 and about 3000, between about 1000 and about 4000, between about 1000 and about 5000, between about 1000 and about 6000, between about 1000 and about 7000; between about 1000 and about 8000, between about 1000 and about 9000, between about 1000 and about 10000, between about 2000 and about 3000, between about 2000 and about 4000, between about 2000 and 5000, between about 2000 and about 6000, between about 2000 and about 7000, between about 2000 and about 8000, between about 2000 and about 9000, between about 2000 and about 10000, between about 3000 and about 4000, between about 3000 and about 5000, between about 3000 and about 6000, between about 3000 and about 7000, between about 3000 and about 8000, between about 3000 and about 9000, between about 3000 and about 10000, between about 4000 and about 5000, between about 4000 and about 6000, between about 4000 and about 7000; between about 4000 and about 8000, between about 4000 and about 9000, between about 4000 and about 10000, between about 5000 and about 6000, between about 5000 and about 7000; between about 5000 and about 8000, between about 5000 and about 9000, between about 5000 and about 10000, between about 6000 and about 7000, between about 6000 and about 8000, between about 6000 and about 9000, between about 6000 and about 10000, between about 7000 and about 8000, between about 7000 and about 9000, between about 7000 and about 10000, between about 8000 and about 9000, between about 8000 and about 10000, between about 9000 and about 10000, implants.

[0076] A volume of an implantation unit of an implant formulation will depend on the number and size of the implants comprised therein, as well as the amount binding agent or liquid carrier, if any, in the formulation. With the above considerations, the volume of an implantation unit may be, for example, between about 1 pl (microliter) and about 500 pl, between about 1 pl and about 50 pl, between about 1 pl and about 100 pl, between about 1 pl and about 200 pl, between about 1 pl and about 300 pl, between about 1 pl and about 400 pl, between about 1 pl and about 40 pl, between about 2 pl and about 50 pl, between about 2 pl and about 100 pl, between about2 pl and about 200 pl, between about 2 pl and about 300 pl, between about 2 pl and about 400 pl, between about 2 pl and about 500 pl, between about 4 pl and about 50 pl, between about 4 pl and about 100 pl, between about 4 pl and about 200 pl, between about 4 pl and about 300 pl, between about 4 pl and about 400 pl, between about 4 pl and about 500 pl, between about 10 pl and about 50 pl, between about 10 pl and about 100 pl, between about 10 pl and about 200 pl, between about 10 pl and about 300 pl, between about 10 pl and about 400 pl, between about 10 pl and about 500 pl, between about 50 pl and about 100 pl, between about 50 pl and about 200 pl, between about 50 pl and about 300 pl, between about 50 pl and about 400 pl, between about 50 pl and about 500 pl.

[0077] Dry implant formulations may be characterized by a density that depends on, e.g., weight of the material out of which the implants are formed (e.g., certain polymers) and packing density. As such, a given amount, measured by weight, of dry implant formulation characterized by a density may be provided as a given volume. By way of example, 5 mg of dry implant formulation characterized by a density of 1.2 mg / pl has a volume of about 4.17 pl. In certain variations, the density of the dry implant formulation may be between about 0.8 mg / pl and about 1.5 mg / pl, between about 0.8 mg / pl and about 1.2 mg / pl, between about 0.8 mg / pl and about 1.0 mg / pl, between about 1 mg / pl and about 1.5 mg / pl, between about 1 mg / pl and about 1.2mg / pl, about 0.8 mg / pl, about 0.9 mg / pl, about 1 mg / pl, about 1.1 mg / pl, about 1.2 mg / pl, about 1.3 mg / pl, about 1.4 mg / pl, and about 1.5 mg / pl.

[0078] In variations in which the implant formulation is a wet implant formulation with a liquid carrier, the volume ratio of the dry implants to the liquid carrier may be between 5 microliters (pL) and 50 pL of dry implants to between 100 pL and 500 pL of carrier, e.g., about 50 pL of dry implants to about 200 pL of carrier. In certain variations, the volume ratio of the dry implants to the liquid carrier is between 1 :2 (e.g., 50 pL implants to 100 pL carrier) and 1 : 100 (e.g., 5 pL implants to 500 pL carrier), between 1 :2 and 1 :50; between 1 :2 and 1 :25; between 1 :2 and 1 :10; between 1 :2 and 1 :5; between 1 :5 and 1 : 100; between 1 :5 and 1 :50; between 1 :5 and 1 :25; between 1 :5 and 1 : 10; between 1 : 10 and 1 :100; between 1 : 10 and 1 :50; between 1 :10 and 1 :25; between 1 :25 and 1 : 100; between 1 :25 and 1 :50; and between 1 :50 and 1 : 100. A wet implant formulation having a dry implant liquid carrier volume ratio of about 1 : 10 or below may be referred to herein as a “microsuspension”.

[0079] In variations where the implant formulation is a wet implant formulation with a liquid carrier, the mass ratio of the mass of the dry implants (e.g., dry implant formulation, dry microparticle implant formulation) to the mass of the liquid carrier may be about 0.5: 1 to about 5: 1, about 1 :1 to about 5: 1, about 1 : 1 to about 4:1, about 1 : 1 to about 3: 1, about 1 : 1 to about 2.5: 1, about 1 : 1 to about 2:1, about 1 : 1 to about 1.5: 1, about 1.25: 1 to about 5: 1, about 1.25: 1 to about 3: 1, about 1.25: 1 to about 2.5: 1, about 1.25:1 to about 2: 1, about 1.5: 1 to about 5: 1, about 1.5: 1 to about 4:1, about 1.5: 1 to about 3: 1, about 1.5:1 to about 2: 1, about 2: 1 to about 5: 1, about 2: 1 to about 4: 1, about 2: 1 to about 3: 1, about 3:1 to about 5:1, about 1.25: 1 to about 1.75: 1, about 1.5: 1 to about 1.75: 1, about 1.75: 1 to about 2: 1, about 2:1 to about 2.25: 1, or about 2.25: 1 to about 2.5: 1, including all subranges and values therein.

[0080] In certain variations, an implant formulation may be configured to elute one drug, while in other variations, an implant formulation may be configured to elute two or more drugs. In certain variations, an implant formulation may comprise two or more subsets of implants. In these variations, a first subset of implants may comprise a first drug and a second subset of implant may comprise a second, different drug. The first and second subsets of implants may be mixed, uniformly or non-uniformly, throughout the implant formulation, so that the combined implant formulation is capable of eluting both drugs. For example, the first subset of implants may comprise a beta-adrenergic blocker, e.g. a propranolol, a pindolol or a timolol (for example timolol maleate or timolol hemihydrate) and the second subset of implants may comprise a carbonic acid inhibitor (CAI), e.g., a dorzolamide (for example dorzolamide hydrochloride or dorzolamide base) or brinzolamide. In another example, the first subset of implants may comprise a beta-adrenergic blocker, e.g., a propranolol, a pindolol or a timolol (for example timolol maleate or timolol hemihydrate) and the second subset of implants may comprise a prostamide analog (e.g. bimatoprost) or a prostaglandin analog, e.g., latanoprost. In another example, the first subset of implants may comprise a beta-adrenergic blocker, e.g., a propranolol, a pindolol or a timolol (for example timolol maleate or timolol hemihydrate) and the second subset of implants may comprise a rho-kinase inhibitor (for example ripasudil or netarsudil). In another example, the first subset of implants may comprise a prostamide analog (e.g. bimatoprost) or a prostaglandin analog, e.g., latanoprost, and the second subset of implants may comprise a rho-kinase inhibitor (for example ripasudil or netarsudil). Additionally or alternatively, in some variations, each individual implant may comprise two or more drugs (e.g., two, three, four, five, six, or more). In these variations, an implant formulation may comprise afirst subset of implants that comprise a first drug, and one or more subsets (e.g., two, three, four, five, six or more subsets) of implants that comprise one or more drugs. For example, the implant formulation may comprise a first subset of implants that comprise a first drug and a second subset of implants in which each implant in the second subset comprises a second drug and a third drug. In some variations, the first drug may be the same as one of the second and third drugs, while in other variations, each of the first drug, the second drug, and third drug may be different drugs. In this manner, a precise amount of one or more drugs (e.g., two, three, four, five, six, or more) can be delivered together to a location of implantation. Drugs

[0081] The drug-eluting implants described herein comprise one or more drugs (e.g., two, three, four, five, or more) useful for treating the condition of the eye. In some variations, the condition of the eye may be glaucoma, dry eye disease, AMD, retinal diseases (e.g., retinal vascular disease), nerve disease, corneal disease, lens diseases, uvea diseases, vitreous diseases, surface diseases, lid diseases, or ocular infections. In some variations, the one or more drugs may comprise a drug suitable for treating glaucoma, and diseases of the retina, lens, cornea, uvea, vitreous, iris, ciliary body, sclera, or ocular surface. Such drugs include, but are not limited to:Corticosteroids, e.g., prednisolone, prednisone, cortisone, cortisol, or triamcinolone; anti-VEGF agents, e.g. ranibizumab, aflibercept, bevacizumab, or brolucizumab; growth factors, e.g., a nerve growth factor, or an insulin-like growth factor; prostaglandins or prostaglandin analogs, e.g., latanoprost, travoprost, tafluprost, or unoprostone; prostamides or prostamide analogs, e.g. bimatoprost; nitric oxide-releasing drugs and nitric oxide donors; alpha-1 adrenergic agonists, e.g. or epinephrine, dipivefrin; alpha-2 adrenergic agonists, e.g. epinephrine, dipivefrin, brimonidine, or apraclonidine; beta-adrenergic blockers “beta blockers”, e.g., a levobunolol, a timolol, a betaxolol, a carteolol, a propranolol, a pindolol, or a metipranolol; miotics, e.g., pilocarpine; carbonic anhydrase inhibitors, e.g. an acetazolamide, a methazolamide, a dorzolamide, a brinzolamide, a diclofenamide, a ethoxzolamide, or a zonisamide;Rho-kinase (ROCK) inhibitors, e.g., ripasudil or netarsudil;Parasympathomimetic;Sympathomimetics, e.g., muscarinic antagonists (e.g., atropine); antimetabolites, e.g., fluoruracil mitomycin C; antibiotics; non-steroidal anti-inflammatory drugs, e.g., an NSAID; antifungal s; immunosuppressants e.g., cyclosporine, sirolimus, everolimus, lifitegrast, or tacrolimus; vitreous hemorrhage drugs; collagenases; vitreous floater treatments; pupil dilators; pupil constrictors; anticoagulants (e.g., heparin); fibrinolytic compounds; monoclonal antibodies or other biologies; and combinations thereof.

[0082] In some variations, the one or more drugs is a nitric oxide-releasing drug in combination with a prostaglandin / prostaglandin analog or other glaucoma drug (e.g., to target multiple mechanisms of action). In certain variations, the drug is useful for lowering intraocular pressure. In certain variations, the drug may suppress production of aqueous humor. In some variations, the drug may increase the drainage of aqueous humor through a trabeculocanalicular pathway and / or a uveoscleral pathway.

[0083] The amount of drug within a given implant (e.g., microsphere or microparticle) or a given dose of a plurality of implants, e.g., an implantation unit of an implant formulation(e.g., a dry implant formulation as disclosed herein), can be adjusted depending on the type of drug and / or application. For instance, an implant (e.g., microparticle implant or microsphere) or an implantation unit of an implant formulation may comprise between about 1 pg and about 500 pg of a drug, or between about 30 ng and about 90 mg of a drug. In some variations, an implant or an implantation unit of an implant formulation may have between about 1 pg and about 400 pg, between about 1 pg and about 300 pg, between about 1 pg and about 200 pg, between about 1 pg and about 100 pg, between about 1 pg and about 10 pg, between about 1 pg and about 5 pg,between about 5 pg and about 10 pg, between about 5 pg and about 100 pg, between about 10 pg and about 100 pg, between about 10 pg and about 90 pg, between about 10 pg and about 80 pg, between about 10 pg and about 70 pg, between about 10 pg and about 60 pg, between about 10 pg and about 50 pg, between about 10 pg and about 40 pg, between about 10 pg and about 30 pg, between about 10 pg and about 20 pg, between about 20 pg and about 100 pg, between about 20 pg and about 90 pg, between about 20 pg and about 80 pg, between about 20 pg and about 70 pg, between about 20 pg and about 60 pg, between about 20 pg and about 50 pg, between about 20 pg and about 40 pg, between about 20 pg and about 30 pg, between about 40 pg and about 100 pg, between about 30 pg and about 90 pg, between about 30 pg and about 80 pg, between about 30 pg and about 70 pg, between about 30 pg and about 60 pg, between about 30 pg and about 50 pg, between about 30 pg and about 40 pg, between about 40 pg and about 100 pg, between about 40 pg between and about 90 pg, about 40 pg and about 80 pg, between about 40 pg and about 70 pg, between about 40 pg and about 60 pg, between about 40 pg and about 50 pg, between about 50 pg and about 100 pg, between about 50 pg and about 90 pg, between about 50 pg and about 80 pg, between about 50 pg and about 70 pg, between about 50 pg and about 60 pg, between about 60 pg and about 100 pg, between about 60 pg and about 90 pg, between about 60 pg and about 80 pg, between about 60 pg and about 70 pg, between about 70 pg and about 100 pg, between about 70 pg and about 90 pg, between about 70 pg and about 80 pg, between about 80 pg and about 100 pg, between about 80 pg and about 90 pg; or between about 90 pg and about 100 pg of drug (including all sub-ranges and values therein). In some variations, an implant (e.g., microsphere), or an implantation unit of an implant formulation may have about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, or 500 pg of a drug. In some variations, an implant or an implantation unit of an implant formulation may have between about 30 ng and about 90 mg, between about 30 ng and about 80 mg, between about 30 ng and about 70 mg, between about 30 ng and about 60 mg, between about 30 ng and about 50 mg, between about 30 ng and about 40 mg, between about 30 ng and about 30 mg, between about 30 ng and about 20 mg, between about 30 ng and about 10 mg, between about 30 ng and about 5 mg, between about 30 ng and about 1 mg, between about 30 ng and about 500 pg, between about 30 ng and about 100 pg, between about 30 ng and about 900 ng, between about 30 ng and about 800 ng, between about 30 ng and about 700 ng, between about 30 ng and about 600 ng, between about 30 ng and about 500 ng, between about 30 ng and about 400 ng, between about 30 ng and about 300 ng, betweenabout 30 ng and about 200 ng, between about 30 ng and about 100 ng, between about 30 ng and about 50 ng, between about 100 ng and about 90 mg, between about 100 ng and about 80 mg, between about 100 ng and about 70 mg, between about 100 ng and about 60 mg, between about 100 ng and about 50 mg, between about 100 ng and about 40 mg, between about 100 ng and about 30 mg, between about 100 ng and about 20 mg, between about 100 ng and about 10 mg, between about 100 ng and about 5 mg, between about 100 ng and about 1 mg, between about 100 ng and about 500 pg, between about 100 ng and about 100 pg, between about 200 ng and about 90 mg, between about 200 ng and about 80 mg, between about 200 ng and about 70 mg, between about 200 ng and about 60 mg, between about 200 ng and about 50 mg, between about 200 ng and about 40 mg, between about 200 ng and about 30 mg, between about 200 ng and about 20 mg, between about 200 ng and about 10 mg, between about 200 ng and about 5 mg, between about 200 ng and about 1 mg, between about 200 ng and about 500 pg, between about 200 ng and about 100 pg, between about 200 ng and about 900 ng, between about 200 ng and about 800 ng, between about 200 ng and about 700 ng, between about 200 ng and about 600 ng, between about 200 ng and about 500 ng, between about 200 ng and about 400 ng of drug (including all sub-ranges and values therein).

[0084] In some variations, an implant or a plurality of implants, e.g., an implantation unit of an implant formulation (e.g., a dry implant formulation as disclosed herein), may have between about 1 pg and about 90 mg, between about 1 pg and about 70 mg, between about 1 pg and about 50 mg, between about 1 pg and about 40 mg, between about 1 pg and about 30 mg, between about 1 pg and about 20 mg, between about 1 pg and about 15 mg, between about 1 pg and about 10 mg, between about 1 pg and about 5 mg, between about 1 pg and about 1 mg, between about 5 pg and about 90 mg, between about 5 pg and about 70 mg, between about 5 pg and about 50 mg, between about 5 pg and about 40 mg, between about 5 pg and about 30 mg, between about 5 pg and about 20 mg, between about 5 pg and about 15 mg, between about 5 pg and about 10 mg, between about 5 pg and about 5 mg, between about 5 pg and about 1 mg, between about 10 pg and about 90 mg, between about 10 pg and about 70 mg, between about 10 pg and about 50 mg, between about 10 pg and about 40 mg, between about 10 pg and about 30 mg, between about 10 pg and about 20 mg, between about 10 pg and about 15 mg, between about 10 pg and about 10 mg, between about 10 pg and about 5 mg, between about 10 pg and about 1 mg, between about 20 pg and about 90 mg, between about 20 pg and about 70 mg, between about 20 pg and about 50 mg, between about 20 pg and about 40 mg, between about 20pg and about 30 mg, between about 20 pg and about 20 mg, between about 20 pg and about 15 mg, between about 20 pg and about 10 mg, between about 20 pg and about 5 mg, between about 20 pg and about 1 mg, between about 40 pg and about 90 mg, between about 40 pg and about 70 mg, between about 40 pg and about 50 mg, between about 40 pg and about 40 mg, between about 40 pg and about 30 mg, between about 40 pg and about 20 mg, between about 40 pg and about 15 mg, between about 40 pg and about 10 mg, between about 40 pg and about 5 mg, between about 40 pg and about 1 mg, between about 60 pg and about 90 mg, between about 60 pg and about 70 mg, between about 60 pg and about 50 mg, between about 60 pg and about 40 mg, between about 60 pg and about 30 mg, between about 60 pg and about 20 mg, between about 60 pg and about 15 mg, between about 60 pg and about 10 mg, between about 60 pg and about 5 mg, between about 60 pg and about 1 mg, between about 80 pg and about 90 mg, between about 80 pg and about 70 mg, between about 80 pg and about 50 mg, between about 80 pg and about 40 mg, between about 80 pg and about 30 mg, between about 80 pg and about 20 mg, between about 80 pg and about 15 mg, between about 80 pg and about 10 mg, between about 80 pg and about 5 mg, between about 80 pg and about 1 mg, between about 100 pg and about 90 mg, between about 100 pg and about 70 mg, between about 100 pg and about 50 mg, between about 100 pg and about 40 mg, between about 100 pg and about 30 mg, between about 100 pg and about 20 mg, between about 100 pg and about 15 mg, between about 100 pg and about 10 mg, between about 100 pg and about 5 mg, or between about 100 pg and about 1 mg of drug (including all sub -ranges and values therein).

[0085] In some variations, an implant (e.g., microsphere) or a plurality of implants (e.g. an implantation unit of an implant formulation as described herein), may have about 30 ng, about 40 ng, about 50 ng, about 60 ng, about 70 ng, about 80 ng, about 90 ng, about 100 ng, about 150 ng, about 200 ng, about 250 ng, about 300 ng, about 350 ng, about 400 ng, about 450 ng, about 500 ng, about 600 ng, about 700 ng, about 800 ng, about 900 ng, or about 1000 ng of a drug, or about 1 pg, about 2 pg, about 3 pg, about 4 pg, about 5 pg, about 6 pg, about 7 pg, about 8 pg, about 9 pg, about 10 pg, about 15 pg, about 20 pg, about 30 pg, about 40 pg, about 50 pg, about 60 pg, about 70 pg, about 80 pg, about 90 pg, about 100 pg, about 150 pg, about 200 pg, about 250 pg, about 300 pg, about 350 pg, about 400 pg, about 450 pg, about 500 pg, about 600 pg, about 700 pg, about 800 pg, about 900 pg, or about 1000 pg of a drug, or about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg,about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, or about 90 mg of a drug of the disclosure.

[0086] In some variations, an implant (e.g., microsphere) or a plurality of implants (e.g. an implantation unit of an implant formulation as described herein), may comprise a drug of the disclosure at a weight percentage (% w / w) of between about 10% and about 60%, between about 10% and about 50%, between about 10% and about 45%, between about 10% and about 40%, between about 10% and about 35%, between about 10% and about 30%, between about 20% and about 60%, between about 20% and about 50%, between about 20% and about 45%, between about 20% and about 40%, between about 20% and about 35%, between about 20% and about 30%, between about 25% and about 60%, between about 25% and about 50%, between about 25% and about 45%, between about 25% and about 40%, between about 25% and about 35%, between about 25% and about 30%, between about 30% and about 60%, between about 30% and about 50%, between about 30% and about 45%, between about 30% and about 40%, between about 30% and about 35%, between about 35% and about 60%, between about 35% and about 50%, between about 35% and about 45%, between about 35% and about 40%, between about 40% and about 60%, between about 40% and about 55%, between about 40% and about 50%, or between about 40% and about 45%. The implants of this disclosure may elute drugs at a rate determined by their composition, size, and / or implant location. Thus, a proper dosage of drug may be administered to the eye by adjusting the properties of the implants (e.g., microparticle implants or microspheres). In some variation of the implants described herein, the drug-eluting implant or an implantation unit of an implant formulation may deliver one or more drugs into the eye at a rate of between about 1 ng / day and about 3000 ng / day, between about 1 mg / day and about 300 mg / day, or between about 1 ng / day and about 300 mg / day. In some variations, the drug-eluting implant or implantation unit of an implant formulation may deliver a drug into the eye at a rate of between about 1 ng / day and about 2000 ng / day, between about 1 ng / day and about 1000 ng / day, between about 1 ng / day and about 500 ng / day, between about 1 ng / day and about 400 ng / day, between about 1 ng / day and about 300 ng / day, between about 1 ng / day and about 200 ng / day, between about 1 ng / day and about 100 ng / day, between about 1 ng / day and about 50 ng / day, between about 5 ng / day and about 3000 ng / day or more, between about 5 ng / day and about 2000 ng / day, between about 5 ng / day and about 1000 ng / day, between about 5 ng / day and about 500 ng / day, between about 5 ng / day and about 400 ng / day, between about 5 ng / day and about 300 ng / day, between about 5 ng / day and about 200 ng / day, between about 5ng / day and about 100 ng / day, between about 5 ng / day and about 50 ng / day, between about 10 ng / day and about 3000 ng / day or more, between about 10 ng / day and about 2000 ng / day, between about 10 ng / day and about 1000 ng / day, between about 10 ng / day and about 500 ng / day, between about 10 ng / day and about 400 ng / day, between about 10 ng / day and about 300 ng / day, between about 10 ng / day and about 200 ng / day, between about 10 ng / day and about 100 ng / day, between about 10 ng / day and about 50 ng / day, between about 50 ng / day and about 3000 ng / day or more, about 50 ng / day and about 2000 ng / day, between about 50 ng / day and about 1000 ng / day, between about 50 ng / day and about 500 ng / day, between about 50 ng / day and about 400 ng / day, between about 50 ng / day and about 300 ng / day, between about 50 ng / day and about 200 ng / day, between about 50 ng / day and about 100 ng / day, between about 100 ng / day and about 3000 ng / day or more, between about 100 ng / day and about 2000 ng / day, between about 100 ng / day and about 1000 ng / day, between about 100 ng / day and about 500 ng / day, between about 100 ng / day and about 400 ng / day, between about 100 ng / day and about 300 ng / day, between about 100 ng / day and about 200 ng / day, about 200 ng / day to 300 ng / day, about 300 ng / day to 400 ng / day, about 400 ng / day to 500 ng / day, about 500 ng / day to 1000 ng / day, about 1000 ng / day to 1500 ng / day, about 1500 ng / day to 2000 ng / day, about 2000 ng / day to 2500 ng / day, or about 2500 ng / day to 3000 ng / day, (including all sub-ranges and values of any of the above). In some variations, the drug-eluting implant or implantation unit of an implant formulation may deliver one or more drugs into the eye at a rate of about 1 ng / day, about 2 ng / day, about 3 ng / day, about 4 ng / day, about 5 ng / day, about 6 ng / day, about 7 ng / day, about 8 ng / day, about 9 ng / day, about 10 ng / day, about 11 ng / day, about 12 ng / day, about 13 ng / day, about 14 ng / day, about 15 ng / day, about 16 ng / day, about 17 ng / day, about 18 ng / day, about 19 ng / day, about 20 ng / day, about 21 ng / day, about 22 ng / day, about 23 ng / day, about 24 ng / day, about 25 ng / day, about 26 ng / day, about 27 ng / day, about 28 ng / day, about 29 ng / day, about 30 ng / day, about 40 ng / day, about 50 ng / day, about 60 ng / day, about 70 ng / day, about 80 ng / day, about 90 ng / day, about 100 ng / day, about 150 ng / day, about 200 ng / day, about 250 ng / day, about 300 ng / day, about 350 ng / day, about 400 ng / day, about 450 ng / day, about 500 ng / day, about 550 ng / day, about 600 ng / day, about 650 ng / day, about 700 ng / day, about 750 ng / day, about 800 ng / day, about 850 ng / day, about 900 ng / day, about 950 ng / day, about 1000 ng / day, about 1500 ng / day, about 2000 ng / day, about 2500 ng / day, or about 3000 ng / day.

[0087] In some variations, the drug-eluting implant or implantation unit of an implant formulation may deliver a drug into the eye at a rate of between about 1 mg / day and about 300mg / day, between about 1 mg / day and about 200 mg / day, between about 1 mg / day and about 100 mg / day, between about 1 mg / day and about 50 mg / day, between about 1 mg / day and about 20 mg / day, between about 1 mg / day and about 10 mg / day, between about 10 mg / day and about 300 mg / day, between about 10 mg / day and about 200 mg / day, between about 10 mg / day and about 100 mg / day, between about 10 mg / day and about 50 mg / day, between about 10 mg / day and about 20 mg / day, between about 100 mg / day and about 300 mg / day, between about 100 mg / day and about 200 mg / day (including all sub-ranges and values of any of the above). In some variations, the drug-eluting implant or implantation unit of an implant formulation may deliver one or more drugs into the eye at a rate of about 1 mg / day, about 2 mg / day, about 3 mg / day, about 4 mg / day, about 5 mg / day, about 6 mg / day, about 7 mg / day, about 8 mg / day, about 9 mg / day, about 10 mg / day, about 11 mg / day, about 12 mg / day, about 13 mg / day, about 14 mg / day, about 15 mg / day, about 16 mg / day, about 17 mg / day, about 18 mg / day, about 19 mg / day, about 20 mg / day, about 21 mg / day, about 22 mg / day, about 23 mg / day, about 24 mg / day, about 25 mg / day, about 26 mg / day, about 27 mg / day, about 28 mg / day, about 29 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 150 mg / day, about 200 mg / day, about 250 mg / day, or about 300 mg / day.

[0088] In some variations, the drug-eluting implant or implantation unit of an implant formulation may deliver a drug into the eye at a rate of between about 1 ng / day and about 300 mg / day, between about 1 ng / day and about 200 mg / day, between about 1 ng / day and about 100 mg / day, between about 1 ng / day and about 50 mg / day, between about 1 ng / day and about 20 mg / day, between about 1 ng / day and about 10 mg / day, between about 10 ng / day and about 300 mg / day, between about 10 ng / day and about 200 mg / day, between about 10 ng / day and about 100 mg / day, between about 10 ng / day and about 50 mg / day, between about 10 ng / day and about 20 mg / day, between about 10 ng / day and about 10 mg / day, between about 10 ng / day and about 1 mg / day, between about 20 ng / day and about 200 mg / day, between about 20 ng / day and about 100 mg / day, between about 20 ng / day and about 50 mg / day, between about 20 ng / day and about 20 mg / day, between about 20 ng / day and about 10 mg / day, between about 20 ng / day and about 1 mg / day, between about 30 ng / day and about 200 mg / day, between about 30 ng / day and about 100 mg / day, between about 30 ng / day and about 50 mg / day, between about 30 ng / day and about 20 mg / day, between about 30 ng / day and about 10 mg / day, between about 30 ng / day and about 1 mg / day, between about 50 ng / day and about 200 mg / day, between about 50 ng / day and about100 mg / day, between about 50 ng / day and about 50 mg / day, between about 50 ng / day and about 20 mg / day, between about 50 ng / day and about 10 mg / day, between about 50 ng / day and about 1 mg / day, between about 100 ng / day and about 300 mg / day, between about 100 ng / day and about 200 mg / day, between about 100 ng / day and about 100 mg / day, between about 100 ng / day and about 50 mg / day, between about 100 ng / day and about 20 mg / day, between about 100 ng / day and about 10 mg / day, between about 100 ng / day and about 1 mg / day, between about 200 ng / day and about 300 mg / day, between about 200 ng / day and about 200 mg / day, between about 200 ng / day and about 100 mg / day, between about 200 ng / day and about 50 mg / day, between about 200 ng / day and about 20 mg / day, between about 200 ng / day and about 10 mg / day, or between about 200 ng / day and about 1 mg / day (including all sub-ranges and values of any of the above).

[0089] As described below, drugs suitable for delivery by the implants described herein may diffuse from the location of implantation in one part / location of the eye (e.g., vitreous, subconjunctival space) to another part / location in the eye (e.g., anterior chamber, posterior chamber), or vice versa. To enhance this diffusion from the implant location to another location in the eye, the drugs described herein may be administered together with the application of one or more penetration enhancers. Penetration enhancers may include, for instance, compounds such as cyclodextrins, chelating agents, crown ethers, bile acids, bile salts, surfactants, cellpenetrating peptides, and amphiphilic compounds. Such penetration enhancers may be combined with the drug to treat a condition of the eye being administered by a drug-eluting implant described herein, or they may be administered separately. In some variations, a first drug-eluting implant delivers a drug to treat a condition of the eye, and a second drug-eluting implant delivers a penetration enhancer. In other variations, one drug-eluting implant delivers both a drug to a treat a condition of the eye and a penetration enhancer. Penetration enhancers may also be noncompound penetration enhancers, which are applied separately and in addition to the implant. For instance, a non-compound penetration enhancer may include electrical currents, iontophoresis, ultrasound, or microneedles. These may, for instance, be applied to a tissue of the eye to increase penetration of a drug delivery by a drug-eluting implant described herein. Selection of the appropriate penetration enhancer may depend upon the properties of the drug being administered (e.g., molecular weight, hydrophobicity / lipophilicity). An appropriate penetration enhancer may be selected for enhancing penetration of a drug through a specific tissue (e.g., cornea, sclera).

[0090] Currently available treatments for eye disorders such as glaucoma use medicated drops that persist for less than 24 hours. For age-related macular degeneration (AMD) and other retinal diseases, certain other ocular injections provide delivery of drugs to eye tissues for a few weeks or a few months. In contrast, the drug-eluting implants described herein allow for the continuous or semi-continuous delivery of one or more drugs for days or weeks, and / or months or years. In some variations, the drug is delivered to the eye over a predetermined period of time, such as, for example, over at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 12 months, about 18 months, about 24 months, about 30 months, about 36 months, about 48 months, about 60 months, or about 72 months (including all values and subranges therein). For example, in some variations, the drug-eluting implant is configured to for sustained-release of drug to the eye for between about 1 month and about 3 months, about 2 months and about 4 months, about 1 month and about 6 months, about 6 months and about 9 months, about 6 months and about 12 months, about 12 months and about 18 months, about 12 months and about 24 months, about 24 months and about 36 months, about 12 months to about 72 months or about 1 month to about 72 months. In some variations, the period of time is from between about 0 months and 1 month, between about 0 months and about 2 months, between about 0 months and about 3 months, between about 0 months and about 4 months, between about 0 months and about 5 months, between about 0 months and about 6 months, between about 0 months and about 7 months, between about 0 months and about 8 months, between about 0 months and about 9 months, between about 0 months and about 10 months, between about 0 months and about 11 months, between about 0 months and about 12 months, between about 1 month and about 2 months, between about 1 month and about 3 months, between about 1 month and about 4 months, between about 1 month and about 5 months, between about 1 month and about 6 months, between about 1 month and about 7 months, between about 1 month and about 8 months, between about 1 month and about 9 months, between about 1 month and about 10 months, between about 1 month and about 11 months, between about 1 month and about 12 months, between about 2 months and about 3 months, between about 2 months and about 4 months, between about 2 months and about 5 months, between about 2 months and about 6 months, between about 2 months and about 7 months, between about 2 months and about 8 months, between about 2 months and about 9 months, between about 2 months and about 10 months, between about 2 months and about 11 months, between about 2 months andabout 12 months, between about 3 months and about 4 months, between about 3 months and about 5 months, between about 3 months and about 6 months, between about 3 months and about 7 months, between about 3 months and about 8 months, between about 3 months and about 9 months, between about 3 months and about 10 months, between about 3 months and about 11 months, between about 3 months and about 12 months, between about 4 months and about 5 months, between about 4 months and about 6 months, between about 4 months and about 7 months, between about 4 months and about 8 months, between about 4 months and about 9 months, between about 4 months and about 10 months, between about 4 months and about 11 months, between about 4 months and about 12 months, between about 5 months and about 6 months, between about 5 months and about 7 months, between about 5 months and about 8 months, between about 5 months and about 9 months, between about 5 months and about 10 months, between about 5 months and about 11 months, between about 5 months and about 12 months, between about 6 months and about 7 months, between about 6 months and about 8 months, between about 6 months and about 9 months, between about 6 months and about 10 months, between about 6 months and about 11 months, between about 6 months and about 12 months, between about 7 months and about 8 months, between about 7 months and about 9 months, between about 7 months and about 10 months, between about 7 months and about 11 months, between about 7 months and about 12 months, between about 8 months and about 9 months, between about 8 months and about 10 months, between about 8 months and about 11 months, between about 8 months and about 12 months, between about 9 months and about 10 months, between about 9 months and about 11 months, between about 9 months and about 12 months, between about 10 months and about 11 months, between about 10 months and about 12 months, between about 11 months and about 12 months, between about 10 months and about 24 months, between about 10 months and about 36 months, between about 12 months and about 24 months, or between about 12 months and about 36 months (including all values and sub-ranges therein). In some variations, the period of time is 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 10 years, at least about 15 years, at least about 20 years, between about 1 year and about 5 years, about 1 year and about 10 years, about 5 years and about 10 years, about 5 years and about 15 years, about 10 years and about 20 years, about 5 years and about 20 years, or about 1 year and about 20 years (including all values and sub-ranges therein). As used above, “ about 0 months” refers to the time of approximate implantation of one implant or a plurality of implants.

[0091] In some variations, multiple implants or a plurality of subsets of implants (for example, in an implant formulation) may have a similar or the same delivery periods. In some variations, multiple implants or a plurality of subsets of implants (for example, in an implant formulation) may have independent delivery periods (e.g., the predetermined periods of time as described above). By way of example only, two subsets of implants (for example, in an implant formulation) may be administered to a subject, wherein the first subset has a period of time of between about 0 months and about 3 months, and the second subset has a period of time of between about 4 months and about 9 months. It is to be understood that each implant or subset of implants may independently have any of the delivery periods described above.

[0092] As discussed, the drug-eluting implants described herein may be at least partly bio- erodible. In some variations, one or more new implants (e.g., replacement implants) may be delivered to one or more locations of the eye when one or more implanted implants degrade within the eye. For instance, a new implant may replace a partially or fully degraded implant every month, every 2 months, every 3 months, every 6 months, every 12 months, every 18 months, every 2 years, every 3 years, or more, or at any interval therein.

[0093] As discussed previously, in variations in which the implant (e.g., microparticle such as a microsphere) is positioned at least partially within the posterior chamber (e.g., sulcus, remainder of the posterior chamber), the drug delivered from the drug-eluting implant may be taken up by anterior and / or posterior flowing currents such that it may be delivered to the anterior and / or posterior chambers of the eye. In some variations, the drug may be delivered to the anterior chamber, the posterior chamber (e.g., the sulcus and / or remainder of the posterior chamber), the cornea, the iris, the lens, the pupil, the retina, or the vitreous body. In variations in which the implant is positioned intramurally (e.g., embedded or positioned entirely within a tissue or tissues of the eye), the drug may be delivered through the sclera to the anterior chamber, through the sclera to the posterior chamber, through the cornea to the anterior chamber, through the cornea to the posterior chamber, through the limbus to the anterior chamber, or through the limbus to the posterior chamber. In some variations, the drug may be delivered through the conjunctiva to the subconjunctival space or through the conjunctiva and Tenon’s capsule to the sub-Tenon’s space. In some variations, the sub-Tenon’s space may be an anterior sub-Tenon’s space or a posterior sub-Tenon’s space. In some variations, the implant ispositioned in the sulcus, and posterior currents deliver the eluted drug to the retina and / or choroid.

[0094] It may be advantageous for the implants (e.g., microparticles such as microspheres) described herein to comprise at least one imaging agent that may assist in the visualization of the implant(s) and / or drug during and / or after implantation. In variations comprising an imaging agent, the imaging agent may be released as the bio-erodible implant degrades, which may further assist in visualizing and / or quantifying how much drug of the initial implant dose remains at any given point in time and / or over a period of time (e.g., days, weeks, years). In other words, the imaging agent acts as a proxy for drug elution. In some variations, the imaging agent may be one or more of a dye, a radiolabel, and a fluorescent marker. In some variations, the imaging agent may be fluorescein. In some variations of the implants described herein, an implant may comprise a drug and an imaging agent and the implant may be configured to deliver the drug and the imaging agent to the eye at the same delivery rate (e.g., elution rate). In other variations, the implant may be configured to deliver the drug and the imaging agent to the eye at different delivery rates. In some instances, a medical professional may visualize the imaging agent to estimate or otherwise quantify the amount of drug delivered, and may personalize treatment based on this determination. For example, the medical profession may determine a characteristic of a future procedure (e.g., number or volume of implants, type of drug, amount of drug, time for a next implantation, amount of time a next implant(s) should remain in the eye) based on the visualization data of the imaging agent and / or the estimate or quantification of the amount of drug delivered.

[0095] The implants (e.g., microparticles such as microspheres) described herein may be configured for placement within the eye. For example, in some variations, the implants may reside partially or wholly in the subconjunctival space, the suprachoroidal space, thejuxta- choroidal space, the Tenon’s capsule, the sub-Tenon’s space, the anterior chamber (including the iridocorneal angle), the posterior chamber (including the sulcus), or the vitreous.Implant Locations

[0096] The drug-eluting implants described herein may be configured to reside in any suitable location in the eye. For example, the implants described herein may reside in the subconjunctival space (which may be the subconjunctival space at the fornix), the Tenon’scapsule, the sub-Tenon’s space (which may be anterior sub-Tenon’s space or posterior subTenon’s space), the juxta-choroidal space, the suprachoroidal space (which can be accessed for implantation via an ab externo approach or ab interno approach through the anterior chamber angle), the subretinal space, the sclera, the cornea, the limbus, the anterior chamber, the posterior chamber (including the sulcus and the remainder of the posterior chamber), and the vitreous. Implants may be delivered to multiple, different implantation sites. In these instances, the implants in one portion of the eye may have one or more different drugs and / or may have different delivery rates (e.g., elution rates, dissolution rates) than the implants in another portion of the eye. By way of example, a first implant or first subset of implants may be configured to reside in a first location, and a second implant or second subset of implants may be configured to reside in a second location. In some variations, a first implant or first subset of implants may be configured to reside in a first location may comprise a first drug, and a second implant or second subset of implants configured to reside in a second location may comprise the same or a different drug. In some variations, a first implant or first subset of implants may be configured to reside in a first location may have a first drug delivery rate, and a second implant or second subset of implants configured to reside in a second location may have the same or a different drug delivery rate.

[0097] Drug-eluting implants may also reside fully intramurally (e.g., embedded or positioned entirely within a tissue or tissues of the eye), such as, for example, the cornea, sclera, limbus, or a combination thereof. In certain variations, one or more implants may reside fully within the cornea, fully within the sclera, or fully within the limbus.Implantation System

[0098] As described herein, an implant and / or an implant formulation (e.g., an implant formulation with or without a carrier as disclosed herein) may be implanted, e.g., into the eye, using an implantation system configured to access a target location of an eye of the subject, and implant one or more implants, or a desired amount, e.g. an implantation unit, of the implant formulation described herein into the target location. In some variations, the implantation system may be configured to implant the implant or an implant formulation, e.g., a dry implant formulation as disclosed herein without a carrier, or an implant formulation comprising a carrier.

[0099] In certain variations, the implantation system may comprise an implantation device comprising a handle and a cannula coupled to a distal end of the handle. The handle may be sized and shaped for a user to comfortably hold and manipulate the cannula to advance the cannula or a portion thereof towards a target location in the eye. In some variations, the lumen of the cannula or a portion thereof may be loaded (e.g., pre-loaded) with one or more implants, such as, for example, an implantation unit of an implant formulation (e.g., a wet or dry implant formulation as disclosed herein). In some variations, the implantation system may further comprise a plunger or a pusher rod that is slidably positioned within the lumen of the cannula. In some variations, the handle may comprise an actuator for the user to control the implantation system (e.g., control the plunger or pusher rod) to eject the implant formulation from the cannula, in order to deliver the implant(s) to the target location in the eye.

[0100] The cannula may comprise a distal portion configured for insertion into a target location in the eye. The cannula may be made of stainless steel, metal, Teflon, or a polymer (e.g., a polycarbonate, a polyethylene, a polyamide, or a polyether ether ketone). The distal portion of the cannula may comprise and terminate at a distal tip, where the lumen terminates as a distal opening in the distal tip. The one or more implants, such as, for example, an implant formulation (e.g., a dry implant formulation as disclosed herein), may be positioned within the lumen of the cannula. The distal tip may be sufficiently sharp to penetrate tissue and / or membranes in the eye. By way of example, the distal tip of the cannula may have a beveled edge. Additionally or alternatively, the distal portion comprising the distal tip may be tapered, so that the outer diameter of the cannula gradually decreases towards the distal tip. In some variations, the cannula is flexible. In some variations, the cannula is transparent. A transparent cannula advantageously provides for visualization of the implants or the implant formulation loaded in the lumen, and visual control of the implantation process.

[0101] In some variations, the implantation device may be a syringe that is operatively coupled to a cannula loaded with one or more implants or an implant formulation (e.g., a dry implant formulation as disclosed herein), and the actuator may be a plunger of the syringe.

[0102] In some variations, the actuator may be or may comprise one or more of a wheel, a switch, a button, knob, lever, a slider, a touchpad, a capacitive touch sensor, or the like. In some variations, a distal tip of the pusher rod or plunger may be in contact with one or more implants or at least a portion of the implant formulation (e.g., a dry implant formulation as disclosedherein). In some variations, the actuator may have markings or colorings to indicate degree of advancement or direction of advancement.

[0103] In some variations, the actuator may be operatively coupled to the plunger or pusher rod, and may be operable to move the pusher rod with respect to the handle and the cannula, thereby advancing the tip of the pusher rod towards a distal opening of the cannula. In some variations, the actuator may be operatively coupled to the cannula, and may be operable to move the cannula with respect to the handle and the pusher rod, thereby retracting the distal opening of the cannula towards the distal tip of the pusher rod. In some variations, the actuator may be operatively coupled to the plunger or pusher rod and to the cannula. The actuator may be operable to move the pusher rod and the cannula in opposite directions. That is, the actuator may be operable to move the pusher rod with respect to the handle and the cannula, thereby advancing the tip of the pusher rod towards a distal opening of the cannula, as well as operable to move the cannula with respect to the handle and the pusher rod, thereby retracting the distal opening of the cannula towards the tip of the pusher rod.

[0104] In some variations, the handle may comprise a drive assembly that translates rotational movement into a linear motion of the pusher rod, the cannula, or both. For example, in some variations, the actuator may be a wheel rotatably coupled to one or more components of the drive assembly, and rotation of the wheel by the user may rotate one or more components (e.g., circular gears) of the drive assembly, which may result in linear movement of the pusher rod as will be described in more detail herein.

[0105] For example, the drive assembly may include at least one elongate member (e.g., a linear gear, which may be referred to as a “rack”) and at least one pinion gear. The at least one elongate member may be connected to the pusher rod and / or the cannula. The elongate member may be configured to engage with the pinion gear, so that rotational motion of the pinion gear is translated to linear motion of the elongate member. In some variations, the elongate member may be a linear gear, which may have teeth on its surface that engage corresponding teeth on the pinion gear. The drive assembly may have one or more idler gears that engage with the elongate member and / or the pinion gear to provide the desired direction of movement for the elongate member with respect to the direction of rotation of the pinion gear. The at least one pinion gear may also be coupled (e.g., coaxially or tangentially) to the wheel. Such coupling may be accomplished with, for example, a pin that can be coupled to (e.g., via threads or the like) acentral opening in the rotatable component and pinion gear. A mechanical or other fastener (e.g., a nut) may be used to secure the rotatable component and pinion gear in a manner so that rotation of the rotatable component also rotates the pinion gear and vice versa. The wheels may be attached to the pinion gear in any suitable manner. For example, in some variations, the wheels may be positioned (e.g., slid) onto the pinion gear and may be secured thereto (e.g., with adhesive or other mechanical fastening technique such as, for example, a compression fit, press fit, or the like). In other variations, the wheels and pinion gears may be integrally formed (e.g., molded as one part using plastic injection molding technology). 2) Regardless of how the wheels may be coupled to the pinion gear, the wheels and pinion gear may rotate coaxially or tangentially, in the same direction, and at the same angular rate.

[0106] In some variations, the cannula and the pusher rod may be configured to move linearly in opposite directions, upon engagement of the actuator. In these variations, the drive assembly may comprise a first pinion gear coupled (e.g., coaxially or tangentially) to the actuator (e.g. a wheel) and configured to engage with a first elongate member connected to the pusher rod, and a second pinion gear coupled (e.g., coaxially or tangentially) to the actuator and configured to engage with a second elongate member connected to the cannula. Moreover, the drive assembly may comprise an idler gear either between the first pinion gear and the first elongate member, or between the second pinion gear and the second elongate member, so that the first and second elongate members may be moved in opposite directions when the actuator is moved (e.g., the wheel is turned) in a given direction.

[0107] Turning now to FIGS. 3 A-3B, shown there is an implantation system 300 configured to deliver an implant or an implant formulation (e.g., a dry implant formulation as disclosed herein). In the variation shown in FIGS. 3A-3B, the implantation system 300 is configured for movement of both the cannula and the pusher rod during an implantation procedure. In this variation, the implantation system 300 may comprise a cannula 310, a pusher rod 320, and a handle 330. The cannula 310 may comprise a distal portion 312, a distal tip 313 having a beveled edge, and a proximal portion 314. The pusher rod 320 may be slidably positioned in the lumen of the cannula 310. The handle 330 may comprise a housing 332 shaped to be comfortably held by a user (not shown) (e.g., in a single handle of the user), and an actuator 334 in the form of a wheel that serves to move the cannula 310 and the pusher rod 320 in opposite directions when actuated (e.g., turned) by the user. In addition, handle 330 may furthercomprises (e.g., at least partially house therein) a drive assembly 340 that translates the movement (e.g., rotational movement) of the actuator 334 with opposing linear movements of the cannula 310 and the pusher rod 320. The housing 332 of the handle 330 is depicted partially cut away to provide a view of the drive assembly 340 and its components, which in this variation, are housed entirely within an interior portion of the housing 332 of the handle 330.

[0108] FIG. 3C shows a top view of the implantation system 300 of FIGS. 3 A and 3B with the housing 332 of the handle 330 removed to provide a better view of the drive assembly 340 and its connection to the cannula 310 and the pusher rod 320. As can be more readily seen in this figure, a proximal portion 324 of the pusher rod 320 may be fixedly connected to the linear gear 346 via pusher rod holder 347, the proximal portion 314 of the cannula 310 may be fixedly connected to the linear gear 356 via the handle 357, and a distal portion of the pusher rod 320 may be slidably positioned in a lumen of cannula 310.

[0109] FIG. 3E shows another variation of a drive assembly 1340 that may be housed in the housing 332, that translates the movement (e.g., rotational movement) of an actuator (e.g. actuator 1334) with opposing linear movements of the cannula (not shown) and the pusher rod (not shown), for delivery of an implant or implant formulation (e.g. a dry implant formulation) loaded in the cannula. In this variation, the drive assembly 1340 may comprise a first linear gear 1346 fixedly coupled to a pusher rod (not shown), and a second linear gear 1356 fixedly coupled to the cannula (not shown). The first linear gear 1346 and the second linear gear 1356 may be engaged with one another via an idler gear 1357. As such, the drive assembly 1340 may be configured to move the pusher rod (via the first linear gear 1346) and the cannula (via the second linear gear 1356) in opposite linear directions.

[0110] The implantation system 330 may be configured so that when the cannula 310 is retracted and pusher rod 320 is advanced through engagement (e.g. rotation) of actuator 334, the dry implant formulation 360 is ejected through a distal opening 318 of the lumen 316. FIG. 3D is a close-up view of a distal portion of the implantation system 300 of FIGS. 3A-3C. In addition, the cannula 310 is depicted as transparent to show the implant or dry implant formulation 360 loaded into the lumen 316 of the cannula 310, as well as to show the distal tip 322 of the pusher rod 320 inserted inside the lumen 316 and contacting the implant or dry implant formulation 360. Therefore, upon advancement of the pusher rod 320 through the lumen 316 and retractionof the cannula 310, implant or dry implant formulation 360 is ejected through the distal opening 318.Method of loading a cannula pre-loaded with a dry implant formulation

[0111] Loading one or more implants, and / or a dry implant formulation, as described herein into an implantation system may be challenging due to the size and characteristics of the implant and / or dry implant formulation as well as the size and configuration of the implantation system (e.g., narrow lumen of a cannula). As such, in some variations, one or more specialized methods and / or loading tools may be utilized to facilitate loading of an implant and / or dry implant formulation into an implantation system. In some variations, the loading process may be performed with a loading block comprising a planar surface, wherein the groove is formed on the planar surface, and is configured to receive a cannula (e.g. a cannula of an implantation system as described herein), a plurality of implants or a dry implant formulation as described herein, and a tamping device or a pusher rod. The loading block may be configured to heat, cool, and / or apply electro static discharge at or near the groove to facilitate implant installation. For example, FIG. 4 provides a flowchart of a method 400 to load an implant or a dry implant formulation, or in the variation provided in FIG. 5 specifically, a dry implant formulation, into a lumen of a cannula of an implantation system. As shown in FIG. 4, a production method 400 may comprise: in a step 402, loading a cannula in a first portion of a groove dimensioned to fit the cannula; in a step 404, loading a dry implant formulation (or one or more implants) in a second portion of the groove near the proximal end of the cannula; and in a step 406, loading a pusher rod in a third portion of the pusher rod so that the loaded dry implantation formulation (or one or more implants) is placed between the proximal end of the cannula and the distal end of the pusher rod.

[0112] After the cannula, implant(s) and / or dry implant formulation, and pusher rod are positioned in the groove, the method 400 may further comprise, in a step 408, advancing the pusher rod towards the cannula, thereby pressing the implant(s) and / or dry implant formulation into the lumen of the cannula through the proximal opening of the lumen. The pusher rod may be advanced such that the distal end of the pusher rod enters the lumen of the cannula. In some variations, the pusher rod may be advanced until the implant(s) or a portion of the dry implant formulation is positioned near a distal opening of the cannula.

[0113] In some variations, such as those in which a dry implant formulation (which may or may not comprise a binding agent) is used, after the dry implant formulation is positioned within the lumen of the cannula, the method may include, in a step 410, treating the dry implant formulation to increase inter-implant adhesion between at least a majority of the implants of the dry implant formulation. In some variations, the treatment may include heating at least a majority of the implants above respective glass transition temperatures of the polymer or polymers comprised in the drug eluting matrix of the individual implants. The glass transition temperature of an implant is based on the substances comprised therein, for example a bio- erodible polymer comprised in a drug-eluting matrix of the implant. In some variations, the glass transition temperature of an implant may be between about 35 degrees Celsius (degC) and about 45 degC, between about 40 degC and about 45 degC, or between about 37 degC and about 40 degC. In some variations, the treating may include compressing the dry implant formulation in the lumen of the cannula, using, for example, a separate tamping device and / or the pusher rod of the implantation system. In some variations, treating may include both heating and compressing. For example, in some variations, the cannula containing the dry implant formulation may be heated so that at least a majority of the implants of the dry implant formulation are heated above the glass transitions temperatures of their respective polymer(s), and the implants of the dry implant formulation may then be compressed (during or shortly after heating, before the temperature of the majority of the implants fall below the respective glass transition temperatures) by inserting a tamping device into the lumen of the cannula and / or by advancing a pusher rod or tamping device while the cannula is capped (e.g., with a removable cap positioned on the distal end thereof) such that the implants are compressed between the pusher rod or tamping device and the cap. Without being bound by theory, heating above the glass transition temperature, applying compression, or combining heating with compression during or shortly after heating induces the surface of individual implants to be partially deformed against neighboring implants.

[0114] FIG. 5 A schematically depicts an exemplary method of loading a cannula with one or more implants and / or a dry implant formulation, using a loading block 500 comprising a groove 502 dimensioned to fit a cannula of an implantation system as described herein. In the exemplary variation depicted, a distal portion of the cannula 550 is positioned within a first portion 504 of the groove and implants(s) and / or a dry implant formulation comprising a plurality of microparticle implants is positioned in a second portion of the groove 506 near (e.g.,adjacent) a proximal end 602 of the cannula 550. A pusher rod or tamping device 570 is positioned within a third portion 508 of the groove 502, proximal the implant and / or dry implant formulation. In this manner, the implant and / or dry implant formulation 560 is positioned between the proximal end 552 of the cannula and the distal tip 572 of the pusher rod or tamping device 570. The pusher rod or tamping device 570 is then advanced towards the cannula (schematically shown in the direction of block arrow 640), thereby pushing the implant and / or dry implant formulation 560 into the lumen of the cannula 550 through the proximal opening 554 of the lumen of the cannula 550. In other variations, the cannula 550 may be loaded into the loading block 500 in reverse, such that the implant and / or dry implant formulation 560 is loaded in a similar manner through the distal opening 556 of the cannula 560. In some variations, the loading block 500 may be heated so that at least a majority of the microparticle implants in the dry implant formulation is heated to be above the glass transition temperature as described in more detail herein. In some variations, while not depicted in FIG. 5 A, a cap may be removably positioned on the end (e.g., distal end) of the cannula 510 during implant and / or dry implant formulation loading. In variations in which compression is with or instead of heating, the pusher rod or tamping device 570 may be advanced until sufficient compression force is applied to the implant and / or dry implant formulation. For example, the pusher rod or tamping device 570 may be advanced so that a distal end of the implant and / or dry implant formulation contacts the cap and the proximal end of the implant and / or dry implant formulation continues to advance distally thereby compressing the implant and / or dry implant formulation. In some variations, the pusher rod of an implantation system may be used in addition to, or instead of, the pusher rod or tamping device 570 to apply a compressive force to the implant and / or dry implant formulation.

[0115] FIG. 5B shows a cannula 550 loaded with a dry implant formulation 560, after compression has been applied by the pusher rod or a tamping device 570. The cannula 550 has a cap 580 releasably coupled to a distal opening 556 of the cannula 550. When coupled to the cannula 550, the cap 580 may be positioned over a distal opening 556 of the cannula 550. The cap 580 may further provide protection of the distal end 556 before the cannula is used for an implantation process, e.g. during transport and storage, and the cap 580 may be removed by a user before the implantation process.Method of loading a cannula pre-loaded with a frozen implant formulation

[0116] Pre-loading a wet implant formulation, as described herein into an implantation system may be challenging due to unwanted, premature elution of the drug from the microparticle implants to the liquid carrier. In order to prevent premature elution, in some variations, the liquid carrier of the wet implant formulation may be frozen after the implant formulation is loaded into an implantation system. Accordingly, methods of forming a system for treating a condition of an eye of a subject may comprise inserting a wet implant formulation comprising a plurality of drug-eluting microparticle implants and a liquid carrier into a lumen of a cannula, where the cannula is configured for insertion into a target location in an eye, and freezing the implant formulation while it is contained within the cannula. The implant formulation may be frozen at a temperature, for example, between -30°C and 0°C, between -25°C and -5°C, between -20°C and -10°C, between -18°C and -12°C, between -80°C and -60°C, between -15°C and -5°C, between - 70°C and -50°C, about -80°C, about -60°C, about -50°C, about -45°C, about -40°C, about - 35°C, about -30°C, about -25°C, about -20°C, about -15°C, about -10°C, or about -5°C. The cannula comprising the frozen implant formulation may then be cold transported to a desired location and ultimately thawed before being provided to a subject.

[0117] The cannula pre-loaded with the frozen implant formulation may be stored for 1 week, 2 weeks, 3, weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months, while preventing between 90% and 99%, between 92% and 98%, between 95% and 99%, 90% or more, 92% or more, 93% or more, 94% or more 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or more than 99% of the drug from eluting. For example, the cannula may be stored for about 1 week to about 6 months, from about 2 weeks to about 6 months, about 1 week to about 1 months, about 1 week to about 2 months, about 2 weeks to about 4 months, about 1 month to about 6 months, about 1 month to about 3 months, or about 1 month to about 4 mounts.

[0118] As noted above, once the cannula is to be used for implanting the implant formation, the implant formation may be thawed so that the liquid carrier returns to a liquid state. As such, in variations in which a pre-loaded frozen implant formulation is used, methods of treating a condition of an eye of a subject may comprise providing a frozen implant formulation comprising a plurality of drug-eluting microparticle implants and a carrier within a lumen of a cannula, thawing the implant formulation within the lumen of the cannula, advancing a distalend of the cannula to a target location in the eye, and implanting the implant formulation in the target location.Methods of Treating Conditions of the Eye

[0119] Methods of treating a condition of the eye of a subject using the implants or one or more implant formulations (e.g., a wet implant formulation or a dry implant formulation as disclosed herein) are also provided. In general, the methods described herein may comprise implanting at least one drug-eluting implant or an implant formulation(e.g., a wet implant formulation or a dry implant formulation as disclosed herein), including a plurality or a plurality of sets or groups of implants, in the eye of the subject. The methods described herein may involve implantation of one or more implants or implant formulations (e.g., a wet or dry implant formulation) described herein with or without a carrier. When an implant formulation (“wet implant formulation”) comprises a carrier, the carrier may comprise, for example, saline, water, glycerin, or other non-toxic aqueous media, e.g., aqueous solution comprising hyaluronate, gelatin, carboxymethylcellulose, polyethylene glycol, or combinations thereof. One particular advantage of certain methods described herein is that the drug-eluting implants are configured to be implanted without the use of a liquid carrier. Implantation of the drug-eluting implants without the use of a liquid carrier may be referred to here as “dry” implantation. Dry implantation limits or eliminates dangerous changes in intraocular pressure that might occur within the eye when a liquid carrier is injected. Additionally, due to at least the size, shape, and structure of the implants as well as the properties of an implant formulations disclosed herein (e.g., a dry implant formulation), a plurality of implants may be implanted closely to one another, and their movement within the eye may be more limited than implants utilizing an aqueous administration, which may assist in avoiding extravasation typically seen with aqueous administration. Other advantages of dry administration without a carrier are higher drug dose per unit volume injected, and elimination of the need for the drug implantation device to be shipped refrigerated or frozen. The dose may be deployed immediately without extra steps or opportunities for mixing errors.

[0120] Additionally, dry implantation may allow the implants to coalesce in one area, increasing visibility to a physician to determine presence and therefore elution of drug in a particular part of the eye. Further, coalescence of the implant formulation may allow for the implants to be removed more easily should an adverse event occur. Additionally or alternatively,coalescence of the implant formulation may serve to reduce the surface area-to-volume ratio of the implanted volume of the implant formulation, thereby increasing total elution time of therapeutic agents comprised in the implants. In some variations, at least one drug-eluting implant may be implanted as a dry implant formulation without a carrier. In some variations, the dry implant formulation may exhibit a longer elution duration compared to a wet implant formulation with the same implants. Elution duration may be measured in various ways. Exemplary measures of elution duration include: a time from implantation at which the implant formulation no longer contains detectable amount of drug; or a time from implantation at which drug levels in surrounding tissue is not below detectable levels. The longer elution duration of a dry implant formulation compared to an equivalent wet implant formulation may be, e.g., between about 2 times (“2x”) and about lOx longer, between about 3x and about lOx longer, between about 4x and about lOx longer, between about 5x and about lOx longer, between about 6x and about lOx longer, between about 8x and about lOx longer, about 2x longer, about 3x longer, about 4x longer, about 5x longer, about 6x longer, about 7x longer, about 8x longer, about 9x longer, a about lOx longer.Implantation locations

[0121] In general, a drug may be delivered from at least one drug-eluting implant (optionally as an implant formulation, e.g., a wet or dry implant formulation, as described herein) to a structure of the eye to reduce a symptom of a condition of the eye, as described previously. In some variations, the methods may comprise implanting at least one drug-eluting implant or an implant formulation in the anterior chamber, and delivering a drug from the implant to the anterior chamber, and / or to another location in the eye (e.g., posterior chamber, sclera, vitreous, subconjunctival space, suprachoroidal space, juxtachoroidal space, Tenon’s capsule, subTenon’s space) to treat the condition of the eye and / or to reduce one or more symptoms of the condition of the eye. In some variations, methods may comprise implanting at least one drugeluting implant or implant formulation in the vitreous, and delivering a drug from the at least one implant or implant formulation to the vitreous, and / or to another location in the eye (e.g., posterior chamber, sclera, anterior chamber, subconjunctival space) to treat the condition of the eye and / or to reduce one or more symptoms of the condition of the eye. In some variations, methods may comprise implanting at least one drug-eluting implant or implant formulation in the subconjunctival space, and delivering a drug from the implant or implant formulation to thesubconjunctival space, and / or to another location in the eye (e.g., posterior chamber, sclera, anterior chamber, vitreous, Tenon’s capsule, sub-Tenon’s space) to treat the condition of the eye and / or to reduce one or more symptoms of the condition of the eye.

[0122] In some variations, methods may comprise implanting at least one drug-eluting implant or implant formulation in the Tenon’s capsule or sub-Tenon’s space, and delivering a drug from the implant or implant formulation to the Tenon’s capsule or sub-Tenon’s space, and / or to another location in the eye (e.g., posterior chamber, sclera, anterior chamber, vitreous, subconjunctival space) to treat the condition of the eye and / or to reduce one or more symptoms of the condition of the eye. In some embodiments, the sub-Tenon’s space may be a posterior sub-Tenon’s space or an anterior sub-Tenon’s space. In some variations, methods may comprise implanting at least one drug-eluting implant or implant formulation in the posterior chamber (including, in the sulcus and / or in the remainder of the posterior chamber), and delivering a drug from the at least one drug-eluting implant or implant formulation to the posterior chamber, and / or to another location in the eye (e.g., subconjunctival space, sclera, anterior chamber, vitreous) to treat the condition of the eye and / or to reduce one or more symptoms of the condition of the eye. In some variations, the methods described herein may comprise implanting at least one drug-eluting implant or implant formulation fully intramurally, and delivering a drug from the implant(s) or implant formulation to another location (e.g., anterior chamber, posterior chamber, vitreous) of the eye to reduce a symptom of the condition of the eye. Any of the above- mentioned drug-eluting implants or implant formulation and implantation systems are suitable for use with the methods described herein.Anesthesia

[0123] Prior to administering the drug-eluting implant, the eye may be anesthetized, and one or more antiseptics may be applied to the eye to prepare it for the implantation procedure. Anesthesia may include one or a combination of the following types of anesthesia: topical, subconjunctival, Tenon’s capsule, sub-Tenon’s space, peribulbar, and retrobulbar. In some instances, an eyelid speculum may be applied to expose the ocular surface and prevent the eyelids from closing. In some instances, it may be advantageous to dilate the pupil. The procedure may also be performed at a slit lamp with the patient seated upright, or it may be performed at a microscope with the patient supine. In some variations, the implant may be advanced and / or positioned using loupes, a sit lamp, or a surgical microscope. The proceduremay be done in an operating room, although, advantageously, the methods described herein are suitable for being performed at a doctor’s office or in a minor procedure room, for example using a slit lamp, under direct visualization, under loupe magnification, or under a microscope. The methods described herein may be performed with or without the use of gonioscopy or microinvasive glaucoma surgery (MIGS)-type implantations. Instead, many of the methods described herein allow for injection into a tissue of the eye, performed at a slit lamp or in an office-based setting by an ophthalmologist or optometrist. While these procedures may be performed in an operating room, there are many advantages to performing them in an officebased setting (e.g., cost savings, convenience for the patients, increased appointment availability and / or access).Implantation process

[0124] In some variations, a cannula pre-loaded with one or more implants or an implant formulation may be advanced through an external tissue (e.g., sclera, conjunctiva, cornea) to reach the desired or target location or position within the eye. The implant formulation may then be ejected or otherwise released from the implantation system into the target location. In some variations, as shown in FIG. 6, an implantation method 700 may comprise, in a step 702, puncturing a tissue of the eye (e.g., sclera, cornea), optionally with a needle or a cannula of an implantation system, and, in a step 704, advancing a distal end of a cannula of an implantation system carrying one or more implants or an implant formulation in a lumen of the cannula to a desired implant location, such as directly within a mural tissue or within a space within the eye. The desired implant location may include, for example, the posterior chamber, the anterior chamber, the subconjunctival space, the Tenon’s capsule, the sub-Tenon’s space (e.g. posterior sub-Tenon’s space or anterior sub-Tenon’s space), or the vitreous. In some variations, the implantation method may comprise, in a step 706, ejecting or otherwise releasing the one or more implants or the implant formulation from the cannula into the target location. In some variations, the ejecting or releasing may comprise operating an actuator of an implantation system, which may result in moving (e.g., advancing) a pusher rod of an implantation system relative to the cannula, retracting the cannula relative to the pusher rod, or a combination of both. In some variations, methods may comprise creating an intramural tunnel or channel separately from, and prior to, advancing the cannula to the target location. In some variations, the tunnel or channel may be created with an instrument such as a needle or a femtosecond laser.In other variations, the channel or tunnel may be created using the implantation system prior to, or during, advancement of the implant or implant formulation to the desired location. In some variations, the implant or implant formulation may be positioned within the mural tissue directly, or within a tunnel or channel. An actuator of an implantation system may then be operated in order to eject or otherwise release the implant or dry implantation formulation into the mural tissue, tunnel or channel, or other naturally occurring space within the eye.

[0125] In some variations, the target location may be Sub-Tenon’s space. In some embodiments, the sub-Tenon’s space may be a posterior sub-Tenon’s space or an anterior subTenon’s space. FIG. 7 depicts an exemplary method of implantation into posterior Sub-Tenon’s space. In this variation, a distal portion 804 of a cannula 802 of an implantation system 800 may puncture the conjunctiva and the Tenon’s capsule and enter the anterior Sub -Tenon’s space. The cannula 802 may be loaded with at least one implant or an implant formulation 806 (which may be a dry or wet implant formulation), which may be positioned within a lumen of the cannula. The distal end 804 may be advanced through the anterior Sub-Tenon’s space and into the posterior sub-Tenon’s space. Once the distal end 804 is in the sub-Tenon’s space, the actuator on the handle of the implantation system may be operated to eject or otherwise release the implant or implant formulation 806 within the cannula 802 into the sub-Tenon’s space. In the variation depicted in FIG. 7, the handle of the implantation system is a syringe 810, and the actuator is a plunger 812. It should be appreciated that while depicted with another variation of the implantation system, the method depicted in FIG. 7 may be performed with any of the implantation systems described herein, such as, for example, the implantation system 300 described with respect to FIGS. 3 A-3D. Other target locations contemplated include the subconjunctival space, including the subconjunctival space at the fornix, where the conjunctiva reflects back from the eyelids to cover the sclera, forming a loose, folded junction.

[0126] In some variations, a guidewire may be used in the implantation procedure. For example, a guidewire may contact a portion of an implant, and the implant may be advanced from the cannula and / or positioned using the guidewire. After delivering the implant to the target tissue with the guidewire, the implant may be released from the guidewire and / or the guidewire may be withdrawn, leaving the implant in place.

[0127] As described above, advancing one or more implants or implant formulations may comprise advancing a portion of an implantation system, e.g., the cannula, through one or moretissues, structures, or membrane of the eye, such as sclera, limbus, or conjunctiva. The method may include advancing the cannula underneath one or more tissues (e.g., conjunctiva, Tenon’s capsule). The implant or implant formulation may be disposed within the implantation system. For example, the implant or implant formulation may be disposed within a cannula of the implantation system, and at least a distal end of the cannula may be advanced through a sclera of the eye. The methods described herein may also allow for positioning a drug-eluting implant fully intramurally with at least a portion of the drug-eluting implant in a limbus of the eye. The methods described herein may also allow for delivering a drug from the drug-eluting implant, after placement of the implant, to a target tissue or tissues of the eye (e.g., anterior chamber, subconjunctival space, sub-Tenon’s space) to reduce a symptom of the condition of an eye. The target tissue or tissues may be one or more tissues in which the implant resides and / or may be one or more different tissues. The target tissue or tissues may not be in contact with the implant.

[0128] The methods described herein are suitable for use with any of the drug-eluting implants including implant formulations (e.g., dry implant formulations as disclosed herein) described herein.Visualization of Cannula

[0129] After advancing the cannula, wherein the implant(s) or implant formulation is disposed, the cannula may be visualized in a particular portion of the eye or at a particular depth, informing where in the eye the implant will reside once the cannula is retracted. Thus, methods may further comprise visualizing the distal tip of the cannula within a particular tissue, cavity, or structure of the eye (e.g., the anterior chamber) prior to releasing the implant from the implantation system. For instance, the cannula may be visualized within one or more tissues, cavities, or structures of the eye, within which the implant will reside. Additionally, or alternatively, the cannula may be visualized within one or more tissues, cavities, or structures of the eye adjacent to, or within the proximity of, the desired implant location.

[0130] Visualizing the cannula through the posterior portion of the eye may assist a user in in properly positioning the implant within the eye, as described above. Accordingly, methods may comprise confirming the distal tip of the cannula is positioned within a desired portion of the eye, such as, but not limited to, within the anterior chamber, posterior chamber, limbus, subconjunctival space, or vitreous of the eye. Once the distal tip of the cannula has beenadvanced to a desired depth within the eye, methods may further comprise retracting the cannula and / or advancing a pusher, and releasing the drug-eluting implant in the target tissue (e.g., at least partially in the anterior chamber, posterior chamber, limbus, subconjunctival space, or vitreous).

[0131] In some variations, a portion of the implantation system (e.g., the cannula) and / or drugeluting implant may be visualized during advancement and / or positioning using loupes, a slit lamp, a surgical microscope, or any combination thereof. Additionally, or alternatively, a drugeluting implant may be implanted in a structure of the eye (e.g., suprachoroidal space) gonioscopically.Spread of drug to locations beyond location of implantation

[0132] The drug-eluting implants, including implant formulations may deliver drugs to various locations, irrespective of where in the eye they reside. In any of the methods described herein, a drug-eluting implant (or implants) may deliver a drug to a location or tissue(s) in which the drug-eluting implant resides, and / or to a location or tissue(s) that is different from the location or tissue in which the drug-eluting implant resides. For instance, a drug-eluting implant may reside fully intramurally, within the posterior chamber, within the subconjunctival space, or within the vitreous, but may deliver a drug to the anterior chamber of the eye (or vice versa) via diffusion through the tissue(s). A drug-eluting implant residing fully in the subconjunctival space or subTenon’s space, may deliver a drug to one or more of the limbus, sclera, cornea, anterior chamber, ciliary body, trabecular meshwork, choroid, retina, retinal pigment epithelium (RPE), posterior chamber, vitreous, or any other nearby tissue or structure of the eye. A drug-eluting implant residing fully in the vitreous may deliver a drug to one or more of the limbus, sclera, cornea, anterior chamber, posterior chamber, or any other nearby tissue or structure of the eye. A drug-eluting implant residing fully in the sulcus may deliver a drug to one or more of the limbus, sclera, cornea, anterior chamber, vitreous, posterior chamber, or any other nearby tissue or structure of the eye. A drug-eluting implant residing partially in the limbus and partially in the sclera may deliver a drug to one or more of the limbus, sclera, cornea, anterior chamber, or any other tissue or structure of the eye. In certain variations, the drug from the drug-eluting implant may diffuse through one or more aqueous outflow channels. In some variations, a plurality of microspheres is implanted in a sulcus of an eye.Ocular conditions

[0133] The methods of treating a condition in of an eye of a subject, as described herein, may be useful for treating a number of ocular disorders or conditions. These ocular disorders include, but are not limited to, glaucoma, dry eye disease, AMD, choroidal diseases, retinal diseases, corneal diseases, iris diseases, uveal diseases, lens diseases, and scleral diseases (e.g., myopia). In some variations, the methods described herein may be useful for treating macular edema, vascular occlusions, diabetic retinopathy, retinal degenerations, and retinal dystrophies, iritis, uveitis, vitritis, cataracts, herpes zoster or simplex infection, keratitis, keratoconus or other corneal degenerations, dry eye disease, scleritis, episcleritis, corneal ulcer, astigmatism, hyperopia, presbyopia, cornea ectasia, corneal dystrophies, corneal scars, graft versus host disease, autoimmune ocular diseases, Thygeson’s keratitis, post- viral keratitis, herpes simplex, viral keratitis, uveitis, Stevens Johnson Disease, conjunctivitis, blepharitis, postoperative inflammation, postoperative infection prophylaxis, postoperative pain, pingueculum, pingueculitis, pterygium, vernal and atopic keratoconjunctivitis, allergic conjunctivitis, chemical injuries, thermal injuries, chemical injuries, mechanical injuries, retinal vasculitis, retinal dystrophies, neuroretinopathies, autoimmune retinal diseases, autoimmune choroidal diseases, retinal detachment, retinal tears, retinal breaks, ischemic and nonischemic optic neuropathies, tapetoretinal dystrophies, ocular trauma, radiation retinopathy, exudative or nonexudative age related macular degeneration, choroidal neovascularization, retinal neovascularization, retinal vascular occlusive disease, choroidal or retinal inflammation, vitreous opacities (e.g., hemorrhage, floaters, asteroid hyalosis), maculopathies, retinopathies, choroidopathies, retinopathy of prematurity, endophthalmitis, epiretinal membrane hole, macular hole, proliferative vitreoretinopathies, edema (e.g., macular, retinal), ischemia (e.g., macular, retinal), or diabetic retinopathy. In some variations, the methods described herein may result in decreased duration, severity, and / or occurrence of one or more symptoms of any of the aforementioned conditions and / or may result in treatment of any of the aforementioned conditions. The methods described herein, therefore, may utilize a drug-eluting implant that delivers a drug to treat any of these, or other, disorders or conditions. In some variations, the dug-eluting implant may deliver a glaucoma drug. In some variations, the methods described herein may utilize a drug-eluting implant located partially in a first part of the eye to treat a disorder in the same part of the eye or another part of the eye.Multiple implantations

[0134] The methods described herein may comprise delivering one or more implants, or implantation units of an implant formulation (e.g., a dry implant formulation described herein), to the eye. Multiple implants or implantation units of an implant formulation may be implanted for various reasons or purposes. For example, previously implanted implants or implantation units of an implant formulation may have become either depleted or dissolved. Multiple doses of a drug or multiple different drugs may be implanted during a same sitting at same location or different location, or may be implanted at staggered times. The implants, or implantation units of an implant formulation (e.g., a dry implant formulation as disclosed herein), may be delivered simultaneously or sequentially, and may reside in the eye simultaneously and / or sequentially (e.g., the implants or implantation units of the implant formulation may all be implanted for the same period of time, for different, overlapping periods of time, or for different non-overlapping periods of time). In variations in which a plurality of implants are employed, any number of implants (e.g., one, a plurality, a subset of all implanted, , or implantation units of an implant formulation all implanted) may comprise the same drug, may comprise different drugs with the same mechanism of action for one or more conditions of the eye, or may comprise different drugs with different mechanisms of action for one or more conditions of the eye. The implants, or implantation units of an implant formulation may comprise a drug intended to treat or reduce a symptom of the same condition of the eye, or may comprise a drug intended to treat or reduce a symptom of different conditions of the eye. Moreover, the implants , or implantation units of an implant formulation may be positioned in the same general location in the eye or in different areas in the eye. It should be appreciated that while the implants are described as comprising a drug, this may include combinations of drugs. In other words, multiple implants , or implantation units of an implant formulation (e.g., a dry implant formulation as disclosed herein)may be delivered sequentially during the same procedure or may be delivered simultaneously. In variations in which the implants or implantation units of the implant formulation are delivered sequentially, the implants or implantation units of the implant formulation may be advanced to a target implant location (e.g., sulcus, posterior chamber, anterior chamber vitreous, sub-Tenon’s space, subconjunctival space) together (e.g., while contained within a common implantation system), or the implants or implantation units of the implant formulation may be advanced to the target implant location separately (e.g., positioned one at a time in a common implantation system, using different implantation systems).

[0135] For example, methods may comprise positioning a first implant or implants (which may be a first subset of implants or a first implant formulation) comprising a first drug or combination of drugs intended to treat or reduce a symptom of a first condition in a first location in the eye and positioning a second implant or implants (which may be a second subset of implants or a second implant formulation) comprising a second drug or combination of drugs intended to treat or reduce a second condition in a second location in the eye. In some variations, the first drug or combination drugs and the second drug or combination of drugs may be the same drug or combination of drugs, the first condition and the second condition may be the same condition, the first implantation location and the second implantation location may be the same location, and / or the first drug or combination of drugs and the second drug or combination of drugs may utilize the same mechanism of action. In other variations, the first drug or combination of drugs and the second drug or combination of drugs may be different drugs or different combinations of drugs, the first condition and the second condition may be different conditions, the first implantation location and the second implantation location may be different locations, and / or the first and second drugs or combination of drugs may utilize different mechanisms of action. Thus, in some variations, the first and second drugs or combinations of drugs may be different drugs or combinations that utilize different mechanisms of action, but the first and second locations may be the same location and the first and second conditions may be the same condition. In another example, the first and second drugs or combinations of drugs may be different drugs or different combinations of drugs that utilize different mechanisms of action and the first and second locations may be different locations, but the first and second conditions of the eye may be the same. It should be appreciated that any combination of drugs, mechanisms of action, locations, and conditions of the eye described herein may be used in combination when utilizing methods comprising use of multiple drug-eluting implants. In any of the embodiments described herein, a drug or combination of drugs may be delivered to one or more locations in different amounts (e.g., a first amount of a drug or drug combination in a first location and a second amount of the drug or the drug combination in a second location).

[0136] For some subjects, it may be advantageous to deliver multiple implants or implant formulations configured to deliver different drugs or to deliver drugs that utilize different mechanisms of action as this may allow for a more comprehensive treatment. For example, methods may comprise positioning a first implant or implants (which may be a first subset of implants in an implant formulation or a first implant formulation) comprising a first drug with afirst mechanism of action in the sulcus and positioning a second implant or implants (which may be a second subset of implants in an implant formulation or a second implant formulation)comprising a second drug with a second mechanism of action at least partially in the anterior chamber or posterior chamber. In some variations, the first mechanism of action may be suppression of production of aqueous humor and the second mechanism of action may be increasing the drainage of aqueous humor using one or more of the trabeculocanicular pathway and the uveoscleral pathway. In other variations, both the first mechanism of action and the second mechanism of action may be suppression of aqueous humor or increasing drainage of aqueous humor using one or more of the trabeculocanicular pathway and the uveoscleral pathway. In some variations, the first and second mechanisms of action may be increasing drainage of aqueous humor, however, the first mechanism of action may be increasing drainage through the trabeculocanicular pathway and the second mechanism of action may be increasing drainage through the uveoscleral pathway. In some variations, the first implant may comprise a drug for treating or reducing one or more symptoms of glaucoma (e.g., by suppression of aqueous humor, increasing drainage of aqueous humor using the trabeculocanicular pathway, increasing drainage of aqueous humor using the uveoscleral pathway) or a condition of the retina, lens, cornea, uvea, vitreous, iris, ciliary body, sclera, or ocular surface, and the second implant may comprise a drug for treating or reducing one or more symptoms of glaucoma or a condition of the retina, lens, cornea, uvea, vitreous, iris, ciliary body, sclera, or ocular surface. For example the first implant or implants (which may be a first subset of implants in an implant formulation or a first implant formulation)and the second implant or implants (which may be a second subset of implants in an implant formulation or a second implant formulation) may each comprise a drug for treating or reducing one or more symptoms of glaucoma, and the drug may be the same drug (or combination of drugs) or a different drug (or different combination of drugs). In some variations, for reducing ocular pressure to, e.g., treat glaucoma, the first mechanism of action may be blocking of beta-2-adrenergic receptors (e.g. using a timolol, a propranolol, or a pindolol) and the second mechanism of action may be inhibiting carbonic anhydrase (e.g. using a brinzolamide or a dorzolamide). In other variations, for reducing ocular pressure to, e.g., treat glaucoma, the first mechanism of action may be blocking of beta-2 - adrenergic receptors (e.g. using a timolol, a propranolol, or a pindolol) and the second mechanism of action may be administration of a prostaglandin analog or a prostamide analog (e.g. using a latanoprost or bimatoprost). In other variations, for reducing ocular pressure to, e.g.,treat glaucoma, the first mechanism of action may be blocking of beta-2-adrenergic receptors (e.g. using a timolol, a propranolol, or a pindolol) and the second mechanism of action may be inhibition of a rho-kinase (e.g. using a ripasudil or netarsudil.). In other variations, for reducing ocular pressure to, e.g., treat glaucoma, the first mechanism of action may be administration of a prostaglandin analog or a prostamide analog (e.g. using a latanoprost or bimatoprost), and the second mechanism of action may be inhibition of a rho-kinase (e.g. using a ripasudil or netarsudil.). In another example, the first implant or implants (which may be a first subset of implants in an implant formulation or a first implant formulation)may comprise a drug for treating or reducing one or more symptoms of glaucoma and the second implant or implants (which may be a second subset of implants in an implant formulation or a second implant formulation) may comprise a drug for treating or reducing one or more symptoms of retinal disease. In some variations, the first implant or implants (which may be a first subset of implants in an implant formulation or a first implant formulation)and the second implant or implants (which may be a second subset of implants in an implant formulation or a second implant formulation)may each comprise a drug for treating or reducing one or more symptoms of AMD, and the drug may be the same drug (or combination of drugs) or a different drug (or combination of drugs). In another example, the first implant or implants (which may be a first subset of implants in an implant formulation or a first implant formulation)may comprise a drug for treating or reducing one or more symptoms of glaucoma and the second implant or implants (which may be a second subset of implants in an implant formulation or a second implant formulation)may comprise a drug for treating or reducing one or more symptoms of AMD. In another example, the first implant or implants (which may be a first subset of implants in an implant formulation or a first implant formulation) may comprise a drug for treating or reducing one or more symptoms of glaucoma and the second implant or implants (which may be a second subset of implants in an implant formulation or a second implant formulation) may comprise a drug for treating or reducing one or more symptoms of dry eye disease.

[0137] It should be understood that a first implant or implants (which may be a first subset of implants or a first implant formulation), may be advanced to a first location, and then a second implant or implants (which may be a second subset of implants or a second implant formulation) may be advanced subsequently to a second location. In some variations, a portion of a single subset of implants in an implantation system could be advanced into a first location, and then a subsequent portion or portions could be advanced into a second location (or third, fourth, etc.)from the same implantation system. In some variations, a first implant or first subset of implants maybe advanced to a first location in the eye from an implantation system, and the same implantation system may be recharged with an additional implant or subset to one or more additional locations in the eye.Cyclosporine-eluting implants

[0138] In certain variations, an implant in accordance with the disclosure may be a cyclosporine-eluting implant. Cyclosporine, also known as cyclosporine A, is an immunosuppressant medication often used to prevent organ transplant rejection and treat certain autoimmune disorders. Additionally, cyclosporine may be used to treat dry eye disease (DED), and may reduce inflammation on the ocular surface and promote tear production, providing relief for individuals with this condition. Chemically, cyclosporine is a cyclic polypeptide composed of 11 amino acids, is hydrophobic, and has a molecular weight of approximately 1200 g / mol.

[0139] The cyclosporine-eluting implants may be configured to provide a particular concentration of cyclosporine in a tissue of an eye, e.g., the conjunctiva, over a pre-defined period of time. In some variations, the eye may be an eye of a subject, e.g., a human subject, being treated for an eye condition and implanted with the implant. In other variations, the eye may be an eye of an animal model. Appropriate animal models include mammals used for testing ophthalmic therapies. For example, in some variations, the animal model may be a rabbit (e.g., a New Zealand white rabbit), a dog, non-human primate, a pig, or a rodent such as a rat or a mouse. Additionally or alternatively, the animal model may be a model for dry eye disease.

[0140] In certain variations, the cyclosporine-eluting implants may be configured to provide, at 1 month post-implantation, a concentration of the cyclosporine of 40 ng / g (ng cyclosporine / g tissue) or greater in the conjunctiva of an eye of an animal model (e.g., a rabbit). In certain variations, the concentration of the cyclosporine at 1 month post-implantation in the conjunctiva of the eye if the animal model may be between 40 ng / g and 1000 ng / g, between 50 ng / g and 1000 ng / g, between 60 ng / g and 1000 ng / g, between 80 ng / g and 1000 ng / g, between 100 ng / g and 1000 ng / g, between 150 ng / g and 1000 ng / g, between 200 ng / g and 1000 ng / g, between 300 ng / g and 1000 ng / g, between 400 ng / g and 1000 ng / g, between 500 ng / g and 1000 ng / g, between 600 ng / g and 1000 ng / g, between 700 ng / g and 1000 ng / g, between 800 ng / g and 1000 ng / g, 40ng / g and 800 ng / g, between 200 ng / g and 800 ng / g, between 400 ng / g and 800 ng / g, between 40 ng / g and 500 ng / g, between 200 ng / g and 500 ng / g, between 400 ng / g and 500 ng / g, between 40 ng / g and 400 ng / g, between 40 ng / g and 350 ng / g, between 40 ng / g and 300 ng / g, between 40 ng / g and 250 ng / g, between 40 ng / g and 400 ng / g, 40 ng / g or greater, 50 ng / g or greater, 60 ng / g or greater, 80 ng / g or greater, 100 ng / g or greater, 150 ng / g or greater, 200 ng / g or greater, 300 ng / g or greater, 400 ng / g or greater, 500 ng / g or greater, 600 ng / g or greater, 700 ng / g or greater, 800 ng / g or greater, or 900 ng / g or greater (including all values and sub-ranges therein).

[0141] In certain variations, the concentration of the cyclosporine post-implantation in the conjunctiva of an eye of the animal model may be higher at the end of a first time-period postimplantation compared to a second, later time-period. For example, the cyclosporine concentration in the conjunctiva of the eye of the animal model at the end of the first time-period may be between about 250 ng / g and about 350 ng / g, between about 200 ng / g and about 250 ng / g, about 250 ng / g and about 300 ng / g, between about 200 ng / g and about 300 ng / g, between about 200 ng / g and about 250 ng / g, between about 250 ng / g and about 500 ng / g, between about 200 ng / g and about 500 ng / g, at least 200 ng / g, at least 250 ng / g, at least 300 ng / g, or at least 350 ng / g, whereas the cyclosporine concentration in the conjunctiva of the eye of the animal model at the end of the second time-period may be between about 40 ng / g and about 200 ng / g, between about 50 ng / g and about 200 ng / g, between about 75 ng / g and about 200 ng / g, between about 100 ng / g and about 200 ng / g, between about 40 ng / g and 100 ng / g, between 50 ng / g and 100 ng / g, between 75 ng / g and 100 ng / g, between 40 ng / g and 75 ng / g, and between 50 ng / g and 75 ng / g (including all values and sub-ranges therein).

[0142] The first time period may be, for example, about 1 month to about 4 months, whereas the second time period may be, for example, about 2 months to about 24 months. For example, the first time-period may be about 1 month (i.e., at about 1 month post-implantation) and the second time-period may be about 2 months (i.e., at about 2 months post-implantation). As another example, the first time-period may be about 1 month and the second time-period may be about 2 months. In yet another example, the first time-period may be about 1 month and the second time-period may be about 3 months. In still another example, the first time-period may be about 1 month and the second time-period may be about 4 months. In yet another example, the first time-period may be about 1 month and the second time-period may be about 5 months.In a further example, the first time-period may be about 1 month and the second time-period may be about 6 months, about 12 months, about 18 months, or about 24 months.

[0143] An advantage of cyclosporine-eluting intraocular implants over eye drops may be in improved localized administration, in which a relatively high concentration of a therapeutic agent may be achieved while keeping systemic concentration (e.g. in blood) low. In certain variations, the concentration of the cyclosporine in the blood of the human subject at 1 month post-implantation, at 2-6 months post-implantation, at 2-12 months post-implantation, or at 2-24 months post-implantation, may be between 0.1 ng / g and 1 ng / g, between 0.1 ng / g and 0.8 ng / g, between 0.1 ng / g and 0.5 ng / g, between 0.1 ng / g and 0.3 ng / g, between 0.1 ng / g and 0.2 ng / g, 1 ng / g or less, 0.8 ng / g or less, 0.6 ng / g or less, 0 / 4 ng / g or less, 0.2 ng / g or less, 0.1 ng / g or less, or below a detectable limit (of, e.g., mass spectroscopy) (including all values and sub-ranges therein).

[0144] In certain variations, the at least one cyclosporine-eluting implant may be implanted in subconjunctival space, sub-Tenon’s space, intrascleral space, suprachoroidal space, or juxta- choroidal space of the eye. In certain variations, the subconjunctival space may be a subconjunctival space of the fornix.

[0145] In certain variations, the at least one cyclosporine-eluting implant is configured to elute, in one month, between about 15 micrograms (pg) and about 100 pg, between about 15 pg and about 50 pg, between about 15 pg and about 40 pg, between about 20 pg and about 40 pg, 15 pg or more, 20 pg or more, 25 pg or more, 30 pg or more, 35 pg or more, or 40 pg or more, of the cyclosporine (including all values and sub-ranges therein).

[0146] In certain variations, at least one cyclosporine-eluting implant is configured to elute, in 4 months, between about 20 pg and about 200 pg, between about 20 pg and about 100 pg, between about 20 pg and about 50 pg, between about 30 pg and about 200 pg, between about 30 pg and about 150 pg, between about 30 pg and about 100 pg, between about 30 pg and about 80 pg, between about 30 pg and about 50 pg, between about 40 pg and about 200 pg, between about 40 pg and about 150 pg, between about 40 pg and about 100 pg, between about 40 pg and about 80 pg, between about 50 pg and about 200 pg, between about 50 pg and about 150 pg, between about 50 pg and about 100 pg, between about 50 pg and about 80 pg, 40 pg or more, 45 pg or more, 50 pg or more, 55 pg or more, 60 pg or more, 65 pg or more, 70 pg or more,75 pg or more, 80 pg or more, 85 pg or more, 90 pg or more, 95 pg or more, or 100 pg or more of the cyclosporine (including all values and sub-ranges therein).

[0147] In certain variations, the at least one cyclosporine-eluting implant is configured to elute 2 pg or less per day, between about 2 pg and about 0.4 pg per day, or between about 1.5 pg and about 0.2 pg per day, or between about 2 pg and about 0.1 pg per day, or between about 1.5 pg and about 0.1 pg per day, for between about 1 month and about 3 months, between about 1 month and about 4 months, between about 1 month and about 5 months, between about 1 month and about 6 months, between about 1 month and about 9 months, between about 1 month and about 12 months, between about 2 months and about 3 months, between about 2 months and about 4 months, between about 2 months and about 5 months, between about 2 months and about 6 months, between about 2 months and about 9 months, between about 2 months and about 12 months, between about 3 months and about 4 months, between about 3 months and about 5 months, between about 3 months and about 6 months, between about 3 months and about 9 months, between about 3 months and about 12 months, between about 4 months and about 5 months, between about 4 months and about 6 months, between about 4 months and about 9 months, between about 4 months and about 12 months, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months (including all values and sub-ranges therein).

[0148] In certain variations, the bio-erodible polymer may comprise one or more of poly(lactic-co-glycolic acid) (PLGA), Poly(lactide-co-s-caprolactone) (PLCL). poly(lactic acid) (PLA), or poly-epsilon-caprolactone (PCL).In certain variations, the bio-erodible polymer may comprise PLGA and PLCL.

[0149] PLGA is a polymer composed of polymerized monomers of lactide and glycolide. Certain properties of the polymer can be tuned based on a ratio of lactide and glycolide monomers. Typically, PLGA with a higher lactide content is more rigid and degrades more slowly, and PLGA with a higher glycolide content is more flexible and degrades faster. In some variations, the implants described herein may comprise PLGA comprising lactide and glycolide monomers at a lactide:glycolide ratio of between about 90: 10 and about 40:60, between about 90: 10 and about 50:50, between about 90: 10 and about 60:40, between about 90: 10 and about 70:30, between about 90: 10 and about 80:20, about 90: 10, about 85: 15, about 80:20, about75:25, 70:30, about 65:35, about 60:40, about 55:45, about 50:50, about 45:55, or about 40:60. In some variations, the bio-erodible polymer of the implants described herein may comprise a mixture of two or more PLGA polymers with different lactide:glycolide ratios. In some variations, where the PLGA is a mixture of two or more PLGA polymers with different lactide:glycolide ratios, the above lactide:glycolide ratios may be a weighted average of lactide:glycolide ratio of the component PLGAs. In some variations, the PLGA may be a mixture of a first PLGA with a first lactide:glycolide ratio and a second PLGA with a second, different lactide :glycolide ratio. The first and second lactide :gycloide ratios may be, respectively, any of the ratios described herein. For example, in some variations, the PLGA may comprise a first PLGA comprising lactide and glycolide monomers at a lactide:glycolide ratio of between about 90: 10 and about 80:20 and a second PLGA comprising lactide and glycolide monomers at a lactide:glycolide ratio of between about 40:60 and about 60:40. In some variations, the PLGA may be ester terminated or acid terminated. PLCL is a polymer composed of polymerized monomers of lactide and £-caprolactone. Certain properties of the PLCL can be tuned based on a ratio of lactide and s-caprolactone monomers. Typically, PLCL with a higher lactide content is more rigid and degrades more slowly, and PLCL with a higher caprolactone context is more flexible and degrades faster. In some variations, the implants described herein may comprise PLCL comprising lactide and e-caprolactone monomers at a lactide:s- caprolactone ratio of between about 60:40 and about 40:60, between about 60:40 and about 50:50, between about 60:40 and about 40:60, about 60:40, about 55:45, about 50:50, about 45:55, or about 40:60 (including all values and sub-ranges therein).

[0150] In certain variations, the bio-erodible polymer of the implants described herein may be a combination of a PLGA of the disclosure and a PLCL of the disclosure. In certain variations, the PLGA may be a mixture of a first PLGA with a first lactide:glycolide ratio and a second PLGA with a second, different lactide: glycolide ratio, as disclosed herein. In certain variations, the bio-erodible polymer of the implants described herein may comprise PLCL and PLGA at a weight ratio of between 65: 10 and 45: 10, between 70: 10 and 40: 10, between 65: 10 and 60:10, or between 45:10 and 50:10 (including all values and sub-ranges therein).

[0151] In certain variations, the cyclosporine may be comprised in a cyclosporine-eluting implant at a weight percentage (% w / w) of between about 10% and about 70%, between about 20% and about 50%, between about 30% and about 50%, between about 25% and about 45%,between about 10% and about 50%, between about 30% and about 60%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75%, of the . In some variations, the cyclosporineeluting implant comprise the cyclosporine at a weight percentage (% w / w) of between about 10% and about 60%, between about 10% and about 50%, between about 10% and about 45%, between about 10% and about 40%, between about 10% and about 35%, between about 10% and about 30%, between about 20% and about 60%, between about 20% and about 50%, between about 20% and about 45%, between about 20% and about 40%, between about 20% and about 35%, between about 20% and about 30%, between about 25% and about 60%, between about 25% and about 50%, between about 25% and about 45%, between about 25% and about 40%, between about 25% and about 35%, between about 25% and about 30%, between about 30% and about 60%, between about 30% and about 50%, between about 30% and about 45%, between about 30% and about 40%, between about 30% and about 35%, between about 35% and about 60%, between about 35% and about 50%, between about 35% and about 45%, between about 35% and about 40%, between about 40% and about 60%, between about 40% and about 55%, between about 40% and about 50%, or between about 40% and about 45% (including all values and sub-ranges therein).

[0152] The at least one cyclosporine-eluting implant may comprise one or more elongated implants and / or one or more microparticle implants. In some variations, the cyclosporine-eluting implant may be an elongated implant (for example, a heat-extruded implant), but may not be a microparticle. In these variations, the length (major axis) of the elongated implant may be of between 1 mm and 10 mm, between 2 mm and 8 mm, between 3 mm and 6 mm, between 1 mm and 6 mm, about 1 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, or about 10 mm. In certain of these variations, the width (minor axis) of the cyclosporine-eluting elongated implant may be between 0.2 mm and 2 mm, 0.3 mm and 1.5 mm, 0.4 mm and 2 mm, 0.5 mm and 1 mm, about 0.2 mm, about 0.3 mm, about 0.4 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, about 1 mm, about 1.2 mm, about 1.4 mm, about 1.6 mm, about 1.8 mm, or about 2 mm (including all values and sub-ranges therein)..

[0153] In other variations, the at least one cyclosporine-eluting implant may be a microparticle implant (e.g., a microsphere, a microspheroid, a microovoid, or a microellipsoid). In thesevariations, the cyclosporine-eluting microparticle may have a maximum linear dimension of between 10 microns and 100 microns, between 20 microns and 50 microns, between 20 microns and 80 microns, between 10 microns and 80 microns, about 10 microns, about 15 microns, about 20 microns, about 25 microns, about 30 microns, about 35 microns, about 40 microns, about 50 microns, about 55 microns, about 60 microns, about 65 microns, about 70 microns, about 75 microns, about 80 microns, about 85 microns, about 90 microns, about 95 microns, and about microns (including all values and sub-ranges therein). In some variations, the at least one cyclosporine-eluting implant may comprise a plurality of cyclosporine-eluting microparticles.EXAMPLESExample 1: Dry Subconjunctival Delivery of Drug-eluting Implants Formulated with a Cyclosporine

[0154] An implantation system loaded with carrier-free drug-eluting microspheres, each of which contains cyclosporine, is removed from its sterile packaging and placed on a sterile surface. The subject’s eye and periocular area are treated with an antiseptic. The eye is then draped in the typical manner for ocular surgery, and an operating microscope and eyelid speculum are properly positioned and placed, respectively. The conjunctiva is grasped with conjunctival forceps.

[0155] The implantation system needle is advanced under direct microscopic visualization into the subconjunctival space. The actuator on the device handle is activated (button, slider, lever, and / or wheel). The pusher inside the needle moves distally toward the distal tip of the needle and advances the microspheres out of the needle into the subconjunctival space. This is visualized with a microscope. Visualization may also be performed with a slit lamp, loupes, or the naked eye. The needle is then withdrawn from the conjunctiva. Antibiotic drops are applied to the eye, and the eyelid speculum is removed.Example 2: Cyclosporine-eluting Implants

[0156] Heat-extruded, elongate cyclosporine-eluting implants were made using various formulations. For heat extrusion, dried polymer pellets and cyclosporine powder were fed into an extruder, which melted the polymer(s) mixed it with the cyclosporine, then fed the mixture through a die of a desired shape, which in this case was cylindrical, with a thickness ofapproximately 1mm diameter. The extruded polymer / cyclosporine mixture was then cooled to and cut into specified lengths, e.g., 3 mm or 6 mm. These implants were tested in in vitro settings. All tested implants comprised a mixture of cyclosporine and one or more polymers. The formulations tested are provided in Table 1.Table 1 : Cyclosporine-eluting implant formulations* Each percentage shown is the % w / w of the given ingredient in the formulation

[0157] In Table 1, each row is a given formulation, and each column shows the weight percentage (% w / w) of a given ingredient. Generally, the formulation was cyclosporine and one or a combination of bio-erodible polymers PLGA type 1, PLCL, and PLGA type 2. As such, for example, an implant of formulation CsAl consisted of 28% w / w cyclosporine and 72% w / w PLGA 1 (with a lactide:glycolide ratio of 85: 15), an implant of formulation CsA7 consisted of 42% w / w cyclosporine, 48% w / w PLGA l(with a lactide :glycolide ratio of 85: 15) and 10% w / w PLGA 2 (with a lactide:glycolide ratio of 50:50), and an implant of formulation CsA12 consisted of 42% w / w cyclosporine, 48% PLCL, and 10% 10% w / w PLGA 2 (with a lactide :glycolide ratio of 50:50).

[0158] The elution of cyclosporine for each formulation was tested in an in vitro setting as follows: Cylindrical implants were produced for each formulation through heat melt extrusion and placed in buffered saline. A sample of the buttered saline in a small volume (e.g. 2 pL-10 pL) was taken at intervals and cyclosporine was measured with HPLC, fresh buffered saline was added to replenish the volume, and a further sample was taken, then replenished at the next time interval. The results of the in vitro elution study are shown in FIG. 8 A. It was found thatformulations CsA9 through CsA12, having PLCL (with or without 10% PLGA) as the polymer, released the cyclosporine more robustly than PLGA-only formulations (CsAl, CsA3, CsA5, and CsA7). For example, the formulations that have PLCL released between about 20 micrograms (pg) and 35 pg of cyclosporine in 1 month and between about 50 pg and 100 pg of cyclosporine in about 4 months (126 days). By contrast, the PLGA-only formulations eluted less than 10 pg of cyclosporine in 1 month and less than 15 pg in about 4 months.

[0159] FIG. 8B shows an alternative plot based on the same results, but with the cumulative release of cyclosporine expressed as %LC (percentage label claim). In drug formulations, %LC refers to the percentage of the labeled amount of active pharmaceutical ingredient (API) that is actually present or measured in a dosage form, e.g. a drug-eluting implant. For example, if a drug-eluting implant is labeled to contain 2 mg of cyclosporine, then 2 mg is the LC. %LC expresses how much of the API is actually found in the product compared to the label claim, and is calculated as:In the context of drug-eluting implants, and as shown in FIG. 8B, the %LC is calculated based on the measured amount of API (in this case cyclosporine) left in an implant after incubation in the buffered saline is used to express what percentage of the API originally loaded into the implant has been released. For example as shown in FIG. 8B, after about 4 months (126 days), formulations CsA9 through CsA12, having PLCL (with or without 10% PLGA), released over 40% of the originally loaded cyclosporine. By contrast, the PLGA-only formulations (CsAl, CsA3, CsA5, and CsA7) released less than 20% of the originally loaded cyclosporine in the same time period (as shown in FIG. 8B).

[0160] FIG. 8C shows an alternative plot based on the same results, showing the average daily release at each time point. As shown in the figure, CsA9. CsAlO. CsAl 1. and CsA12 (which comprise PLCL) generally show higher per day release throughout the 126 day testing period compared to CsAl. CsA3. CsA5. and CsA5 (comprising PLGA). That said, within the PLGA group, CsA7 showed higher daily release compared to, e.g., CsA3 and CsA5. In addition, CsA12 showed a more even distribution of daily release compared to CsAlO, which started with higherrelease rates in the first 42 days, and CsA12 was able to maintain a higher daily release over the 126 day period compared to CsAl 1 (which has a lower loading% of cyclosporine compared to CsA12).Example 3: Subconjunctival Implantation of Cyclosporine-eluting Implants

[0161] Given the advantages discussed above in Example 2, formulations CsA7 and CsA12 produced and tested in Example 2 were selected for proof-of-concept animal studies with rabbit subjects. In each subject, one or two implants of 1 mm in diameter and a length of 3 mm or 6 mm were implanted in subconjunctival space. One control animal was implanted with blank PLGA microspheres. After one (1) month, the animals were sacrificed, and samples were taken of the following: sclera, conjunctiva, lower eyelid, upper eyelid, aqueous humor, vitreous humor, and tear fluid (using Schirmer strips). A blood sample was also taken.

[0162] For the tissue samples, the cyclosporine was quantified as follows: The tissue was homogenized in a 4: 1 acetonitrile:methanol mix, centrifuged for remove cellular debris. The supernatant was run through a high pressure liquid chromatography (HPLC) system using the following materials and conditions, and then analyzed with mass spectroscopy to quantitate the cyclosporine:Mobile phase A: 0.1% formic acid in water with 5 mM Ammonium acetate (NH4Ac) Mobile phase B: 0.1% formic acid in methanol with 2 mM NH4Ac GradientColumn: Waters, Xselect, C18, 50x2 mm, 5 umColumn: 40°CFlow rate: 0.6 mL / minInjection volume: 20 uLRun time: 3 min

[0163] Similar cyclosporine quantification processes were performed for tear and aqueous humor, but without homogenization.

[0164] The results of the cyclosporine quantification are shown in the table in FIG. 9. As shown there, for each eye of each animal, cyclosporine was quantified in the following: sclera, conjunctiva, cornea, lower eyelid, upper eyelid, aqueous humor, vitreous humor, and tear fluid, as well as in blood. Cyclosporine was quantified as ng / g, nanograms of cyclosporine per gram of sample from which the cyclosporine was measured. Therefore, if the cyclosporine was measured from a sclera sample, then, e.g., 100 ng / g would mean that there was 100 ng of cyclosporine per gram of the sclera sample from which the drug was quantified. As can be seen in FIG. 9, implantation of Csl2 formulation implants in subconjunctival space for 1 month resulted in a cyclosporine concentration of between 200 ng / g and 961 ng / g in the conjunctiva (compared to 29.2 ng / g or 21.8 ng / g under control conditions with implantation of blank microspheres). Because of presence of mucus secreting goblet cells, which are one of the targets of DED- induced inflammation, administration of cyclosporine to the conjunctiva or subconjunctival space as target locations may be, for example, desirable for treatment of DED. Therefore, that subconjunctival implantation of the CsA12 implants were able to provide a sustained presence of cyclosporine at substantially elevated concentrations in the conjunctiva indicates that such a treatment would be expected to treat DED. By way of comparison, previous studies have shown that, whereas cyclosporine administered as eye drops were able to provide cyclosporine at similar concentrations over 1-2 hours, the concentration decreased sharply thereafter, so that the cyclosporine concentration went back to at or near baseline by 12-24 hours after administration. Moreover, quantification of the CsA12 implants following extraction from the animal subjects indicated that about half (ranging from 43% to 65%) of the cyclosporine remained in the implants after the month of intraocular elution, indicating that the implants would have sustained elevated concentrations of the cyclosporine for an even longer duration.

[0165] A more modest sustained increase in cyclosporine was also seen following implantation of the CsA12 implant in tear fluid and sclera. Aside from those locations, it was found that cyclosporine did not readily spread to other parts of the eye even after one month: cyclosporine concentrations measured in the lower eyelid, upper eyelid, aqueous humor and vitreous humor were weakly and inconsistently higher than in the eyes treated with blankmicrospheres. For example, the aqueous humor samples taken from eyes implanted with the CsA12 formulation implants all had cyclosporine concentration of below the quantifiable limit (BQL). Moreover, the extended release of the cyclosporine in the subconjunctival space did not result in any measurable increase of cyclosporine in the blood.Example 4: Subconjunctival Implantation of Cyclosporine-eluting Implants - 6 months post-implantation

[0166] The proof-of-concept animal studies with rabbit subjects as disclosed in Example 3 is repeated, and the same protocol is applied as in Example 3 except that the animals are sacrificed at 6 months post-implantation. As with Example 3, samples are taken of the following: sclera, conjunctiva, lower eyelid, upper eyelid, aqueous humor, vitreous humor, tear fluid, and blood. As was the case in Example 3 with a 1 -month implantation, implantation of the cyclosporineeluting implants in the subconjunctival space results in a therapeutically effective concentration of cyclosporine being maintained in the conjunctiva at 6 months post-implantation.Concurrently, at 6 months post-implantation, the concentration of the cyclosporine in blood is below the quantifiable limit, or below a concentration that would indicate risk for non- ophthalmic side effects in the subject.

Claims

CLAIMS1. A method for treating dry eye disease of a human subject comprising: implanting at least one drug-eluting implant in an eye of the subject, wherein the drugeluting implant comprises a drug-eluting matrix comprising a bio-erodible polymer and cyclosporine that, at 1 month post-implantation in an animal model, results in a concentration of cyclosporine in conjunctiva of an eye of the animal model of 40 ng / g or greater, wherein a sufficient amount of the cyclosporine is delivered from the at least one drugeluting implant to the eye of the subject to reduce a symptom of the dry eye disease of the subject.

2. The method of claim 1, wherein the at least one drug-eluting implant is implanted in subconjunctival space, sub-Tenon’s space, intrascleral space, suprachoroidal space, or juxta- choroidal space of the eye.

3. The method of claim 2, wherein the at least one drug-eluting implant is implanted entirely in the subconjunctival space.

4. The method of claim 3, wherein the subconjunctival space is a subconjunctival space of the fornix.

5. The method of any one of claims 1-4, wherein the concentration of the cyclosporine at 1 month post-implantation is 0.2 ng / g or less in the blood of the human subject.

6. The method of any one of claims 1-5, wherein the concentration of the cyclosporine in the conjunctiva at 1 month post-implantation is between 40 ng / g and 1000 ng / g, between 50 ng / g and 1000 ng / g, between 60 ng / g and 1000 ng / g, between 80 ng / g and 1000 ng / g, between 100 ng / g and 1000 ng / g, between 150 ng / g and 1000 ng / g, between 200 ng / g and 1000 ng / g, between 300 ng / g and 1000 ng / g, between 400 ng / g and 1000 ng / g, between 500 ng / g and 1000 ng / g, between 600 ng / g and 1000 ng / g, between 700 ng / g and 1000 ng / g, between 800 ng / g and 1000 ng / g, 50 ng / g or greater, 60 ng / g or greater, 80 ng / g or greater, 100 ng / g or greater, 150 ng / g or greater, 200 ng / g or greater, 300 ng / g or greater, 400 ng / g or greater, 500 ng / g or greater, 600 ng / g or greater, 700 ng / g or greater, 800 ng / g or greater, or 900 ng / g or greater.

7. The method of any one of claims 1-6, wherein the at least one drug-eluting implant is configured to elute 15 micrograms or more of the cyclosporine in one month.

8. The method of any one of claims 1-7, wherein the at least one drug-eluting implant is configured to elute 40 micrograms or more of the cyclosporine in 4 months.

9. The method of any one of claims 1-8, wherein the at least one drug-eluting implant is configured to elute 2 micrograms or less per day for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months.

10. The method of any one of claims 1-9, wherein the bio-erodible polymer comprises one or more of poly(lactic-co-glycolic acid) (PLGA), and Poly(lactide-co-e-caprolactone) (PLCL).

11. The method of any one of claims 1-10, wherein the cyclosporine is between about 10% and about 70% by weight of the at least one drug-eluting implant.

12. The method of any one of claims 1-11, wherein the at least one implant is an elongated implant of between 1 mm and 10 mm in length (major axis) and between 0.2 mm and 2 mm in width (minor axis).

13. The method of any one of claims 1-12, wherein the at least one implant comprises a plurality of drug-eluting microparticles.

14. The method of claim 13, wherein each microparticle of the plurality of drug-eluting microparticles has a maximum linear dimension of between about 10 micron and about 100 microns.

15. An intraocular, drug-eluting implant for treating dry eye disease in a subject, the drug-eluting implant comprising: a drug-eluting matrix comprising a bio-erodible polymer and a cyclosporine, wherein the drug-eluting implant is configured to release a sufficient amount of the cyclosporine to reduce a symptom of the condition of the eye, and at 1 month post-implantation in an animal model maintains a concentration of the cyclosporine of 40 ng / g or greater in conjunctiva of an eye of the animal model.

16. The drug-eluting implant of claim 15, wherein the drug-eluting implant is configured to be implanted in subconjunctival space, sub-Tenon’s space, intrascleral space, suprachoroidal space, or juxta-choroidal space of the eye.

17. The drug-eluting implant of claim 16, wherein the drug-eluting implant is configured to be implanted entirely in the subconjunctival space.

18. The drug-eluting implant of claim 17, wherein the subconjunctival space is a subconjunctival space of the fornix.

19. The drug-eluting implant of any one of claims 15-18, wherein the drug-eluting implant is configured to maintain a concentration of the cyclosporine at 1 month post-implantation that is 0.2 ng / g or less in blood of the human subject.

20. The drug-eluting implant of any one of claims 15-19, wherein the drug-eluting implant is configured to maintain the concentration of the cyclosporine in the conjunctiva at 1 month postimplantation to be between 40 ng / g and 1000 ng / g, between 50 ng / g and 1000 ng / g, between 60 ng / g and 1000 ng / g, between 80 ng / g and 1000 ng / g, between 100 ng / g and 1000 ng / g, between 150 ng / g and 1000 ng / g, between 200 ng / g and 1000 ng / g, between 300 ng / g and 1000 ng / g, between 400 ng / g and 1000 ng / g, between 500 ng / g and 1000 ng / g, between 600 ng / g and 1000 ng / g, between 700 ng / g and 1000 ng / g, between 800 ng / g and 1000 ng / g, 50 ng / g or greater, 60 ng / g or greater, 80 ng / g or greater, 100 ng / g or greater, 150 ng / g or greater, 200 ng / g or greater, 300 ng / g or greater, 400 ng / g or greater, 500 ng / g or greater, 600 ng / g or greater, 700 ng / g or greater, 800 ng / g or greater, or 900 ng / g or greater.

21. The drug-eluting implant of any one of claims 15-20, wherein the drug-eluting implant is configured to elute 15 micrograms or more of the cyclosporine in one month.

22. The drug-eluting implant of any one of claims 15-21, wherein the drug-eluting implant is configured to elute 40 micrograms or more of the cyclosporine in 4 months.

23. The drug-eluting implant of any one of claims 15-22, wherein the drug-eluting implant is configured to elute 2 micrograms or more per day for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months.

24. The drug-eluting implant of any one of claims 15-23, wherein the bio-erodible polymer comprises one or more of poly(lactic-co-glycolic acid) (PLGA) and Poly(lactide-co-e- caprolactone) (PLCL).

25. The drug-eluting implant of any one of claims 15-24, wherein the cyclosporine is between about 10% and about 70% by weight of the drug-eluting implant.

26. The drug-eluting implant of any one of claims 15-25, wherein the drug-eluting implant is an elongated implant of between 1 mm and 10 mm in length (major axis) and between 0.2 mm and 2 mm in width (minor axis).

27. The drug-eluting implant of any one of claims 15-26, wherein the drug-eluting implant comprises a plurality of drug-eluting microparticles.

28. The drug-eluting implant of claim 27, wherein each microparticle of the plurality of drug-eluting microparticles having a maximum linear dimension of between about 10 micron and about 100 microns.

29. An intraocular, drug-eluting implant for treating dry eye disease in a human subject, the drug-eluting implant comprising: a drug-eluting matrix comprising one or more of poly(lactic-co-glycolic acid) (PLGA) or Poly(lactide-co-s-caprolactone) (PLCL); and a cyclosporine, wherein the cyclosporine is between about 10% and about 70% by weight of the drug-eluting implant.

30. The drug-eluting implant of claim 29, wherein the drug-eluting implant is an elongated implant of between 1 mm and 10 mm in length (major axis) and between 0.2 mm and 2 mm in width (minor axis).

31. The drug-eluting implant of claim 29 or claim 30, wherein the drug-eluting matrix comprises the PLGA.

32. The drug-eluting implant of any one of claims 29-31, wherein the PLGA comprises lactide and glycolide monomers at a lactide:glycolide ratio of between about 90: 10 and about 40:60.

33. The drug-eluting implant of any one of claims 29-31, wherein the PLGA comprises lactide and glycolide monomers at a lactide:glycolide ratio of between about 90: 10 and about 80:20.

34. The drug-eluting implant any one of claims 29-31, wherein the PLGA is a mixture of: a first PLGA comprising lactide and glycolide monomers at a lactide:glycolide ratio of between about 90: 10 and about 80:20; and a second PLGA comprising lactide and glycolide monomers at a lactide:glycolide ratio of between about 40:60 and about 60:40.

35. The drug-eluting implant of claim 29 or claim 30, wherein the drug-eluting matrix comprises a mixture of PLGA and PLCL.

36. The drug-eluting implant of claim 35, wherein: the PLGA comprises lactide and glycolide monomers at a lactide:glycolide ratio of between about 90: 10 and about 80:20; and the PCLC comprises lactide and £-caprolactone monomers at a lactide:s-caprolactone ratio of between about 70:30 and 50:50.

37. The drug-eluting implant of claim 29 or claim 30, wherein the drug-eluting matrix comprises the PLCL.

38. The drug eluting implant of claim 37, wherein the PCLC comprises lactide and 8- caprolactone monomers at a lactide:s-caprolactone ratio of between about 70:30 and 50:50.

39. A method for treating dry eye disease of a human subject comprising implanting at least one drug-eluting implant of any one of claims 29-28 in an eye of the subject.

40. A method of forming a system for treating a condition of an eye of a subject, the method comprising: inserting an implant formulation comprising a plurality of drug-eluting microparticles and a liquid carrier into a lumen of a cannula, wherein the cannula is configured for insertion into a target location in an eye; freezing the implant formulation.

41. A method of treating a condition of an eye of a subject, the method comprising: providing an implant formulation comprising a plurality of drug-eluting microparticles and a carrier within a lumen of a cannula, wherein the carrier is frozen; thawing the carrier within the lumen of the cannula, thereby making the carrier into a liquid carrier; advancing a distal end of the cannula to a target location in the eye; and implanting the implant formulation in the target location.

42. A method of delivering microparticles in the eye, the method comprising: providing an implant formulation comprising a plurality of drug-eluting microparticles and a carrier within a lumen of a cannula, wherein the implant formulation is frozen; thawing the carrier within the lumen of the cannula, thereby making the carrier into a liquid carrier; advancing a distal end of the cannula to a target location in the eye; and implanting the implant formulation in the target location.

Images