Bioerodible intraocular implants for the treatment of eye conditions

Abstract

The present disclosure relates to intraocular drug-eluting microparticle implants and dry microparticle formulations comprising a plurality of drug-eluting microparticle implants for treating ocular conditions, wherein the implants are configured to deliver a drug to the eye without a carrier. The present disclosure also relates to methods of treating ocular conditions by delivering one or more drugs or dry microparticle formulations from the drug-eluting implants to the anterior chamber, posterior chamber (e.g., sulcus), iridocorneal angle, sclera, cornea, limbus, subconjunctival space, sub-Tenon space, and vitreous.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates generally to bioerodible ocular implants (eg, drug-eluting implants) for treating ocular conditions, and related methods and systems for treating such ocular conditions.

[0002] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 428,389, filed November 28, 2022. All applications are incorporated herein by reference in their entirety. [Background technology]

[0003] Glaucoma is a group of optic neuropathies associated with specific structural changes in the optic nerve that ultimately result in irreversible visual field loss. This vision loss is often progressive and, if untreated, leads to blindness. According to the National Eye Institute of the National Institutes of Health, glaucoma is the leading cause of irreversible blindness worldwide. In 2020, approximately 3 million people in the United States were diagnosed with glaucoma. Worldwide, the number is 80 million. By 2040, more than 110 million people are expected to live with this potentially blinding condition ("Global Prevalence of Glaucoma and Projections of Glaucoma Burden through 2040," Ophthalmology 2014, H. 121:2081-2090). Glaucoma is broadly divided into two categories: open-angle glaucoma and angle-closure glaucoma. Open-angle glaucoma is approximately seven times more common than the angle-closure form in both the United States and Europe (Quigley HA, Broman AT. Br. J. Ophthalmol. 2006;90(3):262-267). The course of both forms of the disease is typically chronic and progressive vision loss, resulting in narrowing of the visual field. The ultimate outcome is permanent blindness. Because it is typically asymptomatic until the disease has progressed significantly, early diagnosis and treatment with regular eye examinations are important. Although 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). The prevalence of open-angle glaucoma is increased in black and Hispanic individuals. Furthermore, they are often diagnosed with more severe disease. Asians, Southeast Asians, Asian Indians, and Inuits are more commonly diagnosed with angle-closure glaucoma (e.g., Varma R, Ying-Lai M, Francis BA, et al., Los Angeles Latino Eye Study Group. Ophthalmology 2004;111(8):1439-1448; Tielsch JM, Sommer A, Katz J, Royal RM, Quigley HA, Javitt J. JAMA. 1991;266(3):369-374; Wormald 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] Angle-closure glaucoma typically results from an anatomical blockage of the anterior chamber angle and its associated drainage channels. The anatomical blockage prevents aqueous humor from efficiently reaching the drainage pathways, thereby resulting in elevated intraocular pressure. Surgical iridectomy, laser iridotomy, or lensectomy are often considered more definitive surgical options over more palliative medications such as cholinergic agonists (e.g., pilocarpine eye drops) to relieve pupillary obstruction.

[0006] Open-angle glaucoma (OAG) is far more common in the United States and causes significantly more vision loss than its closed-angle counterpart. While the exact pathophysiology of OAG is not fully understood, increased intraocular pressure (IOP) has been demonstrated to correlate with retinal ganglion cell death. A relationship exists between the secretion of aqueous humor by the ciliary body and its outflow from the eye via the conventional trabecular meshwork and the non-conventional uveoscleral pathway. This relationship and resulting imbalance determine IOP. Increased resistance to outflow in the trabecular meshwork or more distal aqueous humor collection channels is thought to be associated with increased IOP in OAG. Elevated IOP can cause mechanical stress in the lamina cribrosa, where retinal ganglion cell axons exit the eye and merge into the optic nerve. IOP-induced stress in the lamina cribrosa can deform, damage, and obstruct retinal axons, resulting in irreversible damage and vision loss. Such IOP-related damage typically occurs when pressure exceeds the population average, but can occur at lower or "normal" pressures depending on the individual's vulnerability. Conversely, many people with higher-than-average IOP do not develop glaucoma. A growing body of research is identifying genomic loci associated with glaucoma susceptibility. Thus, glaucoma may develop in patients with relatively high intraocular pressure relative to 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):e1002654). When ganglion cell death occurs in glaucoma, characteristic changes in the optic nerve head and nerve fiber layer become evident. This ultimately correlates with a characteristic pattern of visual field loss. Prompt referral to an eye care professional is important to treat glaucoma and slow the progression of irreversible damage and subsequent vision loss. There is no single gold standard test for diagnosing glaucoma. Typically, several criteria are considered when making a diagnosis of glaucoma.These include age, family history, ethnic background, IOP, corneal thickness, optical coherence tomography analysis of various retinal tissues, optic disc appearance, and peripheral visual field testing.

[0007] The primary goal of treatment is to slow progressive optic nerve damage to preserve vision and quality of life. Given that vision loss is irreversible, early diagnosis and intervention are important. Lowering IOP with treatment, along with ongoing diagnostic evaluation of treatment efficacy, are part of the mainstay of glaucoma treatment.

[0008] Initially, treatment typically consists of the minimum number of medications required to adequately lower IOP, including drugs from the following families of compounds: prostaglandins, prostaglandin analogs, β-adrenergic blockers, α-adrenergic agonists, carbonic anhydrase inhibitors, Rho-kinase (ROCK) inhibitors, and cholinergic agonists.

[0009] When medical treatment fails, is not tolerated, or is not possible, other forms of treatment may be added to or substituted for medical treatment. For example, laser therapy of the eye in the form of trabeculoplasty or cyclotectomy (endoscopic or transscleral) may be performed. In more advanced cases or under certain circumstances, open surgery may be considered. Trabeculectomies, valves, or shunts can be used to help control IOP. In recent years, minimally invasive glaucoma surgery (MIGS) has become a common surgical approach to treating glaucoma. Various techniques have been employed to reduce IOP while reducing exposure to the surgical risks posed by more invasive treatments such as trabeculectomy or valve placement. Nearly 175,000 surgical procedures were performed in 2017. Surgeries included over 20,000 trabeculectomies, over 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] Medical therapy is the preferred initial treatment for OAG in the United States, but it has many problems. Instillation is cost-prohibitive for patients, and patients may forget to use the drops regularly. Furthermore, proper instillation into the conjunctival fornix can be more difficult, especially in the hands of elderly or arthritic patients. Excessive instillation, such as multiple instillations, and subsequent medication waste are also problems. However, even with proper instillation, medication is wasted. For example, a typical eye drop volume may be 60–90 microliters, but the ocular surface typically retains less than 10 microliters. Therapeutic ingredients and the preservatives often combined with them can lead to ocular surface disease, discomfort, inflammation, dry eyes, and decreased corneal sensitivity, all of which can irritate the eye and further reduce adherence. Multiple eye drop medications can also lead to medication confusion and misuse. All of these factors combine to create problems for the mainstay of glaucoma medications. However, the drug avoids many of the more serious complications that can occur with surgery.

[0011] Surgical treatment of glaucoma is typically reserved as a second-line treatment in the United States. This is gradually changing, with microinvasive glaucoma surgery (MIGS) becoming more mainstream. Nevertheless, glaucoma surgery carries its own risks. One of the more problematic complications is bacterial endophthalmitis, a potentially visually destructive eye infection. However, there are many other complications of glaucoma surgery, including failure, hypotony, hemorrhage, malignant glaucoma, progression, iris hemorrhage, retinal detachment, and many others. Furthermore, the use of antimetabolites and glaucoma drainage devices in addition to trabeculectomy results in long-term complications.

[0012] Although glaucoma is addressed in more detail herein, many other eye diseases are successfully treated with drugs. In addition to being used to medically treat various eye diseases, drugs are also often used as adjuncts in the surgical treatment of eye diseases. They are used to treat ocular surface diseases, corneal diseases, scleral diseases, uveitis, vitreous diseases, and chorioretinal diseases.

[0013] Age-related macular degeneration (AMD) is a common cause of vision loss in the United States and the third leading cause of blindness worldwide. It is associated with degeneration of the retinal pigment epithelium and Bruch's membrane, which can lead to retinal damage and vision loss. Unlike the previously described "dry" degeneration, further degeneration and the resulting growth of neovascularization from the underlying choriocapillaris can lead to significant vision loss. This latter process is referred to as "wet" macular degeneration. One of the more common forms of treatment is periodic intravitreal injections of antibodies or drugs targeting vascular endothelial-derived growth factor (VEGF). Patients often require such injections of antibody-derived therapeutics, including anti-VEGF drugs, typically ranibizumab, aflibercept, or bevacizumab, every 4 to 8 weeks to control wet macular degeneration. At the heart of this treatment are significant issues regarding cost, complications, and associated morbidity.

[0014] Other retinal diseases, including macular edema, vascular occlusion, diabetic retinopathy, retinal degeneration, and retinal dystrophies, require drug treatment. Uveitis can affect the choroid, ciliary body, and iris. Examples include iritis and other forms of uveitis that may respond well to various drugs, such as steroids. Steroids are often administered as oral or topical treatments. For more severe cases, such as Behçet's disease, more aggressive cytotoxic agents and chemotherapy may be used.

[0015] The vitreous can also be the site of ocular disease. It can harbor opacities or hemorrhages that interfere with vision. In other instances, it can accumulate inflammatory cells in the setting of vitritis, which can also lead to vision loss.

[0016] The lens of the eye is subject to many diseases, the most common of which are age-related. Lens opacity or cataracts often require surgical correction in the form of cataract surgery. Many drugs have been used to delay cataract formation, but to date, none have proven significantly effective. After cataract surgery, various drugs are often used to reduce the chance of infection or inflammation.

[0017] Corneas can become opaque, scarred, or distorted due to diseases such as shingles or simple infections, keratitis, keratoconus, various infectious diseases, or other corneal degeneration. Additionally, transplanted corneas can be subject to immune-mediated rejection or recurrence of the primary ocular disease.

[0018] Scleral diseases can result from immune processes or infection. Indeed, one of the most common eye diseases is myopia, or nearsightedness, and the sclera is thought to play a key role in determining the axial length and refractive status of the eye. Diluted topical atropine, which acts by inducing cycloplegia, or paralysis of the cycloid body, has been shown to reduce the incidence of axial myopia in children. Complex pathways likely contribute to the development of myopia in children. Given the large proportion of the world's population affected, this area is of great interest.

[0019] Dry eye disease (DED) encompasses a number of disease states, defined by TFOS DEWS II Ocul. Surf., 2017, 15(3), 269-650, as "a multifactorial disease of the ocular surface characterized by a loss of tear film homeostasis 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 broadly divided into two classes: aqueous tear-deficient dry eye (ADDE) and evaporative dry eye (EDE), each of which can be further divided into subclasses. One of the major conditions associated with DED, particularly EDE, is meibomian gland dysfunction (MGD), an umbrella term that encompasses several disorders. The destruction and obstruction of meibomian glands negatively impacts the quality and quantity of meibum, a lipid-rich secretion that protects the ocular surface from damage and premature tear evaporation (Chhadva et al., Ophthalmology, 2017, 124(11 Suppl), S20-S26). Each eyelid contains approximately 20-40 meibomian glands, which produce meibum, a substance that coats tears and prevents premature tear evaporation. When healthy, patent, and properly functioning, meibomian glands have a liquid, olive-oil-like consistency. Each blink exerts a squeezing force on the meibomian glands, squeezing some of the clear liquid meibum out of the gland opening and strengthening the outermost lipid layer of tears.In MGD-based EDE, the development of imbalances in natural lipids and lipid chemistry leads to a higher meibum melting temperature, which ultimately leads to the meibum transitioning from a healthy, clear, liquid state to a cloudy, semi-hardened state to a hardened state in advanced disease. Ultimately, as the disease progresses and the meibum's lipid chemistry deteriorates, the hardened meibum becomes unavailable and ineffable, leading to a poor tear lipid layer and premature tear evaporation. In obstructive MGD, blinking results in little or no expression of meibum due to its hardened physiochemical state and inability to be excreted (or not), the impaired lipid layer, and accelerated tear evaporation.

[0020] Globally, the prevalence of dry eye disease (DED) is estimated at 5-20 percent, with approximately 16 million Americans diagnosed. It is estimated that 86% of these DED patients have MGD-related EDE (Lemp, et al., Cornea, 2012, pp. 472-478). Individuals with DED suffer from insufficient tear production, poor tear quality, or both, resulting in redness, stinging, burning, itching, light sensitivity, watery eyes, blurred vision, irregularities of the ocular surface, and damage to the corneal or conjunctival epithelium and tissues. The majority of dry eye patients are believed to have at least some degree of both water and lipid deficiency. Treatments are primarily palliative, and no widespread cure for DED has been developed.

[0021] Drugs can be administered in a variety of ways for these and other eye diseases. While there are systemic administration routes, such as oral or intravenous drug administration, the eye, located on the surface of the body, is particularly well suited for topical administration. Therefore, topical drug administration routes are preferred in most cases. This can limit exposure of the rest of the body to the drug and reduce the amount of drug required. Currently, the most common drug administration route for glaucoma is the topical eye drop approach. Such topically administered drugs typically diffuse across the cornea into the eye. For retinal diseases, drug injection is a common route.

[0022] Given the above-mentioned difficulties in treating diseases such as glaucoma, age-related macular degeneration, and dry eye disease, there is a need for safer, more effective, and convenient treatments that address the shortcomings of current standard treatments. [Prior art documents] [Non-patent literature]

[0023] [Non-Patent Document 1] “Global Prevalence of Glaucoma and Projections of Glaucoma Burden through 2040”, Ophthalmology 2014, H.121:2081-2090 Summary of the Invention [Means for solving the problem]

[0024] Disclosed herein are drug-eluting implants for treating ocular conditions and methods of using them. In some variations, the drug-eluting implants are bioerodible microspheres. Such implants are configured to be implanted into a subject's eye without a liquid carrier, for example, in the form of a dry implant formulation containing multiple implants.

[0025] Also disclosed herein are methods for treating an ocular condition in a subject. These methods may include implanting at least one drug-eluting implant into the eye of the subject without the use of a liquid carrier. In such methods, a drug may be delivered from the at least one drug-eluting implant to alleviate symptoms of the ocular condition. [Brief explanation of the drawings]

[0026] [Figure 1] 1 shows a cross-sectional view of the anatomy of a normal human eye. [Figure 2] 1 shows an exemplary drug-eluting implant. [Figure 3A]1 illustrates an exemplary implant system. [Figure 3B] 1 illustrates an exemplary implant system. [Figure 3C] 1 illustrates an exemplary implant system. [Figure 3D] 1 illustrates an exemplary implant system. [Figure 3E] 10 illustrates an alternative drive assembly included in the implant system. [Figure 4] 1 shows a flow chart of a method for loading an embodiment of a cannula of an implantation system with a dry implant formulation. [Figure 5A] 10 illustrates an exemplary method of dry implant formulation into an embodiment of a cannula of an implantation system. [Figure 5B] 10 illustrates an exemplary method of dry implant formulation into an embodiment of a cannula of an implantation system. [Figure 6] 1 shows a flow chart of a method for implanting a dry implant formulation. [Figure 7] An exemplary method for implanting a dry implant formulation into the eye to treat an ocular condition is provided. DETAILED DESCRIPTION OF THE INVENTION

[0027] overview Described herein are devices, systems, and methods for treating ocular conditions (e.g., glaucoma, dry eye disease, and others described herein). Generally, such devices are intended to be implanted in the eye (e.g., one or more of the following: sulcus, posterior chamber, anterior chamber, vitreous body, suprachoroidal space, subretinal space, retrobulbar space, peribulbar space, intracapsular space, Tenon's capsule, sub-Tenon's space, intrascleral space, subconjunctival space, intracapsular space, Berger's space) to release one or more drugs to one or more areas affected by an ocular disease or condition. For example, the devices described herein may be intraocular implants.

[0028] The devices described herein may generally include intraocular drug-eluting implants for treating one or more ocular conditions. 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 bioerodible material (e.g., a bioerodible polymer) that degrades over a predetermined period of days, weeks, months, or years and delivers a drug(s) over some or all of that same period. Additionally or alternatively, the drug-eluting implants and / or drug-eluting matrices of the implants may comprise a material that preferentially releases a drug or drugs when in an aqueous environment, such as tears, body fluids, or serum, e.g., when in the eye or a portion thereof, compared to a dry environment. In some variations, the drug-eluting implants may be spherical (e.g., microspheres), spheroids, ellipsoids, or ovoids. The drug-eluting implants may be approximately spherical. In some variations, the drug-eluting implants may be needle- or rod-shaped. In some variations, the drug eluting implant may be a rectangular prism. In some variations, the drug eluting implant may be a pellet or particle. In some variations, the drug eluting implant may be irregular in shape. The drug eluting implant may be a submillimeter ("sub-mm") drug eluting implant sized such that the implant's largest linear dimension (e.g., diameter if spherical, major axis if oval, or spatial diagonal if rectangular) is less than 1 millimeter. As used herein, a sub-mm drug eluting implant may also be referred to as a "microparticle implant." The drug eluting implant may also be a submicron drug eluting implant sized such that the largest linear dimension is less than 1 micron. As used herein, a submicron drug eluting implant may also be referred to as a "nanoparticle implant."

[0029] Also described herein are implant formulations that may include multiple particulate implants, as well as implant systems configured to deliver the implant formulations to a subject's eye. In some variations, the implant formulation may be a dry implant formulation that does not include a liquid carrier, and the implant system may be configured to deliver the dry implant formulation that does not include a liquid carrier to a subject's eye. In some variations, one or more particulate 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 cases, one or more drug-eluting implants or implant formulations (e.g., a dry implant formulation as described herein) may be pre-loaded into a corresponding implantation system, while in other variations, one or more implants may be provided separately from the implantation system, and the one or more implants may be loaded or otherwise positioned into the implantation system (e.g., into a cannula of the implantation system) by the user. In some of these variations, one or more implants may be provided separately, prepared as an implant formulation (e.g., a dry implant formulation), and the implant formulation may be loaded or otherwise positioned within the implant system (e.g., within a cannula of the implant 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 example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 50, 100, or more implants or implant formulations may be delivered sequentially or simultaneously.

[0030] A method for treating an ocular condition may generally include advancing one or more drug-eluting implants (e.g., microspheres) or an implant formulation comprising multiple implants (e.g., a dry implant formulation disclosed herein) to a target location (e.g., an implantation site) within the eye, positioning the one or more drug-eluting implants or implant formulations at the one or more target locations within the eye, and delivering one or more drugs from the implant(s) to the target location and / or other locations within the eye to treat the ocular condition and / or alleviate one or more symptoms associated with the ocular condition. For example, in some variations, the target location may be the subconjunctival space, and the method may generally include advancing one or more drug-eluting implants or dry implant formulations through the conjunctiva, positioning the one or more implants or implant formulations (e.g., a dry implant formulation as disclosed herein) within the subconjunctival space, and delivering one or more drugs from the implants to the subconjunctival space to treat the ocular condition and / or alleviate one or more symptoms of the ocular condition. In some variations, the target location may be the anterior chamber, and the method may generally include advancing a drug-eluting implant or implant formulation (e.g., a dry implant formulation as disclosed herein) through the conjunctiva and 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 ocular condition and / or alleviate one or more symptoms of the ocular condition. In some variations, the target location may be the vitreous body, and the method may generally include advancing and positioning a drug-eluting implant or implant formulation (e.g., a dry implant formulation as disclosed herein) in the vitreous body to treat the ocular condition and / or alleviate one or more symptoms of the ocular condition.In some variations, the target location may be the suprachoroidal space, and the method may generally include advancing and positioning a drug-eluting implant or implant formulation (e.g., a dry implant formulation as disclosed herein) into the suprachoroidal space, optionally via an ab externo approach or an ab interno approach through the anterior chamber angle, to treat an ocular condition and / or reduce one or more symptoms of the ocular condition. Additionally or alternatively, such an implant or implant formulation (e.g., a dry implant formulation as disclosed herein) may be advanced using an implantation system. Ocular conditions may include, but are not limited to, ocular surface diseases, corneal diseases, scleral diseases, uveitis diseases, vitreous diseases, optic nerve diseases, choroidal diseases, and retinal diseases. Implantation of the drug-eluting implant or implant formulation (e.g., a dry implant formulation as disclosed herein) may be performed in a clinic by a general ophthalmologist, thus avoiding the need for expensive surgery performed by a specialist. Additionally or alternatively, implantation of a drug-eluting implant or implant formulation (e.g., a dry implant formulation disclosed herein) may be performed in an operating room as a stand-alone procedure or may be combined with other procedures (e.g., cataract surgery).

[0031] Implants or implant formulations (e.g., dry implant formulations disclosed herein) present in the posterior chamber (e.g., within the sulcus, partially extending into the remainder of the posterior chamber) may utilize naturally occurring electrical currents (e.g., forward-flowing current, backward-flowing current) that can deliver one or more drugs to different parts of the eye. For example, it has been shown that aqueous humor produced in the ciliary body and released into the ciliary sulcus and / or posterior chamber can move forward into the anterior chamber, where it can move by convection. Furthermore, the posterior aqueous humor flow reaches the retina, thus delivering drugs (e.g., anti-vascular endothelial growth factor antibodies for wet macular degeneration) to the retina and choroid.

[0032] Thus, the devices, systems, and methods described herein can provide effective treatment for many ocular conditions while avoiding the costs and consequences of using a formal operating room, reducing the total amount of medication required, reducing or eliminating systemic drug exposure through spatially targeted implantation, reducing or eliminating the need for frequent injections or daily eye drops, and increasing patient adherence to the proposed treatment regimen by eliminating the repeated administration of eye drops or injections used in conventional treatments. The devices, systems, and methods described herein can deliver much smaller amounts of drug to the target tissue without compromising efficacy, thus reducing the side effects of the drug and preservatives. For example, timolol may be effective in treating ocular hypertension, but systemically available timolol is known in the art to cause cardiac and pulmonary complications. This safety issue imposes limitations on the dosage and frequency of administration when using timolol eye drops to treat ocular hypertension. Dry delivery of a timolol-eluting implant to the eye (e.g., the subconjunctival space or sub-Tenon's space) allows for the delivery of timolol at higher ocular concentrations and lower systemic concentrations (e.g., in the serum) compared to eye drops. Also, for example, dorzolamide hydrochloride eye drops typically cause pain and discomfort due to the low pH typically required to dissolve dorzolamide in solution. Dry delivery of a dorzolamide hydrochloride, dorzolamide base, or brinzolamide-eluting implant eliminates the pH or solubility issues encountered with topical administration and reduces the pain and / or discomfort associated with dorzolamide or brinzolamide eye drops.

[0033] anatomical structure By way of background, FIG. 1 shows a partial cross-section of the anatomy of a normal human eye. The eye can be conceptualized as a fluid-filled sphere. At the anterior, it is bounded by the cornea (100), a three-layered, transparent tissue that allows light to enter, acting like a protective window into the eye. The periphery of the cornea (100) is known as the corneal limbus ("limbus") (102), which defines its junction with the sclera (104). The limbus (102) contains the stem cells of the ocular surface, contains numerous aqueous humor outflow pathways, and is highly vascularized.

[0034] The sclera (104) is the opaque, tough, and protective outer layer of the eye. Like the cornea, it is essentially avascular. Above the sclera (104) is the conjunctiva (106), a thin, transparent tissue that overlies the sclera (104) and the inside of the eyelids. It helps lubricate the ocular surface by providing mucus and tears. Additionally, it is vascularized and helps contribute to the eye's immune response. The space below the conjunctiva is the subconjunctival space (122). The Tenon's capsule (124) is a membrane that covers the outside of the eyeball between the conjunctiva and the sclera. The Tenon's capsule contributes to the structural integrity of the eye and provides another layer of protection for the eyeball. The sub-Tenon's space (125), also known as the episcleral space, is the space between the Tenon's capsule and the sclera. The sub-Tenon's capsule contains loose connective tissue, blood vessels, and fat, providing a cushioning effect to facilitate eye movement.

[0035] Behind the cornea is the iris (108), the colored part of the eye. It is a ring-shaped structure that can adjust its opening (pupil) to regulate the amount of light entering the eye. Bright light causes the pupil to constrict, thereby limiting excessive light exposure or resulting glare. In dim lighting, the pupil opens to capture more of the available light.

[0036] The aqueous humor-filled anterior chamber angle (110) lies between the iris and the cornea. At its periphery is the anterior chamber angle (110), where aqueous humor drains from the eye through the trabecular meshwork and Schlemm's canal. A circular band of the ciliary body is visible during gonioscopy. This region provides intracameral access to the suprachoroidal space.

[0037] Behind the iris (108) is the lens (112). A normal lens is clear and focuses light onto the retina to form a sharp image. With age or disease, the lens (112) can become cloudy, a condition known as a cataract. The lens (112) is suspended within the eye by fibers known as the zonules. One end of the zonules attaches 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 changes the load on the zonules, thereby increasing the curvature of the lens, or flattening of the lens (112). This is the primary mechanism our eyes use for focusing.

[0038] The ciliary body (114) not only contains the muscles that load the zonules, but also secretes aqueous humor, which travels through the ciliary sulcus (116), the periphery of the posterior chamber. Implants or devices present in the ciliary sulcus or peripheral posterior chamber avoid the visual axis and therefore 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 the flow of aqueous humor can also drive fluids and substances through the vitreous body and through the retina. In other words, the current is bidirectional. The posterior chamber is the space of 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 anterior surface of the ciliary body (114) and the posterior surface of the iris. This portion of the posterior chamber is typically 12 mm in diameter.

[0039] The vitreous humor (118) is a gelatinous substance that fills the central cavity of the eye. Its volume is approximately 4–4.5 mL (milliliters). The vitreous is bounded peripherally and posteriorly by the retina. Anteriorly, the vitreous is bounded by Berger's space, which separates the vitreous cavity from the lens centrally, and Petty's canal, also known as the zonular space, which separates the vitreous cavity from the lens peripherally. The retina is the light-sensitive nerve layer lining the back of the eye. In humans, the retina has 10 layers, the outermost of which, closest to the sclera (104), is the retinal pigment epithelium. This layer is involved in macular degeneration.

[0040] Between the sclera and the retina is a portion of the uvea known as the choroid (120). It is a high-flow, low-resistance layer of blood vessels that nourishes and oxygenates the outer two-thirds of the retina. It is also involved in macular degeneration. The macula is the area of ​​the retina responsible for sharp, high-contrast vision. The macula is the functional center of the retina and provides central vision to humans. For example, the ability to clearly read or recognize faces depends on the macula. Macular degeneration affects this area and can therefore have devastating effects on vision. The optic nerve is a union of approximately one million retinal axons that carry visual information from the eye to the visual center in the brain.

[0041] Drug-eluting implants Generally, the devices, systems, and formulations described herein include drug-eluting implants for treating one or more ocular conditions by delivering one or more drugs to the eye. The implants may have a round (e.g., spherical, approximately spherical, spheroidal, oval, elliptical) and / or irregular shape and may be configured to be implanted into one or more structures and / or cavities of the eye. For example, the drug-eluting implants may be configured to reside partially or entirely in one or more of the subconjunctival space, anterior chamber, sulcus, posterior chamber, suprachoroidal space, subretinal space, or vitreous body of one or both eyes. In some variations, the implants may be particulate implants (e.g., microspheres), as discussed in more detail herein.

[0042] In some variations, as described in more detail herein, the implant may be configured to be delivered without a carrier (e.g., a vehicle, etc.). As used herein, a carrier is defined as a substance (e.g., a fluid) used as a vehicle for administration of a pharmaceutical compound or device. For example, an implant may be delivered without a carrier (i.e., dry) or with a carrier (e.g., one or more implants suspended in a fluid). It will be understood that delivery of an implant using a non-fluid additive or composition, such as a binder (e.g., sucrose, gelatin, or cellulose), is considered dry delivery in accordance with the present disclosure.

[0043] The implant may include one or more drugs and may be configured to release or elute the one or more drugs over time (e.g., over a predetermined period of time). In certain variations, the implant may be configured or formulated to preferentially release the one or more drugs when in an aqueous environment, such as in tears, body fluids, interstitial fluid, or serum, e.g., when in the eye or a portion thereof, compared to a dry environment. In variations in which the drug-eluting implant is a particulate implant (e.g., microsphere), the particulate implant may include one or more drugs, such as within a drug-eluting matrix forming the particulate implant and / or within a coating on its outer surface. Nevertheless, the implant may be drug-eluting or otherwise configured to deliver, administer, or provide one or more drugs to the eye.

[0044] FIG. 2 shows an exemplary drug-eluting implant described herein, with multiple drug-eluting implants (202) present within the scleral wall, multiple drug-eluting implants (204) present within the subconjunctival space, multiple drug-eluting implants (206) present within the sulcus, and multiple drug-eluting implants (208) present within the sub-Tenon's space.

[0045] As shown in FIG. 2 , the drug-eluting implant may include rounded shapes, such as microspheres, microspheroids, microovoids, microellipsoids, etc. In some variations, therefore, the round drug-eluting implants described herein may have various cross-sectional shapes, including, for example, circular, oval, elliptical, etc. In some variations, the drug-eluting implant may be any other shape as described above, such as a needle, rod, cuboid, or irregular shape. Generally, 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 exterior surface of the implant may be coated with the drug-eluting matrix, or only a portion of the implant (e.g., one-third, one-half, two-thirds, etc.) 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 a drug-eluting matrix and one or more additional substances that control the elution rate, control the degradation rate, or provide biocompatibility. The one or more additional substances may be mixed with the drug-eluting matrix or coated on the surface of the drug-eluting implant. In some variations, the drug-eluting matrix may comprise a mixture, optionally homogeneously dispersed, of one or more drugs and one or more bioerodible polymers.

[0046] In some variations, the particulate implants described herein may be characterized by their largest linear dimension (diameter if spherical, major axis if ovoid), which may be from about 0.1 μm to about 500 μm. In some variations, the implants may be, independently, from about 0.1 μm to about 40 μm, from about 0.1 μm to about 30 μm, from about 0.1 μm to about 20 μm, from about 0.1 μm to about 10 μm, from about 0.1 μm to about 1 μm, from about 0.1 μm to about 400 μm, from about 0.1 μm to about 300 μm, from about 0.1 μm to about 200 μm, from about 0.1 μm to about 100 μm, from about 0.1 μm to about 10 μm, from about 0.5 μm to about 40 μm, from about 0.5 μm to about 30 μm, from about 0.5 μm to about 20 μm, from about 0.5 μm to about 10 μm, or from about 1 μm to about 400 μm. μm, approximately 1 μm to approximately 300 μm, approximately 1 μm to approximately 200 μm, approximately 1 μm to approximately 100 μm, approximately 1 μm to approximately 10 μm, approximately 1 μm to approximately 5 μm, approximately 5 μm to approximately 100 μm, approximately 10 μm to approximately 100 μm, approximately 10 μm to approximately 90 μm, approximately 10 μm to approximately 80 μm, Approx. 10 μm to approx. 70 μm, approx. 10 μm to approx. 60 μm, approx. 10 μm to approx. 50 μm, approx. 10 μm to approx. 40 μm, approx. 10 μm to approx. 30 μm, approx. 20μm to about 70μm, about 20μm to about 60μm, about 20μm to about 50μm, about 20μm to about 40μm, about 20μm to about 30μm, about 40μm to about 100μm, about 30μm to about 90μm, about 30μm to about 80μm, about 30μm to about 70μm, about 30μm to about 60μm, about 30μm to about 50μm, about 30μm to about 40μm, about 40μm to about 100μm, about 40μm to about 90μm, about 40μm to about 80μm, about 40μm to about 70μm, about 40μm to about 60μm, about 40μm to about 50μm, about It may have a maximum linear dimension of 50 μm to about 100 μm, about 50 μm to about 90 μm, about 50 μm to about 80 μm, about 50 μm to about 70 μm, about 50 μm to about 60 μm, about 60 μm to about 100 μm, about 60 μm to about 90 μm, about 60 μm to about 80 μm, about 60 μm to about 70 μm, about 70 μm to about 100 μm, about 70 μm to about 90 μm, about 70 μm to about 80 μm, about 80 μm to about 100 μm, about 80 μm to about 90 μm, or about 90 μm to about 100 μm (including all subranges and values ​​therein).In some variations, the implant may have a maximum linear dimension of about 0.1 μm, 0.2 μm, 0.3 μm, 0.4 μm, 0.5 μm, 0.6 μm, 0.7 μm, 0.8 μm, 0.9 μm, 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, 15 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, or 500 μm.

[0047] In some variations, a mixture of implants described herein (e.g., implants of different sizes, different shapes, implants with different drugs) may be delivered. In some cases, it may be beneficial to administer a mixture of implants described herein, where the mixture includes implants of similar sizes (e.g., a majority of the implants have a maximum linear dimension (which, in the case of microsphere implants, may be diameter) within 5%, 10%, 15%, or 20% of the average maximum linear dimension of the implants in the mixture). Without being bound by theory, for example, using implants of similar sizes in a dry implant formulation may help prevent lattice formation between individual implants, which may reduce or prevent clogging of an implant system loaded with multiple implants or dry implant formulations.

[0048] When two or more implants are delivered (e.g., as an implant formulation), they may collectively have an average maximum linear dimension, e.g., in some variations, the two or more implants may have an average maximum linear dimension of about 0.1 μm to about 500 μm. In some variations, the implants may collectively have a diameter of about 0.1 μm to about 40 μm, about 0.1 μm to about 30 μm, about 0.1 μm to about 20 μm, about 0.1 μm to about 10 μm, about 0.1 μm to about 1 μm, about 0.1 μm to about 400 μm, about 0.1 μm to about 300 μm, about 0.1 μm to about 200 μm, about 0.1 μm to about 100 μm, about 0.1 μm to about 10 μm, about 0.5 μm to about 40 μm, about 0.5 μm to about 30 μm, about 0.5 μm to about 20 μm, about 0.5 μm to about 10 μm, or about 1 μm to about 400 μm. m, approx. 1 μm to approx. 300 μm, approx. 1 μm to approx. 200 μm, approx. 1 μm to approx. 100 μm, approx. 1 μm to approx. 10 μm, approx. 1 μm to approx. 5 μm, approx. 5 μm to approx. 100 μm, approx. 10μm to about 70μm, about 10μm to about 60μm, about 10μm to about 50μm, about 10μm to about 40μm, about 10μm to about 30μm, about 10μm to about 20μm, about 20μm to about 100μm, about 20μm to about 90μm, about 20μm to about 80μm, about 2 0μm to about 70μm, about 20μm to about 60μm, about 20μm to about 50μm, about 20μm to about 40μm, about 20μm to about 30μm, about 40μm to about 100μm, about 30μm to about 90μm, about 30μm to about 80μm, about 30μm to about 70μm, about 3 0 μm to approx. 60 μm, approx. 30 μm to approx. 50 μm, approx. 30 μm to approx. 40 μm, approx. 40 μm to approx. 100 μm, approx. 40 μm to approx. 90 μm, approx. The crystalline cellulose may have an average maximum linear dimension of from about 100 μm to about 100 μm, from about 50 μm to about 90 μm, from about 50 μm to about 80 μm, from about 50 μm to about 70 μm, from about 50 μm to about 60 μm, from about 60 μm to about 100 μm, from about 60 μm to about 90 μm, from about 60 μm to about 80 μm, from about 60 μm to about 70 μm, from about 70 μm to about 100 μm, from about 70 μm to about 90 μm, from about 70 μm to about 80 μm, from about 80 μm to about 100 μm, from about 80 μm to about 90 μm, or from about 90 μm to about 100 μm (including all subranges and values ​​therein).In some variations, the implants may collectively have an average maximum linear dimension of about 0.1 μm, 0.2 μm, 0.3 μm, 0.4 μm, 0.5 μm, 0.6 μm, 0.7 μm, 0.8 μm, 0.9 μm, 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, 15 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, or 500 μm.

[0049] The implants (e.g., microparticles such as microspheres) described herein may include a drug-eluting matrix. As used herein, "drug-eluting matrix" refers to a material impregnated with a drug, where the drug is released from the material when positioned in the eye. In some variations, the drug may be slowly released from the material over a set period of time. The drug-eluting matrix may include, for example, a polymer impregnated with a drug, where the drug is released from the polymer while implanted in the eye. In certain embodiments, the drug-eluting matrix may be erodible so that it safely dissolves or disintegrates into non-toxic or biocompatible components within a predetermined period of time inside the subject. In some embodiments, the microsphere is composed entirely of the drug-eluting matrix. The drug-eluting matrix described herein may form a coating on or filler within the structure of the drug-eluting implant described herein. For example, in some embodiments, the microspheres may comprise a hollow interior chamber containing a drug-eluting matrix, and the microspheres may further comprise fenestrations (e.g., openings) through the walls of the microspheres for delivery of drug from the drug-eluting matrix in the interior chamber to the eye. Additionally or alternatively, all or a portion of the implant may include a drug-eluting matrix in the form of a coating.

[0050] 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 human subjects, 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), and the like. Examples of suitable biocompatible polymers include polyethylene (HDPE), poly(styrene-block-isobutylene-block-styrene) (SIBS), polyurethane, polycarbonate, polypropylene, polymethylmethacrylate (PMMA), polybutylmethacrylate, polyester, polytetrafluoroethylene (PTFE), silicone, acrylic polymers, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl chloride, ethyl vinyl acetate, collagen, collagen derivatives, flexible fused silica, polyolefins, NYLON® polymers, polyimides, polyacrylamides, fluorinated elastomers, and copolymers and blends thereof. In some variations, the biocompatible polymer can be a thermoresponsive polymer (e.g., poly(N-isopropylacrylamide) (PNIPAM)). The implants (e.g., microspheres) may be fully or partially bioerodible (e.g., biodegradable) and may include, for example, poly(D,L-lactide), poly(D,L-lactide-co-glycolide), poly(D,L-lactide) acid, and polyethylene glycol 3350.In other words, in some variations, the entire drug-eluting implant (e.g., the entire microsphere) may be completely bioerodible (e.g., biodegradable). The elution rate of a drug from an erodible implant (e.g., a microsphere) described herein may be controlled by selecting an appropriate erodible material (e.g., a polymer) with predictable release characteristics (e.g., release rate). In some embodiments, an implant (e.g., a microsphere) may comprise an erodible drug-eluting matrix with a variable erosion rate. 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, drug elution from an implant (e.g., a microsphere) described herein may have a constant or variable rate. In some embodiments, 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 rate, or one or more layers may have different erosion rates. In some variations, the implant may include a drug or an erodible drug-eluting matrix. In some embodiments, the implant may include an erodible material (e.g., a polymer), the erosion rate of which may be tailored by selecting an appropriate material (e.g., a polymer). In some variations, the implant may have a first erosion rate (e.g., the rate at which the outer portion of the implant is degraded or absorbed), and the drug-eluting matrix contained therein may have a second erosion rate (e.g., the rate at which the drug-eluting matrix is ​​degraded or absorbed). In some embodiments, the second erosion rate may be faster than the first erosion rate. Thus, the drug-eluting matrix may elute faster than the outer portion erodes.

[0051] Dry implant formulation As described herein, multiple implants may be formulated as a dry implant formulation without a liquid carrier, e.g., for implantation into the eye. In some variations, the dry implant formulation may be formulated as a semi-solid mass that is malleable but does not easily dissociate into individual implants and may be delivered together as a unit. Utilizing a dry implant formulation that is a semi-solid mass may be advantageous for several reasons. For 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 clog inside the lumen of the implantation system (e.g., the cannula). Additionally or alternatively, utilizing such a dry implant formulation may also prevent unintended or premature expulsion from the implantation system (e.g., the cannula of an implantation system), e.g., due to gravity or during advancement of the cannula through tissue toward the target location.

[0052] The dry implant formulation may be endowed with semi-solid properties without the use of a liquid carrier, for example, through the presence of adhesion between individual implants (inter-implant adhesion). In some variations, a majority of the implants in the dry implant formulation (e.g., about 51%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%) may be adhered to at least one other implant. The basis for inter-implant adhesion may be electrostatic adhesion, adhesion via molecular intermediates, and / or adhesion via the malleability of individual implants and partial deformation of the surface of one implant relative to one or more other implants.

[0053] In some variations, the dry implant formulation may include multiple drug-eluting implants and one or more binders that act as adhesive molecular intermediaries between the individual implants. In some variations, the binder may be selected from sugar, gelatin, collagen, polyethylene glycol (PEG), starch, cellulose, alginate, chitosan, or combinations thereof.

[0054] In some variations, at least a majority of the implant may be heated above the glass transition temperature of the polymer or polymers contained in each individual implant and optionally compressed (during or immediately after heating, before the temperature of the majority of the implant drops below its respective glass transition temperature). The 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 immediately after heating, while at least a majority of the implant is above the glass transition temperature, which may be about 1 minute, about 2 minutes, about 5 minutes, or about 10 minutes, may induce the surfaces of the individual implants to partially deform relative to adjacent implants. In some variations, adhesion between implants may be weakened in an aqueous environment (e.g., the eye), thereby making the individual implants more susceptible to dispersion after implantation.

[0055] A dose of an implant formulation (e.g., a dry implant formulation disclosed herein) for a single implantation into the eye may be referred to herein as the "implantation dose" or "implantation unit" of the dry implant formulation. An implantation unit of an implant formulation (e.g., a dry implant formulation disclosed herein) may contain about 1 to about 100, about 100 to about 1,000, or about 1,000 to about 10,000 or more implants. In some embodiments, the implant units of the implant formulation (e.g., the dry implant formulations disclosed herein) are about 100 to about 200, about 100 to about 300, about 100 to about 400, about 100 to about 500, about 100 to about 600, about 100 to about 700, about 100 to about 800, about 100 to about 900, about 100 to about 1000, about 200 to about 300, about 200 to about 400, about 200 to about 500, about 200 to about 600, about 200 to about 700, about 200 to about 800, about 200 to about 900, about 200 to about 1000, about 300 to about 400, about 300 to about 500, about 300 to about 600, about 300 to about 700, about 300 to about 800, about 300 to about 900, about 300 to about 1000, about 400 to about 500, about 400 to about 600, about 400 to about 700, about 400 to about 800, about 400 to about 900, about 400 to about 1000, about 500 to about 600, about 500 to about 700, about 500 to about 800, about 500 to about The implants may include about 900, about 500 to about 1000, about 600 to about 700, about 600 to about 800, about 600 to about 900, about 600 to about 1000, about 700 to about 800, about 700 to about 900, about 700 to about 1000, about 800 to about 900, about 800 to about 1000, or about 900 to about 1000 implants.In some embodiments, the implant formulation (e.g., the dry implant formulation disclosed herein) has an implant unit of about 1000 to about 2000, about 1000 to about 3000, about 1000 to about 4000, about 1000 to about 5000, about 1000 to about 6000, about 1000 to about 7000, about 1000 to about 8000, about 1000 to about 9000, about 1000 to about 10000, about 2000 to about 3000, about 2000 to about 4000, about 2000 to 5000, about 2000 to about 6000, about 2000 to about 7000, about 2000 to about 8000, about 2000 to about 9000, about 2000 to about 10000, about 3000 to about 4000, about 3000 to about 5000, about 3000 to about 6000, about 3000 to about 7000 , about 3000 to about 8000, about 3000 to about 9000, about 3000 to about 10000, about 4000 to about 5000, about 4000 to about 6000, about 4000 to about 7000, about 4000 to about 8000, about 4000 to about 9000, about 4000 to about 10000, about 5000 to about 6000, about 5000 to about 7000, about 5000 to about 8000, about 5000 to about 9 000, about 5000 to about 10000, about 6000 to about 7000, about 6000 to about 8000, about 6000 to about 9000, about 6000 to about 10000, about 7000 to about 8000, about 7000 to about 9000, about 7000 to about 10000, about 8000 to about 9000, about 8000 to about 10000, and about 9000 to about 10000 implants.

[0056] The volume of a transplant unit of an implant formulation (e.g., a dry implant formulation disclosed herein) depends on the number and size of implants contained therein, as well as the amount of binder, if any, in the formulation. Using the above considerations, the volume of a transplant unit may range, for example, from about 1 μL (microliter) to about 500 μL, from about 1 μL to about 50 μL, from about 1 μL to about 100 μL, from about 1 μL to about 200 μL, from about 1 μL to about 300 μL, from about 1 μL to about 400 μL, from about 1 μL to about 40 μL, from about 2 μL to about 50 μL, from about 2 μL to about 100 μL, from about 2 μL to about 200 μL, from about 2 μL to about 300 μL, from about 2 μL to about 400 μL, from about 2 μL to about 500 μL, from about 4 μL to about 50 μL, or from about 4 μL to about 50 μL. The amount may be about 100 μL to about 100 μL, about 4 μL to about 200 μL, about 4 μL to about 300 μL, about 4 μL to about 400 μL, about 4 μL to about 500 μL, about 10 μL to about 50 μL, about 10 μL to about 100 μL, about 10 μL to about 200 μL, about 10 μL to about 300 μL, about 10 μL to about 400 μL, about 10 μL to about 500 μL, about 50 μL to about 100 μL, about 50 μL to about 200 μL, about 50 μL to about 300 μL, about 50 μL to about 400 μL, or about 50 μL to about 500 μL. In certain variations, an implant formulation (e.g., a dry implant formulation as disclosed herein) may be configured to elute one drug, while in other variations, an implant formulation (e.g., a dry implant formulation as disclosed herein) may be configured to elute two or more drugs. In certain variations, an implant formulation (e.g., a dry implant formulation as disclosed herein) 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 implants may comprise a second, different drug. The first and second subsets of implants may be mixed homogeneously or heterogeneously throughout the implant formulation, such that the combined implant formulation may elute both drugs.For example, a first subset of implants may comprise timolol (e.g., timolol maleate or timolol hemihydrate), and a second subset of implants may comprise dorzolamide (e.g., dorzolamide hydrochloride or dorzolamide base) or brinzolamide. In another example, a first subset of implants may comprise timolol (e.g., timolol maleate or timolol hemihydrate), and a second subset of implants may comprise a prostamide analog (e.g., bimatoprost) or a prostaglandin analog, such as latanoprost. In another example, a first subset of implants may comprise timolol (e.g., timolol maleate or timolol hemihydrate), and a second subset of implants may comprise a rho-kinase inhibitor (e.g., ripasudil or netarsudil). In another example, a first subset of implants may include a prostamide analog (e.g., bimatoprost) or a prostaglandin analog, such as latanoprost, and a second subset of implants may include a rho-kinase inhibitor (e.g., ripasudil or netarsudil). Additionally or alternatively, in some variations, each individual implant may include two or more drugs (e.g., two, three, four, five, six, or more). In these variations, an implant formulation (e.g., a dry implant formulation disclosed herein) may include a first subset of implants including a first drug and one or more subsets (e.g., two, three, four, five, six, or more subsets) of implants including one or more drugs. For example, an implant formulation (e.g., a dry implant formulation disclosed herein) may include a first subset of implants including a first drug and a second subset of implants, where each implant in the second subset includes a second drug and a third drug. In some variations, the first drug may be the same as one of the second drug and the third drug, while in other variations, the first drug, the second drug, and the third drug may each be a different drug.In this way, precise amounts of one or more drugs (eg, two, three, four, five, six, or more) can be delivered together to the implantation site. Drugs.

[0057] The drug-eluting implants described herein comprise one or more (e.g., two, three, four, five, or more) drugs useful for treating an ocular condition. In some embodiments, the ocular condition may be glaucoma, dry eye disease, AMD, a retinal disease (e.g., retinal vascular disease), a neurological disease, a corneal disease, a lens disease, uveitis, a vitreous disease, a surface disease, an eyelid disease, or an ocular infection. In some embodiments, the one or more drugs may include drugs 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, a corticosteroid, such as prednisolone, prednisone, cortisone, cortisol, or triamcinolone; an anti-VEGF agent, such as ranibizumab, aflibercept, bevacizumab, or brolucizumab; a growth factor, such as nerve growth factor or insulin-like growth factor; a prostaglandin or prostaglandin analogue, such as latanoprost, travoprost, tafluprost, or unoprostone; a prostamide or prostamide analogue, such as bimatoprost; a nitric oxide-releasing drug and a nitric oxide donor; alpha-1 adrenergic agonists, e.g., epinephrine, dipivefrin, an alpha-2 adrenergic agonist, such as epinephrine, dipivefrin, brimonidine, or apraclonidine; β-adrenergic blockers "beta blockers" such as levobunolol, timolol, betaxolol, carteolol, or metipranolol; Miotics, such as pilocarpine, carbonic anhydrase inhibitors, such as acetazolamide, methazolamide, dorzolamide, brinzolamide, diclophenamide, ethoxzolamide, or zonisamide; Rho kinase (ROCK) inhibitors, such as ripasudil or netarsudil, Parasympathomimetic drugs, sympathomimetics, such as muscarinic antagonists (e.g., atropine); antimetabolites, such as fluorouracil and mitomycin C; Antibiotics and Nonsteroidal anti-inflammatory drugs, e.g., NSAIDs, an antifungal agent; an immunosuppressant, such as cyclosporine, sirolimus, everolimus, or tacrolimus; Vitreous hemorrhage medications, Collagenase and A drug for treating vitreous floaters, Mydriatics and A miotic, an anticoagulant (e.g., heparin); a fibrinolytic compound; a monoclonal antibody or other biologic; and combinations thereof.

[0058] In certain embodiments, one or more drugs are nitric oxide-releasing drugs in combination with prostaglandins / prostaglandin analogs or other glaucoma drugs (e.g., to target multiple mechanisms of action). In certain variations, the drugs are useful for reducing intraocular pressure. In certain variations, the drugs may suppress aqueous humor production. In some variations, the drugs may increase aqueous humor drainage through the trabecular canalicular and / or uveoscleral pathways.

[0059] The amount of drug in a given implant (e.g., microsphere or microparticle) or a given dose of multiple implants, e.g., an implant unit of an implant formulation (e.g., a dry implant formulation disclosed herein), can be adjusted depending on the type of drug and / or application. For example, an implant (e.g., a microparticle implant or microsphere) or an implant unit of an implant formulation (e.g., a dry implant formulation disclosed herein) may contain from about 1 μg to about 500 μg of drug, or from about 30 ng to about 90 mg of drug. In some variations, the implant unit of the implant or implant formulation (e.g., the dry implant formulation disclosed herein) may be from about 1 μg to about 400 μg, from about 1 μg to about 300 μg, from about 1 μg to about 200 μg, from about 1 μg to about 100 μg, from about 1 μg to about 10 μg, from about 1 μg to about 5 μg, from about 5 μg to about 10 μg, from about 5 μg to about 100 μg, from about 10 μg to about 100 μg, from about 10 μg to about 90 μg, from about 10 μg to about 150 μg, from about 150 μg to about 200 μg, from about 1 μg to about 250 μg, from about 1 μg to about 300 μg, from about 1 μg to about 350 μg, from about 1 μg to about 400 μg, from about 1 μg to about 300 μg, from about 1 μg to about 200 μg, from about 1 μg to about 100 μg, from about 1 μg to about 150 μg, from about 1 μg to about 250 μg, from about 1 μg to about 350 μg, from about 1 μg to about 400 μg, from about 1 μg to about 300 μg, from about 1 μg to about 200 μg, from about 1 μg to about 100 μg, from about 1 μg to about 100 μg, from about 1 μg to about 250 μg, from about 1 μg to about 350 μg, from about 1 μg to about 400 μg, from about 1 μg to about 450 μg, from about 1 μg to about 500 μg, from about μg~about 80μg, about 10μg~about 70μg, about 10μg~about 60μg, about 10μg~about 50μg, about 10μg~about 40μg, about 10μg~about 30μg, about 10μg~about 20μg, about 20μg~about 100μg g, about 20μg to about 90μg, about 20μg to about 80μg, about 20μg to about 70μg, about 20μg to about 60μg, about 20μg to about 50μg, about 20μg to about 40μg, about 20μg to about 30μg, about 40μg Approximately 100μg, approximately 30μg to approximately 90μg, approximately 30μg to approximately 80μg, approximately 30μg to approximately 70μg, approximately 30μg to approximately 60μg, approximately 30μg to approximately 50μg, approximately 30μg to approximately 40μg, approximately 40μg to approximately 100μg, Approximately 40μg to approximately 90μg, approximately 40μg to approximately 80μg, approximately 40μg to approximately 70μg, approximately 40μg to approximately 60μg, approximately 40μg to approximately 50μg, approximately 50μg to approximately 100μg, approximately 50μg to approximately 90μg, approximately 50μg to approximately The amount of the drug may be 80 μg, about 50 μg to about 70 μg, about 50 μg to about 60 μg, about 60 μg to about 100 μg, about 60 μg to about 90 μg, about 60 μg to about 80 μg, about 60 μg to about 70 μg, about 70 μg to about 100 μg, about 70 μg to about 90 μg, about 70 μg to about 80 μg, about 80 μg to about 100 μg, about 80 μg to about 90 μg, or about 90 μg to about 100 μg of the drug (including all subranges and values ​​therein).In some embodiments, an implant (e.g., a microsphere) or an implant unit of an implant formulation (e.g., a dry implant formulation disclosed herein) may have about 1 μg, about 2 μg, about 3 μg, about 4 μg, about 5 μg, about 6 μg, about 7 μg, about 8 μg, about 9 μg, about 10 μg, about 15 μg, about 20 μg, about 30 μg, about 40 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about 90 μg, about 100 μg, about 150 μg, about 200 μg, about 250 μg, about 300 μg, about 350 μg, about 400 μg, about 450 μg, or about 500 μg of drug.In some variations, the implant unit of the implant or implant formulation (e.g., the dry implant formulation disclosed herein) may be from about 30 ng to about 90 mg, from about 30 ng to about 80 mg, from about 30 ng to about 70 mg, from about 30 ng to about 60 mg, from about 30 ng to about 50 mg, from about 30 ng to about 40 mg, from about 30 ng to about 30 mg, from about 30 ng to about 20 mg, from about 30 ng to about 10 mg, from about 30 ng to about 5 mg, from about 30 ng to about 1 mg, from about 30 ng to about 10 ... Approximately 500μg, approximately 30ng to approximately 100μg, approximately 30ng to approximately 900ng, approximately 30ng to approximately 800ng, approximately 30ng to approximately 700ng, approximately 30ng to approximately 600ng, approximately 30ng to approximately 500ng, approximately 30ng to approximately 400ng, approximately 30ng to approximately 300ng, approximately 30ng to approximately 200ng, approximately 30ng to approximately 100ng, approximately 30ng to approximately 50ng, approximately 100ng to approximately 90mg, approximately 100ng to approximately 80mg, approximately 100ng to approximately 70mg, approximately 100ng to approximately 60mg , about 100ng to about 50mg, about 100ng to about 40mg, about 100ng to about 30mg, about 100ng to about 20mg, about 100ng to about 10mg, about 100ng to about 5mg, about 100ng to about 1mg, about 100ng to about 500μg, about 100ng to about 100μg, about 200ng to about 90mg, about 200ng to about 80mg, about 200ng to about 70mg, about 200ng to about 60mg, about 200ng to about 50mg, about 200ng to about 40mg, about 200 The compound may have from about 200 ng to about 30 mg, from about 200 ng to about 20 mg, from about 200 ng to about 10 mg, from about 200 ng to about 5 mg, from about 200 ng to about 1 mg, from about 200 ng to about 500 μg, from about 200 ng to about 100 μg, from about 200 ng to about 900 ng, from about 200 ng to about 800 ng, from about 200 ng to about 700 ng, from about 200 ng to about 600 ng, from about 200 ng to about 500 ng, from about 200 ng to about 400 ng of the drug (including all subranges and values ​​therein).

[0060] In some variations, the implant or implants, e.g., an implant unit of an implant formulation (e.g., a dry implant formulation disclosed herein), can be from about 1 μg to about 90 mg, from about 1 μg to about 70 mg, from about 1 μg to about 50 mg, from about 1 μg to about 40 mg, from about 1 μg to about 30 mg, from about 1 μg to about 20 mg, from about 1 μg to about 15 mg, from about 1 μg to about 10 mg, from about 1 μg to about 5 mg, from about 1 μg to about 1 mg, from about 5 μg to about 90 mg, from about 5 μg to about 70 mg, from about 5 μg to about 50 mg, from about 5 μg to about 40 mg, from about 5 μg to about 30 mg, from about 5 μg to about 20 mg. g, approx. 5 μg ~ approx. 15 mg, approx. 5 μg ~ approx. 10 mg, approx. 5 μg ~ approx. 5 mg, approx. 5 μg ~ approx. 1 mg, approx. 10 μg ~ approx. 90 mg, approx. mg, approx. 10 μg ~ approx. 10 mg, approx. 10 μg ~ approx. 5 mg, approx. 10 μg ~ approx. 1 mg, approx. 20 μg ~ approx. 90 mg, approx. 20 μg ~ approx. 70 mg, approx. g ~ about 10 mg, about 20 μg - about 5 mg, about 20 μg - about 1 mg, about 40 μg - about 90 mg, about 40 μg - about 70 mg, about 40 μg - about 50 mg, about 40 μg - about 40 mg, about 40 μg - about 30 mg, about 40 μg - about 20 mg, about 40 μg - about 15 mg, about 40 μg - about 10 mg , about 40μg to about 5mg, about 40μg to about 1mg, about 60μg to about 90mg, about 60μg to about 70mg, about 60μg to about 50mg, about 60μg to about 40mg, about 60μg to about 30mg, about 60μg to about 20mg, about 60μg to about 15mg, about 60μg to about 10mg, about 60μg to about Approx. 5 mg, approx. 60 μg ~ approx. 1 mg, approx. 80 μg ~ approx. 90 mg, approx. 80 μg ~ approx. 70 mg, approx. 80 μg ~ approx. 50 mg, approx. 80 μg ~ approx. 40 mg, approx. 80 μg ~ approx. 30 mg, approx. 0 μg to about 1 mg, about 100 μg to about 90 mg, about 100 μg to about 70 mg, about 100 μg to about 50 mg, about 100 μg to about 40 mg, about 100 μg to about 30 mg, about 100 μg to about 20 mg, about 100 μg to about 15 mg, about 100 μg to about 10 mg, about 100 μg to about 5 mg,or from about 100 μg to about 1 mg of drug, including all subranges and values ​​therein.

[0061] In some embodiments, an implant (e.g., a microsphere) or a plurality of implants (e.g., an implant unit of an implant formulation described herein (e.g., a dry implant formulation disclosed herein)) contains 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 drug, or about 1 μg, about 2 μg, about 3 μg, about 4 μg, about 5 μg, about 6 μg, about 7 μg, about 8 μg , about 9μg, about 10μg, about 15μg, about 20μg, about 30μg, about 40μg, about 50μg, about 60μg, about 70μg, about 80μg, about 90μg, about 100μg, Approximately 150μg, approximately 200μg, approximately 250μg, approximately 300μg, approximately 350μg, approximately 400μg, approximately 450μg, approximately 500μg, approximately 600μg, approximately 700μg, approximately 80 The dosage may have about 0 μg, about 900 μg, or about 1000 μg of 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 drug.

[0062] Implants of the present disclosure may elute drugs at a rate determined by their composition, dimensions, and / or implant location. Thus, by adjusting the properties of the implant (e.g., a particulate implant or microsphere), an appropriate dose of drug may be administered to the eye. In some embodiments of the implants described herein, an implanted unit of a drug-eluting implant or implant formulation (e.g., a dry implant formulation disclosed herein) may deliver one or more drugs into the eye at a rate of about 1 ng / day to about 3000 ng / day, about 1 mg / day to about 300 mg / day, or about 1 ng / day to about 300 mg / day.In certain embodiments, an implant unit of a drug-eluting implant or implant formulation (e.g., a dry implant formulation disclosed herein) may be administered into the eye in a dose range of about 1 ng / day to about 2000 ng / day, about 1 ng / day to about 1000 ng / day, about 1 ng / day to about 500 ng / day, about 1 ng / day to about 400 ng / day, about 1 ng / day to about 300 ng / day, about 1 ng / day to about 200 ng / day, about 1 ng / day to about 100 ng / day, about 1 ng / day to about 50 ng / day, about 5 ng / day to about 3000 ng / day or more, about 5 ng / day to about 2000 ng / day, about 5 ng / day to about 50 ng / day, or more. / day to about 1000ng / day, about 5ng / day to about 500ng / day, about 5ng / day to about 400ng / day, about 5ng / day to about 300ng / day, about 5ng / day to about 200ng / day, about 5ng / day to about 100ng / day, about 5ng / day to about 50ng / day, about 10ng / day to about 3000ng / day or more, about 10ng / day to about 2000ng / day, about 10ng / day to about 1000ng / day, about 10ng / day to about 500ng / day, about 10ng / day to about 400ng / day, about 10ng / day to about 300ng / day, about 10ng / day to about 200ng / day, about 10ng / day to about 10 0ng / day, about 10ng / day to about 50ng / day, about 50ng / day to about 3000ng / day or more, about 50ng / day to about 2000ng / day, about 50ng / day to about 1000ng / day, about 50ng / day to about 500ng / day, about 50ng / day to about 400ng / day, about 50ng / day to about 300ng / day, about 50ng / day to about 200ng / day, about 50ng / day to about 100ng / day, about 100ng / day to about 3000ng / day or more, about 100ng / day to about 2000ng / day, about 100ng / day to about 1000ng / day, about 100ng / day to about 500ng / day, about 10 The drug may be delivered at a rate of 0 ng / day to about 400 ng / day, about 100 ng / day to about 300 ng / day, about 100 ng / day to about 200 ng / day, about 200 ng / day to about 300 ng / day, about 300 ng / day to about 400 ng / day, about 400 ng / day to about 500 ng / day, about 500 ng / day to about 1000 ng / day, about 1000 ng / day to about 1500 ng / day, about 1500 ng / day to about 2000 ng / day, about 2000 ng / day to about 2500 ng / day, or about 2500 ng / day to about 3000 ng / day (including all subranges and values ​​of any of the above).In certain embodiments, the drug eluting implant or implant unit of the implant formulation (e.g., the dry implant formulations disclosed herein) has a drug eluting amount of about 1 ng, about 2 ng, about 3 ng, about 4 ng, about 5 ng, about 6 ng, about 7 ng, about 8 ng, about 9 ng, about 10 ng, about 11 ng, about 12 ng, about 13 ng, about 14 ng, about 15 ng, about 16 ng, about 17 ng, about 18 ng, about 19 ng, about 20 ng, about 21 ng, about 22 ng, about 23 ng, about 24 ng, about 25 ng, about 26 ng, about 27 ng, about 28 ng, about 29 ng, about 30 ng, about 31 ng, about 32 ng, about 33 ng, about 34 ng, about 35 ng, about 36 ng, about 37 ng, about 38 ng, about 39 ng, about 40 ng, about 41 ng, about 42 ng, about 43 ng, about 44 ng, about 45 ng, about 46 ng, about 47 ng, about 48 ng, about 49 ng, about 50 ng, about 51 ng, about 52 ng, about 53 ng, about 54 ng, about 55 ng, about 56 ng, about 57 ng, about 58 ng, about 59 ng, about 60 ng, about 61 ng, about 62 ng, about 63 ng, about 64 ng, about 65 ng, about 66 ng, about 67 ng, about 68 ng, about 69 The one or more drugs may be delivered into the eye at a rate of 0 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 550 ng, about 600 ng, about 650 ng, about 700 ng, about 750 ng, about 800 ng, about 850 ng, about 900 ng, about 950 ng, about 1000 ng, about 1500 ng, about 2000 ng, about 2500 ng, or about 3000 ng per day.

[0063] In certain embodiments, a drug-eluting implant or implanted unit of an implant formulation (e.g., a dry implant formulation disclosed herein) may deliver drug into the eye at a rate of about 1 mg / day to about 300 mg / day, about 1 mg / day to about 200 mg / day, about 1 mg / day to about 100 mg / day, about 1 mg / day to about 50 mg / day, about 1 mg / day to about 20 mg / day, about 1 mg / day to about 10 mg / day, about 10 mg / day to about 300 mg / day, about 10 mg / day to about 200 mg / day, about 10 mg / day to about 100 mg / day, about 10 mg / day to about 50 mg / day, about 10 mg / day to about 20 mg / day, about 100 mg / day to about 300 mg / day, or about 100 mg / day to about 200 mg / day, including any and all subranges and values ​​of any of the foregoing. In certain embodiments, a drug-eluting implant or implanted unit of an implant formulation (e.g., a dry implant formulation disclosed herein) may deliver one or more drugs into the eye at a rate of 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 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or 300 mg per day.

[0064] In certain embodiments, the drug eluting implant or implant unit of the implant formulation (e.g., the dry implant formulation disclosed herein) provides a drug eluting dose of from about 1 ng / day to about 300 mg / day, from about 1 ng / day to about 200 mg / day, from about 1 ng / day to about 100 mg / day, from about 1 ng / day to about 50 mg / day, from about 1 ng / day to about 20 mg / day, from about 1 ng / day to about 10 mg / day, from about 10 ng / day to about 300 mg / day, from about 10 ng / day to about 200 mg / day, from about 10 ng / day to about 100 mg / day, or from about 1 0ng / day to about 50mg / day, about 10ng / day to about 20mg / day, about 10ng / day to about 10mg / day, about 10ng / day to about 1mg / day, about 20ng / day to about 200mg / day, about 20ng / day to about 100mg / day, about 20ng / day to about 50 mg / day, about 20ng / day to about 20mg / day, about 20ng / day to about 10mg / day, about 20ng / day to about 1mg / day, about 30ng / day to about 200mg / day, about 30ng / day to about 100mg / day, about 30ng / day to about 50mg / day, about 30n g / day ~ about 20mg / day, about 30ng / day - about 10mg / day, about 30ng / day - about 1mg / day, about 50ng / day - about 200mg / day, about 50ng / day - about 100mg / day, about 50ng / day - about 50mg / day, about 50ng / day - about 20mg / day, about 50ng / day to about 10mg / day, about 50ng / day to about 1mg / day, about 100ng / day to about 300mg / day, about 100ng / day to about 200mg / day, about 100ng / day to about 100mg / day, about 100ng / day to about 50mg / day, about The drug may be delivered into the eye at a rate of 100 ng / day to about 20 mg / day, about 100 ng / day to about 10 mg / day, about 100 ng / day to about 1 mg / day, about 200 ng / day to about 300 mg / day, about 200 ng / day to about 200 mg / day, about 200 ng / day to about 100 mg / day, about 200 ng / day to about 50 mg / day, about 200 ng / day to about 20 mg / day, about 200 ng / day to about 10 mg / day, or about 200 ng / day to about 1 mg / day (including all subranges and values ​​of any of the above).

[0065] As described below, drugs suitable for delivery by the implants described herein may diffuse from the location of implantation in one part / location within the eye (e.g., vitreous, subconjunctival space) to another part / location within the eye (e.g., anterior chamber, posterior chamber), or vice versa. To enhance this diffusion from the implantation location to another location within the eye, the drugs described herein may be administered in conjunction with the application of one or more penetration enhancers. Penetration enhancers may include compounds such as cyclodextrins, chelating agents, crown ethers, bile acids, bile salts, surfactants, cell-penetrating peptides, and amphiphilic compounds. Such penetration enhancers may be combined with the drug for treating an ocular condition administered by the drug-eluting implants described herein, or may be administered separately. In some variations, a first drug-eluting implant delivers a drug for treating an ocular condition, and a second drug-eluting implant delivers a penetration enhancer. In other variations, one drug-eluting implant delivers both a drug for treating an ocular condition and a penetration enhancer. The penetration enhancer may also be a non-compound penetration enhancer, which is applied separately and in addition to the implant. For example, the non-compound penetration enhancer may include electric current, iontophoresis, ultrasound, or microneedles. These may be applied to ocular tissues, for example, to increase the penetration of drug delivery by the drug-eluting implants described herein. The selection of an appropriate penetration enhancer may depend on the characteristics (e.g., molecular weight, hydrophobicity / lipophilicity) of the administered drug. An appropriate penetration enhancer may be selected to promote the penetration of the drug through a specific tissue (e.g., cornea, sclera).

[0066] Currently available treatments for ocular disorders such as glaucoma use medicated drops that last less than 24 hours. For age-related macular degeneration (AMD) and other retinal diseases, certain other ophthalmic injections provide drug delivery to ocular tissues for weeks or months. In contrast, the drug-eluting implants described herein allow for continuous or semi-continuous delivery of one or more drugs for days or weeks and / or months or years. In some embodiments, the drug is delivered to the eye for a predetermined period of time, for example, at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 12 months, 18 months, 24 months, 30 months, 36 months, 48 ​​months, 60 months, or 72 months (including all subranges and values ​​therein). For example, in some variations, the drug-eluting implant is configured for sustained release of drug to the eye for about 1 month to about 3 months, about 2 months to about 4 months, about 1 month to about 6 months, about 6 months to about 9 months, about 6 months to about 12 months, about 12 months to about 18 months, about 12 months to about 24 months, about 24 months to about 36 months, about 12 months to about 72 months, or about 1 month to about 72 months.In certain embodiments, the period is from about 0 months to about 1 month, from about 0 months to about 2 months, from about 0 months to about 3 months, from about 0 months to about 4 months, from about 0 months to about 5 months, from about 0 months to about 6 months, from about 0 months to about 7 months, from about 0 months to about 8 months, from about 0 months to about 9 months, from about 0 months to about 10 months, from about 0 months to about 11 months, from about 0 months to about 12 months, from about 1 month to about 2 months, from about 1 month to about 3 months, from about 1 month to about 4 months, from about 1 month to about 5 months, from about 1 month to about 6 months, from about 1 month to about 7 months, from about 1 month to about 8 months, from about 1 month to about 9 months, or from about 1 month to about 1 month. ~approx. 10 months, ~approx. 1 month to ~approx. 11 months, ~approx. 1 month to ~approx. 12 months, ~approx. 2 months to ~approx. 3 months, ~approx. 2 months to ~approx. 4 months, ~approx. 2 months to ~approx. 5 months, ~approx. 2 months to ~approx. 6 months, ~approx. 2 months to ~approx. 7 months, ~approx. 2 months to ~approx. 8 months, ~approx. 2 months to ~approx. 9 months, ~approx. 2 months to ~approx. 10 months, ~approx. 2 months to ~approx. 11 months, ~approx. 2 months to ~approx. 12 months, ~approx. 3 months to ~approx. 4 months, ~approx. 3 months to ~approx. 5 months, ~approx. 3 months to ~approx. 6 months, ~approx. 3 months to ~approx. 7 months, ~approx. 3 months to ~approx. 8 months, ~approx. 3 months to ~approx. 9 months, ~approx. 3 months to ~approx. 10 months, ~approx. 3 months to ~approx. 11 months, ~approx. 3 months to ~approx. 1 2 months, about 4 months to about 5 months, about 4 months to about 6 months, about 4 months to about 7 months, about 4 months to about 8 months, about 4 months to about 9 months, about 4 months to about 10 months, about 4 months to about 11 months, about 4 months to about 12 months, about 5 months to about 6 months, about 5 months to about 7 months, about 5 months to about 8 months, about 5 months to about 9 months, about 5 months to about 10 months, about 5 months to about 11 months, about 5 months to about 12 months, about 6 months to about 7 months, about 6 months to about 8 months, about 6 months to about 9 months, about 6 months to about 10 months, about 6 months to about 11 months, about 6 months to about 12 months months, about 7 months to about 8 months, about 7 months to about 9 months, about 7 months to about 10 months, about 7 months to about 11 months, about 7 months to about 12 months, about 8 months to about 9 months, about 8 months to about 10 months, about 8 months to about 11 months, about 8 months to about 12 months, about 9 months to about 10 months, about 9 months to about 11 months, about 9 months to about 12 months, about 10 months to about 11 months, about 10 months to about 12 months, about 11 months to about 12 months, about 10 months to about 24 months, about 10 months to about 36 months, about 12 months to about 24 months, or about 12 months to about 36 months. In certain embodiments, the period is at least about 1 year, 2 years, 3 years, 4 years, 5 years, 10 years, 15 years, 20 years, or from about 1 year to about 5 years, from about 1 year to about 10 years, from about 5 years to about 10 years, from about 5 years to about 15 years, from about 10 years to about 20 years, from about 5 years to about 20 years, or from about 1 year to about 20 years.As used above, "about 0 months" refers to the approximate time of implantation of an implant or implants.

[0067] In some variations, multiple implants or subsets of multiple implants (e.g., in an implant formulation) may have similar or identical delivery periods. In some variations, multiple implants or subsets of multiple implants (e.g., in an implant formulation) may have independent delivery periods (e.g., predetermined periods as described above). By way of example only, two subsets of implants (e.g., in an implant formulation) may be administered to a subject, the first subset having a duration of about 0 months to about 3 months and the second subset having a duration of about 4 months to about 9 months. It should be understood that each implant or subset of implants may independently have any of the delivery periods described above.

[0068] As mentioned above, the drug-eluting implants described herein may be at least partially bioerodible. In some variations, one or more new implants (e.g., replacement implants) may be delivered to one or more locations in the eye as one or more implanted implants degrade within the eye. For example, new implants may replace partially or completely degraded implants every month, every two months, every three months, every six months, every 12 months, every 18 months, every two years, every three years, or more, or any interval therein.

[0069] As mentioned above, in variations in which the implant (e.g., microparticles such as microspheres) is positioned at least partially within the posterior chamber (e.g., the sulcus, the remainder of the posterior chamber), the drug delivered from the drug-eluting implant may be taken up by the anterior and / or posterior flow streams so that it may be delivered to the anterior and / or posterior chamber of the eye. In some variations, the drug may be delivered to the anterior chamber, the posterior chamber (e.g., the sulcus and / or the remainder of the posterior chamber), the cornea, the iris, the lens, the pupil, the retina, or the vitreous. In variations in which the implant is positioned intramurally (e.g., fully embedded or positioned within one or more 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 implant is positioned in the sulcus and posterior flow delivers the eluted drug to the retina and / or choroid.

[0070] It may be advantageous for the implants (e.g., microparticles such as microspheres) described herein to include at least one imaging agent, which may aid in visualization of the implant and / or drug during and / or after implantation. In variations that include an imaging agent, the imaging agent may be released as the bioerodible implant degrades, which may further aid in visualizing and / or quantifying how much of the initial implant dose of drug remains at any given time and / or over a period of time (e.g., days, weeks, years). In other words, the imaging agent acts as a surrogate for drug elution. In some variations, the imaging agent may be one or more of a dye, a radioactive label, and a fluorescent marker. In particular embodiments, the imaging agent may be fluorescein. In some variations of the implants described herein, the implant may include 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 cases, a medical professional may visualize the contrast agent and estimate or otherwise quantify the amount of drug delivered and may personalize treatment based on this determination. For example, a medical professional may determine characteristics of the upcoming procedure (e.g., number or volume of implants, type of drug, amount of drug, time of subsequent implantation, amount of time the subsequent implant should remain in the eye) based on the contrast agent visualization data and / or the estimate or quantification of the amount of drug delivered.

[0071] The implants (e.g., microparticles such as microspheres) described herein may be configured for placement within the eye. For example, in some variations, the microspheres may be partially or entirely present in the subconjunctival space, Tenon's capsule, sub-Tenon's space, anterior chamber (including the iridocorneal angle), posterior chamber (including the sulcus), or vitreous.

[0072] Implant position The drug-eluting implants described herein may be configured to reside in any suitable location within the eye. For example, the implants described herein may reside in the subconjunctival space, Tenon's capsule, sub-Tenon's space, suprachoroidal space (which may be accessed for implantation via an ab externo or ab interno approach through the anterior chamber angle), subretinal space, sclera, cornea, limbus, anterior chamber, posterior chamber (including the sulcus and remainder of the posterior chamber), and vitreous. The implants may be delivered to multiple different implantation sites. In these cases, the implants in one part of the eye may have one or more different drugs and / or may have a different delivery rate (e.g., elution rate, dissolution rate) than the implants in another part of the eye. For example, a first implant or a first subset of implants may be configured to reside in a first location, and a second implant or a second subset of implants may be configured to reside in a second location. In some embodiments, a first implant or a first subset of implants may be configured to reside at a first location and may include a first drug, and a second implant or a second subset of implants configured to reside at a second location may include the same or a different drug. In some embodiments, a first implant or a first subset of implants may be configured to reside at a first location and may have a first drug delivery rate, and a second implant or a second subset of implants configured to reside at a second location may have the same or a different drug delivery rate.

[0073] The drug-eluting implant may also be entirely intramural (e.g., entirely implanted or positioned within one or more tissues of the eye), such as, for example, the cornea, sclera, limbus, or a combination thereof. In certain variations, one or more implants may be entirely intracorneal, entirely intrascleral, or entirely limbus.

[0074] Transplantation System As described herein, implants and / or implant formulations (e.g., dry implant formulations disclosed herein) may be implanted, e.g., intraocularly, using an implantation system configured to access a target location in a subject's eye and implant a desired amount, e.g., an implant unit, of one or more implants or implant formulations described herein into the target location. In some embodiments, the implantation system may be configured to implant an implant or dry implant formulation disclosed herein without a carrier.

[0075] In some variations, the implantation system may comprise an implantation device including a handle and a cannula coupled to the distal end of the handle. The handle may be sized and shaped to allow a user to comfortably hold and manipulate the cannula and advance the cannula, or a portion thereof, toward a target location within the eye. In some variations, the lumen of the cannula, or a portion thereof, may be filled (e.g., pre-filled) with one or more implants, such as, for example, an implant unit of an implant formulation (e.g., a dry implant formulation as disclosed herein). In some variations, the implantation system may further comprise a plunger or pusher rod slidably positioned within the lumen of the cannula. In some variations, the handle may comprise an actuator for a user to control the implantation system (e.g., control the plunger or pusher rod) to expel the implant formulation from the cannula to deliver the implant to a target location within the eye.

[0076] The cannula may include a distal portion configured for insertion into a target location within the eye. The cannula may be made of stainless steel, metal, Teflon, or a polymer (e.g., polycarbonate, polyethylene, polyamide, or polyetheretherketone). The distal portion of the cannula may include and terminate at a distal tip, with the lumen terminating as a distal opening within the distal tip. One or more implants, such as an implant formulation (e.g., a dry implant formulation disclosed herein), may be positioned within the lumen of the cannula. The distal tip may be sufficiently sharp to penetrate ocular tissue and / or membranes. For example, the distal tip of the cannula may have a beveled edge. Additionally or alternatively, the distal portion including the distal tip may be tapered such that the outer diameter of the cannula gradually decreases toward the distal tip, the outer diameter of the distal tip being smaller than the outer diameter of the proximal portion of the cannula. In some variations, the cannula is flexible. In some variations, the cannula is transparent, which advantageously provides visualization of the implant or implant formulation (e.g., a dry implant formulation disclosed herein) loaded into the lumen and visual control of the implantation process.

[0077] In some variations, the implantation device may be a syringe operably coupled to a cannula filled with one or more implants or implant formulations (e.g., dry implant formulations as disclosed herein), and the actuator may be the plunger of the syringe.

[0078] In some variations, the actuator may be or include one or more of a wheel, switch, button, knob, lever, slider, touchpad, capacitive touch sensor, etc. In some variations, the distal tip of the pusher rod or plunger may contact at least a portion of one or more implants or implant formulations (e.g., dry implant formulations as disclosed herein). In some variations, the actuator may have markings or coloring to indicate the degree or direction of advancement.

[0079] In some variations, the actuator may be operably coupled to the plunger or pusher rod and may be operable to move the pusher rod relative to the handle and cannula, thereby advancing the tip of the pusher rod toward the distal opening of the cannula. In some variations, the actuator may be operably coupled to the cannula and may be operable to move the cannula relative to the handle and pusher rod, thereby retracting the distal opening of the cannula toward the distal tip of the pusher rod. In some variations, the actuator may be operably coupled to the plunger or pusher rod and the cannula. The actuator may be operable to move the pusher rod and cannula in opposite directions. That is, the actuator may be operable to move the pusher rod relative to the handle and cannula, thereby advancing the tip of the pusher rod toward the distal opening of the cannula, and may be operable to move the cannula relative to the handle and pusher rod, thereby retracting the distal opening of the cannula toward the tip of the pusher rod.

[0080] In some variations, the handle may include a drive assembly that converts rotational motion into 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 a user may rotate one or more components of the drive assembly (e.g., a circular gear), which may result in linear movement of the pusher rod, as described in more detail herein.

[0081] For example, the drive assembly may include at least one elongated member (e.g., a linear gear, which may be referred to as a "rack") and at least one pinion gear. The at least one elongated member may be connected to the pusher rod and / or cannula. The elongated member may be configured to engage with the linear gear, whereby rotational motion of the linear gear is converted into linear motion of the elongated member. In some variations, the elongated member may be a linear gear, which may have teeth on its surface that engage with corresponding teeth on the linear gear. The drive assembly may include one or more idler gears that engage with the elongated member and / or the linear gear to provide a desired direction of movement of the elongated member relative to the direction of rotation of the linear gear. The at least one linear gear may also be coupled (e.g., coaxially or tangentially) to a wheel. Such coupling may be achieved, for example, using a pin that can couple (e.g., via a screw thread, etc.) to a rotatable component and a central opening in the linear gear. Mechanical or other fasteners (e.g., nuts) may be used to secure the rotatable component and the linear gear such that rotation of the rotatable component rotates the linear gear, and vice versa. The wheel may be attached to the linear gear in any suitable manner. For example, in some variations, the wheel may be positioned (e.g., slid) on the linear gear and secured thereto (e.g., using adhesive or other mechanical fastening techniques, such as, for example, a compression fit, press fit, etc.). In other variations, the wheel and linear gear may be integrally formed (e.g., molded as one piece using plastic injection molding techniques). 2) Regardless of how the wheel may be coupled to the linear gear, the wheel and linear gear may rotate coaxially or tangentially, in the same direction, and at the same angular velocity.

[0082] In some variations, the cannula and pusher rod may be configured to move linearly in opposite directions in response to engagement of the actuator. In these variations, the drive assembly may include a first linear gear coupled (e.g., coaxially or tangentially) to the actuator (e.g., a wheel) and configured to engage a first elongated member connected to the pusher rod, and a second linear gear coupled (e.g., coaxially or tangentially) to the actuator and configured to engage a second elongated member connected to the cannula. Additionally, the drive assembly may include an idler gear either between the first linear gear and the first elongated member or between the second linear gear and the second elongated member, such that when the actuator is moved in a given direction (e.g., the wheel is rotated), the first elongated member and the second elongated member may be moved in opposite directions.

[0083] 3A-3B, an implantation system 300 configured to deliver an implant or implant formulation (e.g., a dry implant formulation disclosed herein) is shown. In the variation shown in FIGS. 3A-3B, the implantation system 300 is configured to move both a cannula and a pusher rod during the implantation procedure. In this variation, the implantation system 300 may include a cannula 310, a pusher rod 320, and a handle 330. The cannula 310 may include 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 within the lumen of the cannula 310. Handle 330 may include a housing 332 shaped to be comfortably held by a user (not shown) (e.g., by the user's single hand) and an actuator 334 in the form of a wheel that, when actuated (e.g., rotated) by the user, serves to move cannula 310 and pusher rod 320 in opposite directions. Additionally, handle 330 may further include (e.g., at least partially housed within) a drive assembly 340 that translates motion (e.g., rotational motion) of actuator 334 with opposing linear motion of cannula 310 and pusher rod 320. Housing 332 of handle 330 is shown partially cut away to provide a view of drive assembly 340 and its components, which in this version are completely contained within the interior portion of housing 332 of handle 330.

[0084] 3A 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 easily seen in this view, the proximal portion 324 of the pusher rod 320 may be fixedly connected to the linear gear 346 via the 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 the distal portion of the pusher rod 320 may be slidably positioned within the lumen of the cannula 310.

[0085] FIG. 3E shows another variation of a drive assembly 1340 that may be housed within the housing 332 to translate motion (e.g., rotational motion) of an actuator (e.g., actuator 1334) with opposing linear motion of a cannula (not shown) and a pusher rod (not shown) for delivery of an implant or implant formulation (e.g., a dry implant formulation) loaded into the cannula. In this variation, the drive assembly 1340 may include a first linear gear 1346 fixedly coupled to the 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. Thus, 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.

[0086] The implantation system 330 may be configured such that when the cannula 310 is retracted and the pusher rod 320 is advanced through engagement (e.g., rotation) of the actuator 334, the dry implant formulation 360 is released through the distal opening 318 of the lumen 316. Figure 3D is an enlarged view of the distal portion of the implantation system 300 of Figures 3A-3C. Additionally, 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 the distal tip 322 of the pusher rod 320 inserted inside the lumen 316 and contacting the implant or dry implant formulation 360. Thus, upon advancement of the pusher rod 320 through the lumen 316 and retraction of the cannula 310, the implant or dry implant formulation 360 is released through the distal opening 318.

[0087] Method for loading a cannula pre-filled with a dry implant formulation As described herein, loading one or more implants and / or dry implant formulations into an implant system can be challenging due to the dimensions and characteristics of the implants and / or dry implant formulations, as well as the dimensions and configuration of the implant system (e.g., the narrow lumen of a cannula). Therefore, in some variations, one or more specialized methods and / or loading tools may be utilized to facilitate loading of the implants and / or dry implant formulations into the implant system. In some variations, the loading process may be performed using a loading block comprising a flat surface, with grooves formed thereon configured to receive a cannula (e.g., a cannula of an implant system as described herein), multiple implants or a dry implant formulation as described herein, and a tamping device or pusher rod. The loading block may be configured to apply heat, cooling, and / or electrostatic discharge at or near the grooves to facilitate placement of the implants. For example, FIG. 4 provides a flowchart of a method 400 for loading an implant or a dry implant formulation, or in the variation provided in FIG. 5, specifically a dry implant formulation, into the lumen of a cannula of an implant system. As shown in FIG. 4, manufacturing method 400 may include, in step 402, loading a cannula into a first portion of a groove sized to fit the cannula, in step 404, filling a dry implant formulation (or one or more implants) into a second portion of the groove near the proximal end of the cannula, and in step 406, loading a pusher rod into a third portion of the pusher rod such that the filled dry implant formulation (or one or more implants) is positioned between the proximal end of the cannula and the distal end of the pusher rod.

[0088] After the cannula, implant and / or dry implant formulation, and pusher rod are positioned within the groove, method 400 may further include advancing the pusher rod toward the cannula, thereby forcing the implant and / or dry implant formulation into the lumen of the cannula and through a proximal opening of the lumen, at step 408. The pusher rod may be advanced so that a distal end of the pusher rod enters the lumen of the cannula. In some variations, the pusher rod may be advanced until a portion of the implant or dry implant formulation is positioned near the distal opening of the cannula.

[0089] In some variations, such as those using a dry implant formulation (which may or may not include a binder), after the dry implant formulation is positioned within the lumen of the cannula, the method may include, in 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, this treating may include heating at least a majority of the implants at a temperature higher than the glass transition temperature of the polymer or polymers contained in the drug-eluting matrix of each individual implant. The glass transition temperature of the implant is based on the materials contained therein, e.g., the bioerodible polymer contained in the drug-eluting matrix of the implant. In some variations, the glass transition temperature of the implant may be about 35 degrees Celsius (°C) to about 45°C, about 40°C to about 45°C, or about 37°C to about 40°C. In some variations, treating may include compressing the dry implant formulation within the lumen of the cannula, e.g., using a separate tamping device and / or a pusher rod of the implantation system. In some variations, treating may include both heating and compressing. For example, in some variations, a cannula containing a dry implant formulation may be heated such that at least a majority of the implant of the dry implant formulation is heated above the glass transition temperature of their respective polymer(s), and the implant of the dry implant formulation may then be compressed (during or immediately after heating, before the temperature of the majority of the implant falls below its respective glass transition temperature) 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 its distal end) such that the implant is 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 a combination of heating and compression during or immediately after heating induces the surface of individual implants to partially deform relative to adjacent implants.

[0090] 5A schematically illustrates an exemplary method of loading one or more implants and / or dry implant formulations into a cannula using a loading block 500 including a groove 502 sized to fit over the cannula of an implantation system as described herein. In the illustrated exemplary variation, a distal portion of a cannula 550 is positioned within a first portion 504 of the groove, and the implant and / or dry implant formulation including multiple particulate implants is positioned in a second portion of the groove 506 near (e.g., adjacent to) the 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 to 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. A pusher rod or tamping device 570 is then advanced toward the cannula (schematically shown in the direction of block arrow 640), thereby forcing the implant and / or dry implant formulation 560 into the lumen of the cannula 550 through a proximal opening 554 of the lumen of the cannula 550. In other variations, the cannula 550 may be reverse-loaded into the loading block 500 such that the implant and / or dry implant formulation 560 is loaded in a similar manner through a distal opening 556 of the cannula 560. In some variations, the loading block 500 may be heated such that at least a majority of the particulate implant in the dry implant formulation is heated above its glass transition temperature, as described in more detail herein. In some variations, although not shown in FIG. 5A , a cap may be removably positioned on the end (e.g., distal end) of the cannula 510 during loading of the implant and / or dry implant formulation. In variations in which compression is performed in conjunction with or instead of heating, the pusher rod or tamping device 570 may be advanced until sufficient compressive force is applied to the implant and / or dry implant formulation.For example, the pusher rod or tamping device 570 may be advanced such that the 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, a pusher rod of the 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.

[0091] 5B shows cannula 550 filled with dry implant formulation 560 after compression has been applied by a pusher rod or tamping device 570. Cannula 550 has a cap 580 releasably coupled to a distal opening 556 of cannula 550. When coupled to cannula 550, cap 580 may be positioned over distal opening 556 of cannula 550. Cap 580 may provide further protection for distal end 556 before the cannula is used in an implantation process, for example, during shipping and storage, and cap 580 may be removed by the user prior to the implantation process.

[0092] How to Treat Eye Conditions Also provided are methods for treating an ocular condition in a subject using an implant or one or more implant formulations (e.g., a dry implant formulation disclosed herein). Generally, the methods described herein may include implanting at least one drug-eluting implant or implant formulation (e.g., a dry implant formulation disclosed herein), including a plurality, or a set or group of a plurality of implants, into the eye of a subject. The methods described herein may include implanting one or more implants or implant formulations (e.g., a dry implant formulation) described herein, with or without a carrier. When administered with a carrier / vehicle, saline, water, or other non-toxic aqueous medium may be used as the carrier / vehicle. One particular advantage of the methods described herein is that the drug-eluting implant is configured to be implanted without the use of a liquid carrier. Implantation of a drug-eluting implant without a liquid carrier may be referred to herein as "dry" implantation. Dry implantation limits or eliminates dangerous changes in intraocular pressure that can occur within the eye when a liquid carrier is injected. Furthermore, due to at least the size, shape, and structure of the implants and the properties of the implant formulations (e.g., dry implant formulations) disclosed herein, multiple implants can be implanted in close proximity to one another, and their movement within the eye can be more limited than implants utilizing aqueous administration, which may help avoid extravasation typically seen with aqueous administration. Other advantages of carrier-free administration include a higher drug dose per injected unit volume and the elimination of the need to refrigerate or freeze the drug implant device for transportation. The dose may be immediately deployed without extra steps or opportunities for mixing errors. Furthermore, dry implantation allows the implants to coalesce into a single area, increasing the physician's visibility to determine the presence, and therefore elution, of the drug in specific parts of the eye. Furthermore, this allows for easier removal of the implant in the event of an adverse event. In some embodiments, at least one drug-eluting implant is implanted without a carrier.

[0093] transplant positionGenerally, a drug may be delivered to an ocular structure from at least one drug-eluting implant (optionally as an implant formulation, e.g., a dry implant formulation as described herein) to alleviate symptoms of an ocular condition, as described above. In some embodiments, the method may include implanting at least one drug-eluting implant or implant formulation (e.g., a dry implant formulation disclosed herein) into the anterior chamber and delivering a drug from the implant to the anterior chamber and / or to another location within the eye (e.g., the posterior chamber, sclera, vitreous, subconjunctival space, Tenon's capsule, sub-Tenon's space) to treat the ocular condition and / or alleviate one or more symptoms of the ocular condition. In some embodiments, the method may include implanting at least one drug-eluting implant or implant formulation (e.g., a dry implant formulation disclosed herein) into the vitreous body and delivering a drug from the at least one implant or implant formulation (e.g., a dry implant formulation disclosed herein) to the vitreous body and / or to another location within the eye (e.g., the posterior chamber, the sclera, the anterior chamber, the subconjunctival space) to treat the ocular condition and / or alleviate one or more symptoms of the ocular condition. In some embodiments, the method may include implanting at least one drug-eluting implant or implant formulation (e.g., a dry implant formulation disclosed herein) into the subconjunctival space and delivering a drug from the implant or implant formulation (e.g., a dry implant formulation disclosed herein) to the subconjunctival space and / or to another location within the eye (e.g., the posterior chamber, the sclera, the anterior chamber, the vitreous body, Tenon's capsule, the sub-Tenon's space) to treat the ocular condition and / or alleviate one or more symptoms of the ocular condition.In some embodiments, the method may include implanting at least one drug-eluting implant or implant formulation (e.g., a dry implant formulation disclosed herein) into the Tenon's capsule or sub-Tenon's space, and delivering a drug from the implant or implant formulation (e.g., a dry implant formulation disclosed herein) to the Tenon's capsule or sub-Tenon's space and / or to another location within the eye (e.g., the posterior chamber, the sclera, the anterior chamber, the vitreous body, the subconjunctival space) to treat the ocular condition and / or alleviate one or more symptoms of the ocular condition. In some embodiments, the methods may include implanting at least one drug-eluting implant or implant formulation (e.g., a dry implant formulation disclosed herein) into the posterior chamber (including the sulcus and / or remainder of the posterior chamber) and delivering a drug from the at least one drug-eluting implant or implant formulation (e.g., a dry implant formulation disclosed herein) to the posterior chamber and / or another location within the eye (e.g., the subconjunctival space, the sclera, the anterior chamber, the vitreous) to treat the ocular condition and / or alleviate one or more symptoms of the ocular condition. In some embodiments, the methods described herein may include implanting at least one drug-eluting implant or implant formulation (e.g., a dry implant formulation disclosed herein) entirely intramurally and delivering a drug from the implant or implant formulation to another location in the eye (e.g., the anterior chamber, the posterior chamber, the vitreous) to alleviate the symptoms of the ocular condition. Any of the drug-eluting implants or implant formulations (e.g., a dry implant formulation disclosed herein) and implantation systems described above are suitable for use with the methods described herein.

[0094] anesthesia Prior to administering the drug-eluting implant, the eye may be anesthetized and one or more disinfectants may be applied to the eye to prepare it for the transplantation procedure. Anesthesia may include one or a combination of the following types of anesthesia: topical, subconjunctival, Tenon's, sub-Tenon's, peribulbar, and retrobulbar. In some cases, a lid retractor may be applied to expose the ocular surface and prevent the eyelids from closing. In some cases, it may be advantageous to dilate the pupil. This procedure may also be performed with the patient seated upright at a slit lamp, or with the patient supine and under a microscope. In some embodiments, the implant may be advanced and / or positioned using loupes, a sit lamp, or a surgical microscope. While this procedure may be performed in an operating room, advantageously, the methods described herein are suitable for performing in a doctor's office or small procedure room, for example, under direct visualization using a slit lamp, under loupe magnification, or under a microscope. The methods described herein may be performed with or without gonioscopy or microinvasive glaucoma surgery (MIGS)-type implants. Instead, many of the methods described herein allow for injection into ocular tissues performed at a slit lamp or in an office-based setting by an ophthalmologist or optometrist. While these procedures can be performed in an operating room, there are many advantages to performing them in an office-based setting (e.g., cost savings, convenience for the patient, increased appointment availability and / or access).

[0095] Injection Process In some variations, a cannula pre-filled with one or more implants or implant formulations (e.g., dry implant formulations as disclosed herein) may be advanced through external tissue (e.g., the sclera, conjunctiva, cornea) to reach a desired or target location or position within the eye. The implant formulation may then be released or otherwise expelled from the implantation system to the target location. In some variations, as shown in FIG. 6 , an implantation method 700 may include, at step 702, puncturing an ocular tissue (e.g., the sclera, cornea), optionally with a needle or cannula of the implantation system, and, at step 704, advancing the distal end of the cannula of the implantation system, carrying one or more implants or implant formulations (e.g., dry implant formulations as disclosed herein) within the lumen of the cannula, to a desired implantation location, such as directly into an intramural tissue or intraocular space. The desired implantation location may include, for example, the posterior chamber, anterior chamber, subconjunctival space, Tenon's capsule, sub-Tenon's space, or vitreous body. In some variations, the implantation method may include, at step 706, expelling or otherwise releasing one or more implants or implant formulations (e.g., a dry implant formulation disclosed herein) from the cannula into the target location. In some variations, the expelling or releasing may include operating an actuator of the implantation system, which may result in moving (e.g., advancing) a pusher rod of the implantation system relative to the cannula, retracting the cannula relative to the pusher rod, or a combination of both. In some variations, the method may include creating an intramural tunnel or channel separate from and prior to advancing the cannula to the target location. In some variations, the tunnel or channel may be created using an instrument such as a needle or 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 directly within the wall tissue or within the tunnel or channel.An actuator of the implantation system may then be operated to expel or release the implant or dry implant formulation into the wall tissue, tunnel or channel, or other naturally occurring space within the eye.

[0096] In some variations, the target location may be the sub-Tenon's space. FIG. 7 illustrates an exemplary method of implantation into the 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 Tenon's capsule. The cannula 802 may be loaded with at least one implant or dry implant formulation 806, which may be positioned within the cannula's lumen. The distal end 804 may be advanced into the sub-Tenon's space. Once the distal end 804 enters the sub-Tenon's space, an actuator on the handle of the implantation system may be operated to expel or release the implant or dry implant formulation 806 within the cannula 802 into the sub-Tenon's space. In the variation illustrated in FIG. 7, the handle of the implantation system is a syringe 810, and the actuator is a plunger 812. Although shown with another variation of the injection system, it should be understood that the method illustrated in FIG. 7 may be performed with any of the injection systems described herein, such as, for example, injection system 300 described with respect to FIGS. 3A-3D.

[0097] In some variations, a guidewire may be used in the implantation procedure. For example, the guidewire may contact a portion of the implant, and the implant may be advanced from a 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 removed, leaving the implant in place.

[0098] As described above, advancing one or more implants or implant formulations (e.g., dry implant formulations disclosed herein) may include advancing a portion of a transplant system, e.g., a cannula, through one or more tissues, structures, or membranes of the eye, such as the sclera, limbus, or conjunctiva. The method may also include advancing a cannula under one or more tissues (e.g., the conjunctiva, Tenon's capsule). The implant or implant formulation (e.g., a dry implant formulation disclosed herein) may be disposed within the transplant system. For example, the implant or implant formulation (e.g., a dry implant formulation disclosed herein) may be disposed within a cannula of the transplant system, and at least the distal end of the cannula may be advanced through the sclera of the eye. The methods described herein may also enable fully intramural placement of a drug-eluting implant, with at least a portion of the drug-eluting implant in the limbus of the eye. The methods described herein may also allow for the delivery of a drug from a drug-eluting implant to a target tissue of the eye (e.g., the anterior chamber, the subconjunctival space, the sub-Tenon space) after placement of the implant to alleviate symptoms of an ocular condition. The target tissue may be one or more tissues in which the implant is present and / or may be one or more different tissues. The target tissue may not be in contact with the implant.

[0099] The methods described herein are suitable for use with any of the drug-eluting implants, including the implant formulations described herein (e.g., the dry implant formulations disclosed herein).

[0100] Cannula visualization After advancing the cannula into which the implant or implant formulation (e.g., a dry implant formulation disclosed herein) is to be placed, the cannula may be visualized at a particular portion or depth of the eye, indicating where the implant is located within the eye as the cannula is retracted. Thus, the method may further include visualizing the distal tip of the cannula within a particular tissue, cavity, or structure of the eye (e.g., the anterior chamber) before releasing the implant from the implantation system. For example, the cannula may be visualized within one or more tissues, cavities, or structures of the eye in which the implant resides. Additionally or alternatively, the cannula may be visualized within one or more tissues, cavities, or structures of the eye adjacent to or near the desired implantation location.

[0101] Visualizing the cannula through the posterior portion of the eye may assist the user in properly positioning the implant within the eye, as described above. Thus, the method may include confirming that the distal tip of the cannula is positioned within a desired portion of the eye, such as, but not limited to, the anterior chamber, posterior chamber, limbus, subconjunctival space, or vitreous body of the eye. Once the distal tip of the cannula has been advanced to a desired depth within the eye, the method may further include retracting the cannula and / or advancing a pusher and releasing the drug-eluting implant into the target tissue (e.g., at least partially into the anterior chamber, posterior chamber, limbus, subconjunctival space, or vitreous body).

[0102] In some variations, portions of the implantation system (e.g., the cannula) and / or the drug-eluting implant may be visualized during advancement and / or positioning using loupes, a slit lamp, a surgical microscope, or any combination thereof. Additionally or alternatively, the drug-eluting implant may be implanted into a structure of the eye (e.g., the suprachoroidal space) gonioscopically.

[0103] Diffusion of drugs beyond the implantation site Drug-eluting implants, including implant formulations (e.g., dry implant formulations disclosed herein), may deliver drugs to various locations regardless of where the drug is present in the eye. In any of the methods described herein, the drug-eluting implant (or implants) may deliver drugs to the location or tissue(s) where the drug-eluting implant is present and / or to a location or tissue different from the location or tissue where the drug-eluting implant is present. For example, a drug-eluting implant may be present entirely intramurally in the posterior chamber, subconjunctival space, or vitreous body, but may deliver drugs to the anterior chamber of the eye via diffusion through tissue (or vice versa). A drug-eluting implant present entirely in the subconjunctival space or sub-Tenon's space may deliver drugs to one or more of the limbus, sclera, cornea, anterior chamber, ciliary body, trabecular meshwork, choroid, retina, retinal pigment epithelium (RPE), posterior chamber, vitreous body, or any other nearby tissue or structure of the eye. A drug-eluting implant that resides entirely 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 that resides entirely 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 that is 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 nearby 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 embodiments, multiple microspheres are implanted in the sulcus of the eye.

[0104] Eye conditions As described herein, the methods of treating an ocular condition in a subject may be useful for treating several ocular disorders or conditions, including, but not limited to, glaucoma, dry eye, AMD, choroidal disease, retinal disease, corneal disease, iris disease, uveal disease, lens disease, and scleral disease (e.g., myopia). In some embodiments, the methods described herein are useful for treating conditions such as macular edema, vascular occlusion, diabetic retinopathy, retinal degeneration and dystrophies, iritis, uveitis, vitritis, cataracts, herpes zoster or herpes simplex infection, keratitis, keratoconus or other corneal degeneration, dry eye disease, scleritis, episcleritis, corneal ulcers, astigmatism, hyperopia, presbyopia, corneal ectasia, corneal dystrophies, corneal scarring, graft versus host disease, autoimmune eye diseases, Thigeson's keratitis, post viral keratitis, herpes simplex, viral keratitis, uveitis, Stevens-Johnson disease, conjunctivitis, blepharitis, post surgical inflammation, post surgical infection prophylaxis, post surgical pain, pinguecula, pterygium, vernal and atopic keratoconjunctivitis, allergies, and the like. The compositions may be useful for treating allergic conjunctivitis, chemical injury, thermal injury, chemical injury, mechanical injury, retinal vasculitis, retinal dystrophies, neuroretinopathy, autoimmune retinal disease, autoimmune choroidal disease, retinal detachment, retinal breaks, retinal tears, ischemic and non-ischemic optic neuropathy, papillary retinal dystrophies, ocular trauma, radiation retinopathy, exudative or non-exudative age-related macular degeneration, choroidal neovascularization, retinal neovascularization, retinal vascular occlusive disease, choroid or retinitis, vitreous opacities (e.g., hemorrhage, floaters, astrocytosis), maculopathy, retinopathy, choroidopathy, retinopathy of prematurity, endophthalmitis, epiretinal hole, macular hole, proliferative vitreoretinopathy, edema (e.g., macula, retina), ischemia (e.g., macula, retina), or diabetic retinopathy. In some variations, the methods described herein may result in a reduction in the duration, severity, and / or occurrence of one or more symptoms of any of the aforementioned conditions, and / or may result in a treatment of any of the aforementioned conditions. Accordingly, the methods described herein may utilize a drug-eluting implant that delivers a drug to treat any of these or other disorders or conditions. In some embodiments, the drug-eluting implant may deliver a glaucoma medication.In some variations, the methods described herein may utilize a drug-eluting implant partially located in a first portion of the eye to treat a disorder in the same portion of the eye or another portion of the eye.

[0105] Multiple implants The methods described herein may include delivering one or more implants or implant units of an implant formulation (e.g., a dry implant formulation described herein) to the eye. Multiple implants or implant units of an implant formulation (e.g., a dry implant formulation disclosed herein) may be implanted for various reasons or purposes. For example, a previously implanted implant or implant unit of an implant formulation (e.g., a dry implant formulation disclosed herein) may be depleted or dissolved. Multiple doses of a drug or multiple different drugs may be implanted at the same or different locations during the same sitting, or may be implanted at different times. The implants or implant units of an implant formulation (e.g., a dry implant formulation disclosed herein) may be delivered simultaneously or sequentially and may be present in the eye simultaneously and / or sequentially (e.g., the implants or implant units of an implant formulation may all be implanted for the same period of time, different overlapping periods, or different non-overlapping periods). In variations in which multiple implants are used, any number of the implants (e.g., one, several, a subset of all implants, or all implanted implant units of an implant formulation) may contain the same drug, may contain different drugs with the same mechanism of action for one or more ocular conditions, or may contain different drugs with different mechanisms of action for one or more ocular conditions. The implants, or implant units of an implant formulation (e.g., a dry implant formulation disclosed herein), may contain drugs intended to treat or alleviate the symptoms of the same ocular condition, or may contain drugs intended to treat or alleviate the symptoms of different ocular conditions. Furthermore, the implants, or implant units of an implant formulation (e.g., a dry implant formulation disclosed herein), may be positioned in the same general location within the eye or in different regions within the eye. While the implant is described as containing a drug, it should be understood that it may contain a combination of drugs.In other words, multiple implants or implant units of an implant formulation (e.g., a dry implant formulation disclosed herein) may be delivered sequentially or simultaneously during the same procedure. In variations in which implants or implant units of an implant formulation are delivered sequentially, the implants or implant units of the implant formulation may be advanced together (e.g., while contained within a common implantation system) to the target implantation location (e.g., the sulcus, posterior chamber, anterior chamber vitreous, sub-Tenon's space, subconjunctival space), or the implants or implant units of the implant formulation may be advanced separately to the target implantation location (e.g., using different implantation systems, positioned one at a time within a common implantation system).

[0106] For example, a method may include placing a first implant or multiple implants (which may be a first subset of implants or a first implant formulation) at a first location within the eye, the first implant or multiple implants including a first drug or drug combination intended to treat or alleviate symptoms of a first condition, and placing a second implant or multiple implants (which may be a second subset of implants or a second implant formulation) at a second location within the eye, the second drug or drug combination intended to treat or alleviate a second condition. In some variations, the first drug or drug combination and the second drug or drug combination may be the same drug or drug combination, 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 drug combination and the second drug or drug combination may utilize the same mechanism of action. In other variations, the first drug or drug combination and the second drug or drug combination 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 drug and the second drug or drug combination may utilize different mechanisms of action. Thus, in some variations, the first drug and the second drug or drug combination may be different drugs or combinations utilizing different mechanisms of action, but the first location and the second location may be the same location, and the first condition and the second condition may be the same condition. In another example, the first drug and the second drug or drug combination may be different drugs or different combinations of drugs utilizing different mechanisms of action, and the first location and the second location may be different locations, but the first ocular condition and the second ocular condition may be the same. When utilizing methods involving the use of multiple drug-eluting implants, it is understood that any combination of drugs, mechanisms of action, locations, and ocular conditions described herein may be used in combination.In any of the embodiments described herein, the drug or drug combination may be delivered to one or more locations in different amounts (e.g., a first amount of the drug or drug combination at a first location and a second amount of the drug or drug combination at a second location).

[0107] For some subjects, it may be advantageous to deliver multiple implants or implant formulations (e.g., the dry implant formulations disclosed herein) configured to deliver different drugs or drugs utilizing different mechanisms of action, as this may allow for more comprehensive treatment. For example, a method may include positioning a first implant or multiple implants (which may be an implant formulation or a first subset of implants in the first implant formulation) containing a first drug having a first mechanism of action in the sulcus, and positioning a second implant or multiple implants (which may be an implant formulation or a second subset of implants in the second implant formulation) containing a second drug having a second mechanism of action at least partially in the anterior or posterior chamber. In some variations, the first mechanism of action may be inhibition of aqueous humor production, and the second mechanism of action may increase aqueous humor drainage using one or more of the trabecular meshwork and uveoscleral pathways. In other variations, the first mechanism of action and the second mechanism of action, or both, may be suppression of aqueous humor or increased drainage of aqueous humor using one or more of the trabecular meshwork pathway and the uveoscleral pathway. In some variations, the first mechanism of action and the second mechanism of action may be increased drainage of aqueous humor, but the first mechanism of action may be increased drainage through the trabecular meshwork pathway and the second mechanism of action may be increased drainage through the uveoscleral pathway. In some variations, the first implant may comprise a drug for treating or alleviating one or more symptoms of glaucoma or a condition of the retina, lens, cornea, uvea, vitreous body, iris, ciliary body, sclera, or ocular surface (e.g., by suppressing aqueous humor, increasing aqueous humor drainage using the trabecular pathway, or increasing aqueous humor drainage using the uveoscleral pathway), and the second implant may comprise a drug for treating or alleviating one or more symptoms of glaucoma or a condition of the retina, lens, cornea, uvea, vitreous body, iris, ciliary body, sclera, or ocular surface.For example, a first implant or plurality of implants (which may be an implant formulation or a first subset of implants in the first implant formulation) and a second implant or plurality of implants (which may be an implant formulation or a second subset of implants in the second implant formulation) may each comprise a drug for treating or alleviating one or more symptoms of glaucoma, which may be the same drug (or combination of drugs) or different drugs (or different combinations of drugs). In some variations, the first mechanism of action may be beta-2-adrenergic receptor blockade (e.g., using timolol) and the second mechanism of action may be carbonic anhydrase inhibition (e.g., using brinzolamide or dorzolamide), e.g., to reduce intraocular pressure to treat glaucoma. In another variation, for example, to reduce intraocular pressure to treat glaucoma, the first mechanism of action may be blockade of beta-2-adrenergic receptors (e.g., using timolol), and the second mechanism of action may be administration of a prostaglandin analog or prostamide analog (e.g., using latanoprost or bimatoprost). In another variation, for example, to reduce intraocular pressure to treat glaucoma, the first mechanism of action may be blockage of beta-2-adrenergic receptors (e.g., using timolol), and the second mechanism of action may be inhibition of rho-kinase (e.g., using ripasudil or netarsudil). In another variation, for example, to reduce intraocular pressure to treat glaucoma, the first mechanism of action may be administration of a prostaglandin analog or prostamide analog (e.g., using latanoprost or bimatoprost), and the second mechanism of action may be inhibition of rho-kinase (e.g., using ripasudil or netarsudil).In another example, a first implant or plurality of implants (which may be a first subset of implants in an implant formulation or a first implant formulation) may include a drug for treating or alleviating one or more symptoms of glaucoma, and a second implant or plurality of implants (which may be a second subset of implants in an implant formulation or a second implant formulation) may include a drug for treating or alleviating one or more symptoms of a retinal disease. In some variations, the first implant or plurality of implants (which may be an implant formulation or a first subset of implants in the first implant formulation) and the second implant or plurality of implants (which may be an implant formulation or a second subset of implants in the second implant formulation) may each include a drug for treating or alleviating one or more symptoms of AMD, which may be the same drug (or combination of drugs) or different drugs (or combinations of drugs). In another example, a first implant or plurality of implants (which may be an implant formulation or a first subset of implants in the first implant formulation) may comprise a drug for treating or alleviating one or more symptoms of glaucoma, and a second implant or plurality of implants (which may be an implant formulation or a second subset of implants in the second implant formulation) may comprise a drug for treating or alleviating one or more symptoms of AMD. In another example, a first implant or plurality of implants (which may be a first subset of implants in the implant formulation or the first implant formulation) may comprise a drug for treating or alleviating one or more symptoms of glaucoma, and a second implant or plurality of implants (which may be a second subset of implants in the implant formulation or the second implant formulation) may comprise a drug for treating or alleviating one or more symptoms of dry eye disease.

[0108] It should be understood that a first implant or plurality of 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 plurality of implants (which may be a second subset of implants or a second implant formulation) may be subsequently advanced to a second location. In some variations, a portion of a single subset of implants within an implant system may be advanced to a first location, and then one or more subsequent portions may be advanced to a second location (or a third location, a fourth location, etc.) from the same implant system. In some embodiments, a first implant or a first subset of implants may be advanced from an implant system to a first location within the eye, and the same implant system may be reloaded with additional implants or subsets at one or more additional locations within the eye.

[0109] Illustrative Embodiments Embodiment I-1. A drug-eluting implant for treating an ocular condition in a subject, comprising bioerodible microspheres, wherein the drug-eluting implant is configured to be implanted into the eye of the subject without a carrier.

[0110] Embodiment I-2. The drug-eluting implant of embodiment I-1, wherein the bioerodible microspheres comprise a drug-eluting matrix.

[0111] Embodiment I-3. The drug eluting implant of embodiment I-2, wherein the drug eluting matrix comprises a bioerodible polymer and a drug.

[0112] Embodiment I-4. The drug-eluting implant of any one of embodiments I-1 to I-3, wherein the bioerodible microspheres comprise poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA), poly-ε-caprolactone (PCA), or poly(glycolic acid) (PGA).

[0113] Embodiment I-5. The drug-eluting implant of any one of embodiments I-1 to I-4, wherein the bioerodible microspheres comprise a mixture of two bioerodible polymers.

[0114] Embodiment I-6. The drug-eluting implant of any one of Embodiments I-1 to I-5, wherein the bioerodible microspheres have a diameter of about 1 μm to about 500 μm.

[0115] Embodiment I-7. The drug-eluting implant of any one of Embodiments I-1 to I-6, wherein the bioerodible microspheres have a diameter of about 10 μm to about 100 μm.

[0116] Embodiment I-8. The drug-eluting implant of any one of Embodiments I-1 to I-7, wherein the ocular condition is glaucoma and / or dry eye disease.

[0117] Embodiment I-9. A drug-eluting implant according to any one of embodiments I-1 to I-8, wherein the drug-eluting implant is configured to be positioned in one or more of the sulcus, posterior chamber, anterior chamber, vitreous body, and subconjunctival space of the eye.

[0118] Embodiment I-10. The drug-eluting implant of any one of Embodiments I-3 to I-9, wherein the drug is a prostaglandin or a prostaglandin analog.

[0119] Embodiment I-11. The drug-eluting implant according to any one of embodiments I-3 to I-10, wherein the drug is latanoprost, bimatoprost, travoprost, nerve growth factor, anti-VEGF antibody, or cyclosporine.

[0120] Embodiment I-12. The drug-eluting implant of any one of Embodiments I-3 to I-11, wherein the bioerodible microspheres comprise from about 1 μg to about 500 μg of drug.

[0121] Embodiment I-13. The drug-eluting implant of any one of Embodiments I-3 to I-12, wherein the bioerodible microspheres comprise from about 5 μg to about 100 μg of drug.

[0122] Embodiment I-14. The drug-eluting implant of any one of embodiments I-3 to I-13, wherein the drug is delivered to the eye at a rate of about 1 ng / day to about 3000 ng / day.

[0123] Embodiment I-15. The drug-eluting implant of any one of embodiments I-3 to I-14, wherein the drug is delivered to the eye at a rate of about 5 ng / day to about 2000 ng / day.

[0124] Embodiment I-16. The drug-eluting implant of any one of embodiments I-3 to I-15, wherein the drug is delivered to the eye over a period of time, the period being at least 1 month, at least 4 months, at least 6 months, at least 8 months, at least 1 year, at least 2 years, or at least 3 years.

[0125] Embodiment I-17. The drug-eluting implant of any one of Embodiments I-1 through I-16, wherein the microspheres comprise an imaging agent.

[0126] Embodiment I-18. The drug-eluting implant of embodiment I-17, wherein the imaging agent is one or more of a dye, a radioactive label, and a fluorescent marker.

[0127] Embodiment I-19. The drug-eluting implant of any one of embodiments I-17 to I-18, wherein the imaging agent is fluorescein.

[0128] Embodiment I-20. A drug-eluting implant according to any one of embodiments I-17 to I-19, wherein the microspheres comprise a drug and a contrast agent, and the microspheres are configured to deliver the drug and the contrast agent into the eye at the same rate.

[0129] Embodiment I-21. A method for treating an ocular condition in a subject, the method comprising: implanting at least one drug-eluting implant into the eye of the subject, wherein the at least one implant is implanted without a carrier; The method, wherein a drug is delivered to the eye from at least one drug-eluting implant to alleviate the symptoms of the ocular condition.

[0130] Embodiment I-22. The method of embodiment I-21, wherein the ocular condition is glaucoma and / or dry eye disease.

[0131] Embodiment I-23. The method of embodiment I-21 or I-22, wherein the at least one drug-eluting implant is delivered from the at least one drug-eluting implant to the sulcus, posterior chamber, anterior chamber, vitreous body, and subconjunctival space of the eye.

[0132] Embodiment I-24. The method of any one of embodiments I-21 to I-23, further comprising advancing at least one drug-eluting implant to an implantation site within the eye within the implantation system.

[0133] Embodiment I-25. The method of embodiment I-24, wherein the advancing step comprises pushing at least one drug-eluting implant with a pusher rod.

[0134] Embodiment I-26. The method of embodiment I-24 or I-25, wherein the implantation system includes a needle or cannula, and the method further includes puncturing ocular tissue with the needle or cannula.

[0135] Embodiment I-27. The method of any one of embodiments I-24 to I-26, wherein the method further comprises operating an actuator of the implant system to release at least one drug-eluting implant from the implant system.

[0136] Embodiment I-28. The method of embodiment I-27, wherein two or more drug-eluting implants are released from an implantation system.

[0137] Embodiment I-29. The method of embodiment I-28, wherein operating the actuator advances the pusher rod.

[0138] Embodiment I-30. The method of any one of embodiments I-27 to I-29, wherein the actuator comprises one or more of a button, a knob, a slider, a lever, and a wheel.

[0139] Embodiment I-31. A method according to any one of embodiments I-21 to I-30, wherein at least one drug-eluting implant is advanced and / or positioned using one or more of a loop, a slit lamp, and a surgical microscope.

[0140] Embodiment I-32. The method of any one of Embodiments I-21 through I-31, wherein at least one drug-eluting implant delivers a glaucoma medication and / or a dry eye disease medication.

[0141] Embodiment I-33. The method of any one of Embodiments I-21 through I-32, wherein at least one drug-eluting implant delivers a prostaglandin or a prostaglandin analog.

[0142] Embodiment I-34. The method of any one of embodiments I-21 to I-33, wherein at least one drug-eluting implant delivers latanoprost, bimatoprost, travoprost, nerve growth factor, anti-VEGF antibody, or cyclosporine.

[0143] Embodiment I-34. The method of any one of embodiments I-21 to I-34, wherein the at least one drug-eluting implant includes a first drug-eluting implant, and the method further includes implanting a second drug-eluting implant into the eye.

[0144] Embodiment I-36. The method of embodiment I-35, wherein the first drug-eluting implant comprises a first drug having a first mechanism of action, and the second drug-eluting implant comprises a second drug having a second mechanism of action.

[0145] Embodiment I-37. The method of embodiment I-36, wherein the first mechanism of action and the second mechanism of action are the same.

[0146] Embodiment I-38. The method of embodiment I-36, wherein the first mechanism of action is different from the second mechanism of action.

[0147] Embodiment I-39. The method of any one of embodiments I-34 to I-38, wherein a first drug-eluting implant is implanted at a first site within the eye and a second drug-eluting implant is implanted at a second site within the eye.

[0148] Embodiment I-40. The method of any one of embodiments I-34 to I-38, wherein the first drug-eluting implant and the second drug-eluting implant are implanted at the same site in the eye.

[0149] Embodiment I-41. The method of any one of embodiments I-21 to I-40, wherein at least one drug-eluting implant comprises a plurality of microspheres, and the plurality of microspheres are implanted into the sulcus of the eye.

[0150] Embodiment II-1. A dry implant formulation for treating an ocular condition in a subject, comprising a plurality of drug-eluting microparticle implants, the dry implant formulation being configured to be implanted into the eye of the subject without a carrier.

[0151] Embodiment II-2. The dry implant formulation of embodiment II-1, wherein each of the plurality of particulate implants comprises a drug-eluting matrix.

[0152] Embodiment II-3. The dry implant formulation of Embodiment II-2, wherein the drug-eluting matrix comprises a bioerodible polymer and a drug.

[0153] Embodiment II-4. The drug-eluting implant of any one of Embodiments II-1 to II-3, wherein the particulate implant comprises poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA), poly-ε-caprolactone (PCA), or poly(glycolic acid) (PGA).

[0154] Embodiment II-5. The drug-eluting implant of any one of Embodiments II-1 to II-4, wherein the particulate implant comprises a mixture of two bioerodible polymers.

[0155] Embodiment II-6. The dry implant formulation of any one of Embodiments II-1 to II-5, wherein each of the plurality of particulate implants has a diameter of about 1 μm to about 500 μm.

[0156] Embodiment II-7. A dry implant formulation according to any one of Embodiments II-1 to II-6, wherein each of the plurality of particulate implants has a maximum linear dimension of about 10 μm to about 100 μm.

[0157] Embodiment II-8. The dry implant formulation of any one of Embodiments II-1 to II-7, wherein the ocular condition is glaucoma and / or dry eye disease.

[0158] Embodiment II-9. The dry implant formulation of any one of Embodiments II-1 to II-8, wherein the dry implant formulation is configured to be positioned in one or more of the ocular sulcus, posterior chamber, anterior chamber, vitreous body, sub-Tenon's space, and subconjunctival space.

[0159] Embodiment II-10. The dry implant formulation of any one of Embodiments II-3 to II-9, wherein the drug is a prostaglandin or a prostaglandin analog.

[0160] Embodiment II-11. The dry implant formulation of any one of Embodiments II-3 to II-10, wherein the drug is latanoprost, bimatoprost, travoprost, a beta-adrenergic blocker, a carbonic anhydrase inhibitor, a nerve growth factor, an anti-VEGF antibody, or cyclosporine.

[0161] Embodiment II-12. The dry implant formulation of any one of Embodiments II-3 to II-11, wherein the plurality of particulate implants comprises a total of about 5 μg to about 15 mg of drug.

[0162] Embodiment II-13. The dry implant formulation of any one of Embodiments II-3 to II-12, wherein the plurality of particulate implants comprises a total of about 10 μg to about 10 mg of drug.

[0163] Embodiment II-14. The dry implant formulation of any one of Embodiments II-3 to II-13, wherein the plurality of particulate implants are configured to deliver a drug to the eye at a rate of about 1 ng / day to about 50 μg / day in total.

[0164] Embodiment II-15. The dry implant formulation of any one of Embodiments II-3 to II-14, wherein the plurality of particulate implants are configured to deliver a drug to the eye at a rate of about 5 ng / day to about 2000 ng / day in total.

[0165] Embodiment II-16. The dry implant formulation of any one of Embodiments II-3 to II-15, wherein the dry implant formulation is configured to deliver the drug to the eye over a period of time, the period being at least 1 month, at least 4 months, at least 6 months, at least 8 months, at least 1 year, at least 2 years, or at least 3 years.

[0166] Embodiment II-17. The dry implant formulation of any one of Embodiments II-1 through II-16, wherein at least a subset of the plurality of particulate implants comprises an imaging agent.

[0167] Embodiment II-18. The dry implant formulation of embodiment II-17, wherein the imaging agent is one or more of a dye, a radioactive label, and a fluorescent marker.

[0168] Embodiment II-19. The dry implant formulation according to Embodiments II-17 to II-18, wherein the contrast agent is fluorescein.

[0169] Embodiment II-20. A dry implant formulation described in any one of Embodiments II-17 to II-19, wherein each of the plurality of microparticle implants comprises a drug and a contrast agent, and each of the plurality of microparticle implants is configured to deliver the drug and the contrast agent into the eye at the same rate.

[0170] Embodiment II-21. A dry implant formulation according to any one of embodiments II-1 to II-20, comprising a first particulate implant comprising a first drug and a second particulate implant comprising a second, different drug.

[0171] Embodiment II-22. The dry implant formulation of embodiment II-21, wherein the first drug is a β-adrenergic blocker.

[0172] Embodiment II-23. The dry implant formulation of embodiment II-22, wherein the beta-adrenergic blocker is timolol.

[0173] Embodiment II-24. The dry implant formulation of embodiment II-23, wherein the timolol is timolol maleate or timolol hemihydrate.

[0174] Embodiment II-25. The dry implant formulation of any one of Embodiments II-21 to II-24, wherein the second drug is a carbonic anhydrase inhibitor.

[0175] Embodiment II-26. The dry implant formulation of Embodiment II-25, wherein the carbonic anhydrase inhibitor is dorzolamide or brinzolamide.

[0176] Embodiment II-27. The dry implant formulation of embodiment II-26, wherein the dorzolamide is dorzolamide hydrochloride or dorzolamide base.

[0177] Embodiment II-28. The dry implant formulation of any one of Embodiments II-22 to II-24, wherein the second drug is a prostaglandin analog or a prostamide analog.

[0178] Embodiment II-29. The dry implant formulation of Embodiment II-28, wherein the prostaglandin analog is latanoprost, travoprost, tafluprost, or unoprostone, and the prostamide analog is bimatoprost.

[0179] Embodiment II-30. The dry implant formulation of Embodiment II-28, wherein the second drug is a prostaglandin analog, and the prostaglandin analog is latanoprost.

[0180] Embodiment II-31. The dry implant formulation of any one of Embodiments II-22 to II-24, wherein the second drug is a rho kinase inhibitor.

[0181] Embodiment II-32. The dry implant formulation of embodiment II-31, wherein the Rho kinase inhibitor is ripasudil or netarsudil.

[0182] Embodiment II-33. The dry implant formulation of embodiment II-21, wherein the first drug is a prostaglandin analog or a prostamide analog.

[0183] Embodiment II-34. The dry implant formulation of Embodiment II-33, wherein the prostaglandin analog is latanoprost, travoprost, tafluprost, or unoprostone, and the prostamide analog is bimatoprost.

[0184] Embodiment II-35. The dry implant formulation of Embodiment II-34, wherein the first drug is a prostaglandin analog, and the prostaglandin analog is latanoprost.

[0185] Embodiment II-36. The dry implant formulation of any one of Embodiments II-32 to II-35, wherein the second drug is a rho kinase inhibitor.

[0186] Embodiment II-37. The dry implant formulation of Embodiment II-36, wherein the Rho kinase inhibitor is ripasudil or netarsudil.

[0187] Embodiment II-38. A dry implant formulation for treating glaucoma in an eye of a subject, comprising a first microparticle implant comprising timolol and a second microparticle implant comprising dorzolamide or brinzolamide, the dry implant formulation being configured to be implanted into the sub-Tenon's space in the eye of the subject without a carrier.

[0188] Embodiment II-39. The dry implant formulation of any one of Embodiments II-1 to II-38, wherein each of the plurality of particulate implants is a microsphere.

[0189] Embodiment II-40. A dry implant formulation according to any one of Embodiments II-1 to II-39, wherein each of the plurality of particulate implants comprises a bioerodible polymer, and at least a majority of the plurality of microspheres have been heated above the glass transition temperature of the bioerodible polymer.

[0190] Embodiment II-41. The dry implant formulation of any one of Embodiments II-1 to II-40, further comprising a binder.

[0191] Embodiment II-42. The dry implant formulation of embodiment II-41, wherein the binder is selected from the group consisting of sugar, gelatin, collagen, polyethylene glycol (PEG), starch, cellulose, alginate, and chitosan.

[0192] Embodiment II-43. The dry implant formulation of embodiment II-42, wherein the binder is a sugar, and the sugar is glucose, sucrose, lactose, or fructose.

[0193] Embodiment II-44. The drug eluting implant of any one of Embodiments II-1 to II-42, wherein the dry implant formulation is malleable and does not readily dissociate into individual implants.

[0194] Embodiment II-45. A system for treating an ocular condition in a subject, comprising: a cannula having an inner cavity and a distal tip configured for insertion into a portion of the eye; and a dry implant formulation comprising a plurality of drug-eluting microparticle implants positioned within the inner cavity of the cannula without a carrier.

[0195] Embodiment II-46. The system of embodiment II-44, wherein the dry implant formulation is malleable and does not easily dissociate into individual implants.

[0196] Embodiment II-47. The system of embodiment II-45 or II-46, wherein the distal tip of the cannula has a chamfered edge.

[0197] Embodiment II-48. A system described in embodiment II-45 or II-46, wherein the cannula comprises a proximal portion and a distal portion terminating in a distal tip, the distal tip being tapered and having a smaller outer diameter than the proximal portion.

[0198] Embodiment II-49. A system according to any one of embodiments II-45 to II-48, wherein the cannula is transparent.

[0199] Embodiment II-50. A system described in any one of embodiments II-45 to II-49, further comprising a pusher rod slidably positioned within the lumen, wherein a distal tip of the pusher rod is in contact with at least a portion of the dry implant formulation.

[0200] Embodiment II-51. The system of embodiment II-50, further comprising a handle connected to the cannula, the handle being sized and shaped for comfortable holding and manipulation of the cannula.

[0201] Embodiment II-52. A system as described in embodiment II-51, wherein the handle comprises an actuator operably coupled to the pusher rod, the cannula, or both, and engaging the actuator moves the pusher rod, the cannula, or both.

[0202] Embodiment II-53. A system as described in embodiment II-52, wherein the actuator is a wheel configured to be rotated by a user, and the handle includes a drive assembly that converts rotational motion of the wheel into linear motion of the pusher rod.

[0203] Embodiment II-54. The system described in embodiment II-53, wherein the drive assembly comprises a first linear gear mounted coaxially or tangentially to the wheel, an idler gear engaging with the first linear gear, and a first elongated member connected to the pusher rod, the first elongated member engaging with the idler gear to convert rotational motion of the wheel into a first linear motion of the first elongated member.

[0204] Embodiment II-55. The system of embodiment II-54, wherein the first elongated member is a first straight gear.

[0205] Embodiment II-56. A system as described in embodiment II-53, wherein the actuator is operably coupled to the cannula and operable to move the cannula relative to the handle and pusher rod, thereby retracting the distal opening of the cannula toward the tip of the pusher rod.

[0206] Embodiment II-57. A system as described in embodiment II-56, wherein the actuator is a wheel configured to be rotated by a user, and the handle includes a drive assembly that converts rotational motion of the wheel into linear motion of the cannula.

[0207] Embodiment II-58. A system as described in embodiment II-57, wherein the drive assembly comprises a second linear gear mounted coaxially or tangentially to the wheel, and a second elongated member connected to the cannula and engaging with the linear gear to convert rotational motion of the wheel into a second linear motion of the second elongated member.

[0208] Embodiment II-59. The system of embodiment II-58, wherein the second elongated member is a second straight gear.

[0209] Embodiment II-60. A system as described in embodiment II-53, wherein the actuator is operably coupled to the pusher rod and is operable to move the pusher rod relative to the handle and cannula, thereby advancing the tip of the pusher rod toward the distal opening of the cannula, and to move the cannula relative to the handle and pusher rod, thereby retracting the distal opening of the cannula toward the tip of the pusher rod.

[0210] Embodiment II-61. A system as described in embodiment II-60, wherein the actuator is a wheel configured to be rotated by a user, and the cannula holder includes a drive assembly that converts the rotational motion of the wheel into linear motion of the pusher rod and an opposite linear motion of the cannula.

[0211] Embodiment II-62. The system of embodiment II-61, wherein the drive assembly comprises: a first linear gear mounted coaxially or tangentially to the wheel; an idler gear engaged with the first linear gear; a first elongated member connected to the pusher rod, the first elongated member engaging the idler gear to convert rotational motion of the wheel into a first linear motion of the first elongated member; a second linear gear mounted coaxially or tangentially to the wheel; and a second elongated member connected to the cannula, the second elongated member engaging the linear gear to convert rotational motion of the wheel into a second linear motion of the second elongated member; A system in which the first linear motion and the second linear motion are in opposite directions.

[0212] Embodiment II-63. A method of forming a system for treating an ocular condition in a subject, the method comprising: inserting a dry implant formulation comprising a plurality of drug-eluting particulate implants into a lumen of a cannula, the cannula being configured to be inserted into a target location within the eye, the dry implant formulation being carrier-free; and heating and / or compressing the dry implant formulation, thereby increasing adhesion between the plurality of particulate implants.

[0213] Embodiment II-64. A method according to embodiment II-63, comprising heating the cannula, wherein each of the plurality of particulate implants comprises a bioerodible polymer, and wherein at least a majority of the plurality of particulate implants are heated above the glass transition temperature of the bioerodible polymer, thereby increasing adhesion of at least some of the particulate implants to each other.

[0214] Embodiment II-65. The method of embodiment II-64, comprising compressing the dry implant formulation while a majority of the plurality of particulate implants are heated to a temperature above the glass transition temperature of the bioerodible polymer.

[0215] Embodiment II-66. The method of any one of Embodiments II-63 to II-65, wherein the dry implant formulation comprises a binder.

[0216] Embodiment II-67. The method of embodiment II-66, wherein the binder is selected from the group consisting of sugar, gelatin, collagen, polyethylene glycol (PEG), starch, cellulose, alginate, and chitosan.

[0217] Embodiment II-68. The method of embodiment II-67, wherein the binder is a sugar, and the sugar is glucose, sucrose, lactose, or fructose.

[0218] Embodiment II-69. The method of embodiment II-68, wherein the dry implant formulation is compressed, thereby increasing adhesion between the plurality of particulate implants and the binder.

[0219] Embodiment II-70. A method for treating an ocular condition in a subject, comprising implanting at least one drug-eluting implant into the eye of the subject, wherein the at least one implant is implanted without a carrier, and wherein a drug is delivered to the eye from the at least one drug-eluting implant to alleviate symptoms of the ocular condition.

[0220] Embodiment II-71. The method of embodiment II-70, wherein the ocular condition is glaucoma and / or dry eye disease.

[0221] Embodiment II-72. The method of embodiment II-70 or II-71, wherein the at least one drug-eluting implant is delivered from the at least one drug-eluting implant to the sulcus, posterior chamber, anterior chamber, vitreous body, sub-Tenon's space, and subconjunctival space of the eye.

[0222] Embodiment II-73. The method of any one of embodiments II-70 to II-72, further comprising advancing at least one drug-eluting implant to an implantation site within the eye within the implantation system.

[0223] Embodiment II-74. The method of embodiment II-73, wherein the advancing step comprises pushing at least one drug-eluting implant with a pusher rod.

[0224] Embodiment II-75. The method described in embodiment II-73, wherein the implantation system includes a cannula, and the at least one implant is contained within the cannula, and the method further includes puncturing eye tissue with the cannula.

[0225] Embodiment II-76. The method of embodiment II-74 or II-75, wherein the method further comprises operating an actuator of the implant system to release at least one drug-eluting implant from the implant system.

[0226] Embodiment II-77. The method of any one of Embodiments II-74 to II-76, wherein two or more drug-eluting implants are released from the implantation system.

[0227] Embodiment II-78. The method of any one of embodiments II-74 to II-77, wherein operating the actuator advances the pusher rod.

[0228] Embodiment II-79. The method of any one of embodiments II-75 to II-78, wherein the actuator comprises one or more of a button, a knob, a slider, a lever, and a wheel.

[0229] Embodiment II-80. A method according to any one of embodiments II-70 to II-79, wherein at least one drug-eluting implant is advanced and / or positioned using one or more of a loop, a slit lamp, and a surgical microscope.

[0230] Embodiment II-81. The method of any one of Embodiments II-70 to II-80, wherein at least one drug-eluting implant delivers a glaucoma medication and / or a dry eye disease medication.

[0231] Embodiment II-82. The method of any one of Embodiments II-70 to II-81, wherein at least one drug-eluting implant delivers a prostaglandin or a prostaglandin analog.

[0232] Embodiment II-83. The method of any one of embodiments II-70 to II-82, wherein at least one drug-eluting implant delivers a beta-adrenergic blocker, a carbonic anhydrase inhibitor, a prostaglandin analog, an immunosuppressant, a rho kinase inhibitor, or a combination thereof.

[0233] Embodiment II-84. The method of any one of embodiments II-70 to II-83, wherein the at least one drug-eluting implant includes a first drug-eluting implant, and the method further includes implanting a second drug-eluting implant into the eye.

[0234] Embodiment II-85. The method of embodiment II-84, wherein the first drug-eluting implant comprises a first drug having a first mechanism of action, and the second drug-eluting implant comprises a second drug having a second mechanism of action.

[0235] Embodiment II-86. The method of embodiment II-85, wherein the first mechanism of action and the second mechanism of action are the same.

[0236] Embodiment II-87. The method of embodiment II-86, wherein the first mechanism of action is different from the second mechanism of action.

[0237] Embodiment II-88. The method of any one of embodiments II-84 to II-87, wherein a first drug-eluting implant is implanted at a first site within the eye and a second drug-eluting implant is implanted at a second site within the eye.

[0238] Embodiment II-89. The method of any one of Embodiments II-84 to II-87, wherein the first drug-eluting implant and the second drug-eluting implant are implanted at the same site in the eye.

[0239] Embodiment II-90. The method of any one of embodiments II-70 to II-89, wherein at least one drug-eluting implant is a drug-eluting particulate implant and is implanted as part of a dry implant formulation comprising a plurality of drug-eluting particulate implants.

[0240] Embodiment II-91. A method for treating an ocular condition in a subject, the method comprising: advancing a distal portion of a cannula of an implantation system toward a target location within the eye, the cannula having an inner lumen and a distal tip configured to pierce tissue, the cannula containing a dry implant formulation comprising a plurality of drug-eluting microparticle implants without a carrier; and actuating the implantation system such that the dry implant formulation is released from the distal portion of the cannula into the target location.

[0241] Embodiment II-92. The method of embodiment II-91, wherein each of the plurality of microparticle implants comprises a drug selected from the group consisting of a beta-adrenergic blocker, a carbonic anhydrase inhibitor, a prostaglandin analog, an immunosuppressant, a Rho kinase inhibitor, or a combination thereof.

[0242] Embodiment II-93. The method of embodiment II-91 or II-92, wherein the target location within the eye is the sulcus, the posterior chamber, the anterior chamber, the vitreous body, the sub-Tenon's space, or the subconjunctival space.

[0243] Embodiment II-94. The method of any one of Embodiments II-91 to II-93, wherein the dry implant formulation, after being released to the target location, delivers the drug to the target location at a rate of about 1 ng / day to about 50 μg / day.

[0244] Embodiment II-95. The method of any one of Embodiments II-91 to II-93, wherein the dry implant formulation, after being released to the target location, delivers the drug to the eye at a rate of about 5 ng / day to about 2000 ng / day.

[0245] Embodiment II-96. The method of any one of embodiments II-91 to II-95, wherein the dry implant formulation delivers the drug to the eye for a period of time after being released to the target location, the period being at least 1 month, at least 4 months, at least 6 months, at least 8 months, at least 1 year, at least 2 years, or at least 3 years.

[0246] Embodiment II-97. The method of any one of embodiments II-91 to II-96, wherein the dry implant formulation comprises a first subset of particulate implants comprising a first drug and a second subset of particulate implants comprising a second, different drug.

[0247] Embodiment II-98. The method of embodiment II-96, wherein the ocular condition is glaucoma or ocular hypertension.

[0248] Embodiment II-99. The method of embodiment II-97 or II-98, wherein the first drug is a beta-adrenergic blocker.

[0249] Embodiment II-100. The method of embodiment II-99, wherein the β-adrenergic blocker is timolol.

[0250] Embodiment II-101. The method of embodiment II-100, wherein the timolol is timolol maleate or timolol hemihydrate.

[0251] Embodiment II-102. The method of any one of embodiments II-99 to II-101, wherein the second drug is a carbonic anhydrase inhibitor.

[0252] Embodiment II-103. The method of embodiment II-102, wherein the carbonic anhydrase inhibitor is dorzolamide or brinzolamide.

[0253] Embodiment II-104. The method of embodiment II-103, wherein the dorzolamide is dorzolamide hydrochloride or dorzolamide base.

[0254] Embodiment II-105. The method of any one of embodiments II-99 to II-101, wherein the second drug is a prostaglandin analog or a prostamide analog.

[0255] Embodiment II-106. The method of embodiment II-105, wherein the prostaglandin analog is latanoprost, travoprost, tafluprost, or unoprostone, and the prostamide analog is bimatoprost.

[0256] Embodiment II-107. The method of embodiment II-105, wherein the second drug is a prostaglandin analog, and the prostaglandin analog is latanoprost.

[0257] Embodiment II-108. The method of any one of embodiments II-99 to II-101, wherein the second drug is a rho kinase inhibitor.

[0258] Embodiment II-109. The method of embodiment II-108, wherein the rho kinase inhibitor is ripasudil or netarsudil.

[0259] Embodiment II-110. The method of embodiment II-97 or II-98, wherein the first drug is a prostaglandin analog or a prostamide analog.

[0260] Embodiment II-111. The method of embodiment II-110, wherein the prostaglandin analog is latanoprost, travoprost, tafluprost, or unoprostone, and the prostamide analog is bimatoprost.

[0261] Embodiment II-112. The method of embodiment II-111, wherein the first drug is a prostaglandin analog, and the prostaglandin analog is latanoprost.

[0262] Embodiment II-113. The method of any one of embodiments II-110 to II-112, wherein the second drug is a rho kinase inhibitor.

[0263] Embodiment II-114. The method according to embodiment II-113, wherein the rho kinase inhibitor is ripasudil or netarsudil. [Example]

[0264] Example 1: Dry subconjunctival delivery of drug-eluting implants formulated with prostaglandins or cyclosporines The implantation system, loaded with carrier-free drug-eluting microspheres, each containing at least one prostaglandin or cyclosporin, 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 a typical manner for ophthalmic surgery, and the surgical microscope and lid speculum are positioned and positioned accordingly. The conjunctiva is grasped with conjunctival forceps.

[0265] The needle of the implantation system is advanced under direct microscopic visualization into the subconjunctival space. An actuator on the device handle is activated (button, slider, lever, and / or wheel). A pusher inside the needle moves distally toward the distal tip of the needle, advancing a predetermined number of microspheres from the needle into the subconjunctival space. This is visualized microscopically. Visualization may also be performed with a slit lamp, loupe, 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.

[0266] Example 2: Dry delivery of drug-eluting implants formulated with prostaglandins to the posterior chamber / sulcus The implantation system, loaded with carrier-free drug-eluting microspheres, each containing at least one prostaglandin, 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 a typical manner for ophthalmic surgery, and the surgical microscope and lid speculum are positioned and positioned appropriately.

[0267] The needle of the implantation system is advanced through the cornea near the limbus and into the anterior chamber under direct microscopic visualization. The tip of the needle is advanced into the pupil, just past the pupillary collar. The needle may be curved or straight. An actuator on the device handle is activated (button, slider, lever, or wheel). A pusher rod inside the needle moves forward / distal toward the tip of the needle, displacing a predetermined amount of microspheres from the needle into the posterior chamber. This is visualized microscopically. Alternatively, a flexible, atraumatic catheter is inserted into the posterior chamber prior to implantation of the pre-administered microspheres. Visualization may also be performed with a slit lamp, loupe, 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.

[0268] Example 3: Dry subconjunctival delivery of drug-eluting implants formulated with timolol and dorzolamide An implantation system having a cannula loaded with carrier-free drug-eluting microspheres (e.g., a dry implant formulation) and a handle including a housing and an actuator connected to the cannula is removed from its sterile packaging and placed on a sterile surface. Optionally, the loaded cannula and handle are packaged separately, and the cannula is attached to the handle prior to use. A first subset of pre-loaded microspheres contains timolol (e.g., timolol maleate or timolol hemihydrate), and a second subset of pre-loaded microspheres contains dorzolamide (e.g., dorzolamide hydrochloride, dorzolamide base) or brinzolamide. The first and second subsets of microspheres may be combined into one implant unit of a dry implant formulation containing both implant subsets. The subject's eye and periocular area are treated with a disinfectant. The eye is then draped in a typical manner for ophthalmic surgery, and the operating microscope (or slit lamp) and lid speculum are appropriately positioned and positioned, respectively. The conjunctiva is grasped with conjunctival forceps.

[0269] The cannula of the implantation system is advanced under direct microscopic visualization, penetrating the conjunctiva and into the target location within the eye, which may be the subconjunctival or sub-Tenon's space. An actuator on the handle is actuated (button, slider, lever, and / or wheel). A pusher rod within the cannula moves distally toward the distal tip of the cannula, expelling pre-loaded microspheres from the cannula into the target location. The release of the microspheres is visualized with a microscope or slit lamp. Visualization may also be performed with a slit lamp, loupes, or the naked eye. The cannula is then withdrawn from the conjunctiva. Antibiotic drops are applied to the eye, and the lid speculum is removed.

Claims

1. A dry implant formulation for treating an ocular condition in a subject, comprising a plurality of drug-eluting microparticle implants, wherein the dry implant formulation is configured to be implanted into the eye of the subject without a carrier.

2. The dry implant formulation of claim 1 , wherein each of the plurality of particulate implants comprises a drug-eluting matrix.

3. The dry implant formulation of claim 2 , wherein the drug-eluting matrix comprises a bioerodible polymer and a drug.

4. 4. The drug-eluting implant of claim 1, wherein the particulate implant comprises poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA), poly-ε-caprolactone (PCA), or poly(glycolic acid) (PGA).

5. The drug eluting implant of any one of claims 1 to 4, wherein the particulate implant comprises a mixture of two bioerodible polymers.

6. The dry implant formulation of any one of claims 1 to 5, wherein each of the plurality of particulate implants has a diameter of from about 1 μm to about 500 μm.

7. 7. The dry implant formulation of claim 1, wherein each of said plurality of said particulate implants has a maximum linear dimension of about 10 μm to about 100 μm.

8. The dry implant formulation of any one of claims 1 to 7, wherein the eye condition is glaucoma and / or dry eye disease.

9. 9. The dry implant formulation of claim 1, wherein the dry implant formulation is configured to be positioned in one or more of the ocular sulcus, the posterior chamber, the anterior chamber, the vitreous body, the sub-Tenon's space, and the subconjunctival space.

10. The dry implant formulation according to any one of claims 3 to 9, wherein the drug is a prostaglandin or a prostaglandin analogue.

11. The dry implant formulation according to any one of claims 3 to 10, wherein the drug is latanoprost, bimatoprost, travoprost, a β-adrenergic blocker, a carbonic anhydrase inhibitor, a nerve growth factor, an anti-VEGF antibody, or cyclosporine.

12. 12. The dry implant formulation of claim 3, wherein the plurality of particulate implants comprises a total of about 5 μg to about 15 mg of the drug.

13. 13. The dry implant formulation of any one of claims 3 to 12, wherein the plurality of particulate implants comprises a total of about 10 μg to about 10 mg of the drug.

14. 14. The dry implant formulation of any one of claims 3 to 13, wherein the plurality of microparticle implants are configured to collectively deliver the drug to the eye at a rate of about 1 ng / day to about 50 μg / day.

15. 15. The dry implant formulation of any one of claims 3 to 14, wherein the plurality of microparticle implants are configured to collectively deliver the drug to the eye at a rate of about 5 ng / day to about 2000 ng / day.

16. 16. The dry implant formulation of any one of claims 3 to 15, wherein the dry implant formulation is configured to deliver the drug to the eye over a period of time, wherein the period of time is at least 1 month, at least 4 months, at least 6 months, at least 8 months, at least 1 year, at least 2 years, or at least 3 years.

17. The dry implant formulation of any one of claims 1 to 16, wherein at least a subset of said plurality of particulate implants comprises an imaging agent.

18. 18. The dry implant formulation of claim 17, wherein the imaging agent is one or more of a dye, a radioactive label, and a fluorescent marker.

19. The dry implant formulation according to claims 17 to 18, wherein the contrast agent is fluorescein.

20. 20. The dry implant formulation of any one of claims 17 to 19, wherein each of the plurality of particulate implants comprises a drug and a contrast agent, and each of the plurality of particulate implants is configured to deliver the drug and the contrast agent into the eye at the same rate.

21. 21. The dry implant formulation of any one of claims 1 to 20, wherein the dry implant formulation comprises a first particulate implant comprising a first drug and a second particulate implant comprising a second, different drug.

22. 22. The dry implant formulation of claim 21, wherein the first drug is a beta-adrenergic blocker.

23. 23. The dry implant formulation of claim 22, wherein the beta-adrenergic blocker is timolol.

24. 24. The dry implant formulation of claim 23, wherein the timolol is timolol maleate or timolol hemihydrate.

25. The dry implant formulation of any one of claims 21 to 24, wherein the second drug is a carbonic anhydrase inhibitor.

26. 26. The dry implant formulation of claim 25, wherein the carbonic anhydrase inhibitor is dorzolamide or brinzolamide.

27. 27. The dry implant formulation of claim 26, wherein the dorzolamide is dorzolamide hydrochloride or dorzolamide base.

28. The dry implant formulation according to claims 22 to 24, wherein the second drug is a prostaglandin analog or a prostamide analog.

29. 29. The dry implant formulation of claim 28, wherein the prostaglandin analog is latanoprost, travoprost, tafluprost, or unoprostone, and the prostamide analog is bimatoprost.

30. 29. The dry implant formulation of claim 28, wherein the second drug is a prostaglandin analog, and the prostaglandin analog is latanoprost.

31. The dry implant formulation of claims 22 to 24, wherein the second drug is a rho kinase inhibitor.

32. 32. The dry implant formulation of claim 31, wherein the rho-kinase inhibitor is ripasudil or netarsudil.

33. 22. The dry implant formulation of claim 21, wherein the first drug is a prostaglandin analog or a prostamide analog.

34. 34. The dry implant formulation of claim 33, wherein the prostaglandin analog is latanoprost, travoprost, tafluprost, or unoprostone, and the prostamide analog is bimatoprost.

35. 35. The dry implant formulation of claim 34, wherein the first drug is a prostaglandin analog, and the prostaglandin analog is latanoprost.

36. The dry implant formulation of any one of claims 32 to 35, wherein the second drug is a rho kinase inhibitor.

37. 37. The dry implant formulation of claim 36, wherein the rho-kinase inhibitor is ripasudil or netarsudil.

38. A dry implant formulation for treating glaucoma in the eye of a subject, comprising: a first microparticle implant comprising timolol; and a second microparticle implant comprising dorzolamide or brinzolamide, wherein the dry implant formulation is configured to be implanted into the sub-Tenon space in the eye of the subject without a carrier.

39. 39. The dry implant formulation of any one of claims 1 to 38, wherein each of the plurality of particulate implants is a microsphere.

40. 40. The dry implant formulation of any one of claims 1 to 39, wherein each of the plurality of particulate implants comprises a bioerodible polymer, and at least a majority of the plurality of microspheres have been heated above the glass transition temperature of the bioerodible polymer.

41. The dry implant formulation according to any one of claims 1 to 40, further comprising a binder.

42. 42. The dry implant formulation of claim 41, wherein the binder is selected from the group consisting of sugar, gelatin, collagen, polyethylene glycol (PEG), starch, cellulose, alginate, and chitosan.

43. 43. The dry implant formulation of claim 42, wherein the binder is a sugar, the sugar being glucose, sucrose, lactose, or fructose.

44. 43. The drug eluting implant of any one of claims 1 to 42, wherein the dry implant formulation is malleable and does not readily dissociate into individual implants.

45. 1. A system for treating an ocular condition in a subject, the system comprising: a cannula including an inner lumen and a distal tip configured for insertion into a portion of the eye; a dry implant formulation comprising a plurality of drug-eluting particulate implants positioned within the lumen of the cannula without a carrier.

46. 45. The system of claim 44, wherein the dry implant formulation is malleable and does not easily dissociate into individual implants.

47. 47. The system of claim 45 or 46, wherein the distal tip of the cannula has a chamfered edge.

48. 47. The system of claim 45 or 46, wherein the cannula comprises a proximal portion and a distal portion terminating in a distal tip, the distal tip being tapered and having a smaller outer diameter than the proximal portion.

49. The system of any one of claims 45 to 48, wherein the cannula is transparent.

50. 50. The system of any one of claims 45 to 49, further comprising a pusher rod slidably positioned within the lumen, a distal tip of the pusher rod in contact with at least a portion of the dry implant formulation.

51. 51. The system of claim 50, further comprising a handle connected to the cannula, the handle being sized and shaped to comfortably hold and manipulate the cannula.

52. 52. The system of claim 51, wherein the handle comprises an actuator operably coupled to the pusher rod, the cannula, or both, and wherein engaging the actuator moves the pusher rod, the cannula, or both.

53. 53. The system of claim 52, wherein the actuator is a wheel configured to be rotated by a user, and the handle includes a drive assembly that converts rotational motion of the wheel into linear motion of the pusher rod.

54. the drive assembly: a first linear gear mounted coaxially or tangentially to the wheel; an idler gear engaged with the first straight gear; 54. The system of claim 53, comprising: a first elongated member connected to the pusher rod, the first elongated member engaging the idler gear to convert rotational motion of the wheel into a first linear motion of the first elongated member.

55. 55. The system of claim 54, wherein the first elongated member is a first linear gear.

56. 54. The system of claim 53, wherein the actuator is operably coupled to the cannula and operable to move the cannula relative to the handle and the pusher rod, thereby retracting the distal opening of the cannula toward the tip of the pusher rod.

57. 57. The system of claim 56, wherein the actuator is a wheel configured to be rotated by a user, and the handle includes a drive assembly that converts rotational motion of the wheel into linear motion of the cannula.

58. the drive assembly: a second straight gear mounted coaxially or tangentially to the wheel; 58. The system of claim 57, comprising a second elongated member connected to the cannula, the second elongated member engaging the linear gear to convert rotational motion of the wheel into a second linear motion of the second elongated member.

59. 59. The system of claim 58, wherein the second elongated member is a second linear gear.

60. the actuator is operably coupled to the pusher rod; and moving the pusher rod relative to the handle and the cannula, thereby advancing the tip of the pusher rod toward the distal opening of the cannula; 54. The system of claim 53, operable to move the cannula relative to the handle and the pusher rod, thereby retracting the distal opening of the cannula toward the tip of the pusher rod.

61. 61. The system of claim 60, wherein the actuator is a wheel configured to be rotated by a user, and the cannula holder includes a drive assembly that converts rotational motion of the wheel into linear motion of the pusher rod and an opposing linear motion of the cannula.

62. the drive assembly: a first linear gear mounted coaxially or tangentially to the wheel; an idler gear engaged with the first straight gear; a first elongated member connected to the pusher rod, the first elongated member engaging the idler gear to convert rotational motion of the wheel into a first linear motion of the first elongated member; a second straight gear mounted coaxially or tangentially to the wheel; a second elongated member connected to the cannula, the second elongated member engaging the linear gear to convert rotational motion of the wheel into a second linear motion of the second elongated member; 62. The system of claim 61, wherein the first linear motion and the second linear motion are in opposite directions.

63. 1. A method of forming a system for treating an ocular condition in a subject, the method comprising: inserting a dry implant formulation comprising a plurality of drug-eluting particulate implants into a lumen of a cannula, the cannula being configured to be inserted into a target location within an eye, the dry implant formulation being carrier-free; heating and / or compressing said dry implant formulation, thereby increasing adhesion between said plurality of particulate implants.

64. 64. The method of claim 63, comprising heating the cannula, wherein each of the plurality of particulate implants comprises a bioerodible polymer, and wherein at least a majority of the plurality of particulate implants are heated above the glass transition temperature of the bioerodible polymer, thereby increasing adhesion of at least some of the particulate implants to one another.

65. 65. The method of claim 64, comprising compressing the dry implant formulation while the majority of the plurality of particulate implants are heated to a temperature above the glass transition temperature of the bioerodible polymer.

66. 66. The method of any one of claims 63 to 65, wherein the dry implant formulation comprises a binder.

67. 67. The method of claim 66, wherein the binder is selected from the group consisting of sugar, gelatin, collagen, polyethylene glycol (PEG), starch, cellulose, alginate, and chitosan.

68. 68. The method of claim 67, wherein the binder is a sugar, and the sugar is glucose, sucrose, lactose, or fructose.

69. 69. The method of claim 68, wherein the dry implant formulation is compressed, thereby increasing adhesion between the plurality of particulate implants and the binder.

70. 1. A method for treating an ocular condition in a subject, the method comprising: implanting at least one drug-eluting implant into the eye of the subject, wherein the at least one implant is implanted without a carrier; The method, wherein a drug is delivered to the eye from at least one drug-eluting implant to alleviate symptoms of the condition of the eye.

71. 71. The method of claim 70, wherein the condition of the eye is glaucoma and / or dry eye disease.

72. 72. The method of claim 70 or 71, wherein the at least one drug-eluting implant is delivered from the at least one drug-eluting implant to the sulcus, posterior chamber, anterior chamber, vitreous body, sub-Tenon's space, and subconjunctival space of the eye.

73. 73. The method of any one of claims 70-72, further comprising advancing the at least one drug-eluting implant to an implantation site within the eye in an implantation system.

74. 74. The method of claim 73, wherein the advancing step comprises pushing the at least one drug-eluting implant with a pusher rod.

75. 74. The method of claim 73, wherein the implantation system comprises a cannula, the at least one implant is housed within the cannula, and the method further comprises piercing the ocular tissue with the cannula.

76. 76. The method of claim 74 or 75, wherein the method further comprises operating an actuator of the implant system to release the at least one drug eluting implant from the implant system.

77. 77. The method of any one of claims 74 to 76, wherein two or more drug-eluting implants are released from the implantation system.

78. 78. The method of any one of claims 74 to 77, wherein operating the actuator advances the pusher rod.

79. 79. The method of any one of claims 75 to 78, wherein the actuator comprises one or more of a button, a knob, a slider, a lever, and a wheel.

80. 80. The method of any one of claims 70 to 79, wherein the at least one drug eluting implant is advanced and / or positioned using one or more of a loop, a slit lamp, and a surgical microscope.

81. 81. The method of any one of claims 70 to 80, wherein the at least one drug-eluting implant delivers a glaucoma medication and / or a dry eye disease medication.

82. 82. The method of any one of claims 70 to 81, wherein the at least one drug-eluting implant delivers a prostaglandin or a prostaglandin analog.

83. 83. The method of any one of claims 70-82, wherein the at least one drug-eluting implant delivers a beta-adrenergic blocker, a carbonic anhydrase inhibitor, a prostaglandin analog, an immunosuppressant, a rho-kinase inhibitor, or a combination thereof.

84. 84. The method of any one of claims 70-83, wherein the at least one drug eluting implant comprises a first drug eluting implant, and the method further comprises implanting a second drug eluting implant into the eye.

85. 85. The method of claim 84, wherein the first drug-eluting implant comprises a first drug having a first mechanism of action and the second drug-eluting implant comprises a second drug having a second mechanism of action.

86. 86. The method of claim 85, wherein the first mechanism of action and the second mechanism of action are the same.

87. 87. The method of claim 86, wherein the first mechanism of action is different from the second mechanism of action.

88. 88. The method of any one of claims 84-87, wherein the first drug-eluting implant is implanted at a first site within the eye and the second drug-eluting implant is implanted at a second site within the eye.

89. 88. The method of any one of claims 84 to 87, wherein the first drug-eluting implant and the second drug-eluting implant are implanted at the same site in the eye.

90. 90. The method of any one of claims 70-89, wherein the at least one drug-eluting implant is a drug-eluting particulate implant and is implanted as part of a dry implant formulation comprising a plurality of drug-eluting particulate implants.

91. 1. A method for treating an ocular condition in a subject, the method comprising: advancing a distal portion of a cannula of the implantation system toward a target location within the eye, the cannula having an internal lumen and a distal tip configured to pierce tissue, the cannula containing a dry implant formulation including a plurality of drug-eluting microparticle implants without a carrier; and actuating the implantation system such that the dry implant formulation is released from the distal portion of the cannula into the target location.

92. 92. The method of claim 91, wherein each of the plurality of particulate implants comprises a drug selected from the group consisting of a beta-adrenergic blocker, a carbonic anhydrase inhibitor, a prostaglandin analog, an immunosuppressant, a Rho kinase inhibitor, or a combination thereof.

93. 93. The method of claim 91 or 92, wherein the target location within the eye is the sulcus, the posterior chamber, the anterior chamber, the vitreous body, the sub-Tenon's space, or the subconjunctival space.

94. 94. The method of any one of claims 91 to 93, wherein the dry implant formulation, after being released into the target location, delivers the drug to the target location at a rate of about 1 ng / day to about 50 μg / day.

95. 94. The method of any one of claims 91 to 93, wherein the dry implant formulation delivers the drug to the eye at a rate of about 5 ng / day to about 2000 ng / day after release into the target location.

96. 96. The method of any one of claims 91-95, wherein the dry implant formulation delivers the drug to the eye for a period of time after release to the target location, wherein the period is at least 1 month, at least 4 months, at least 6 months, at least 8 months, at least 1 year, at least 2 years, or at least 3 years.

97. 97. The method of any one of claims 91-96, wherein the dry implant formulation comprises a first subset of particulate implants comprising a first drug and a second subset of particulate implants comprising a second, different drug.

98. 97. The method of claim 96, wherein the condition of the eye is glaucoma or ocular hypertension.

99. 99. The method of claim 97 or 98, wherein the first drug is a beta-adrenergic blocker.

100. 100. The method of claim 99, wherein the beta-adrenergic blocker is timolol.

101. 101. The method of claim 100, wherein the timolol is timolol maleate or timolol hemihydrate.

102. 102. The method of any one of claims 99 to 101, wherein the second drug is a carbonic anhydrase inhibitor.

103. 103. The method of claim 102, wherein the carbonic anhydrase inhibitor is dorzolamide or brinzolamide.

104. 104. The method of claim 103, wherein the dorzolamide is dorzolamide hydrochloride or dorzolamide base.

105. 102. The method of any one of claims 99 to 101, wherein the second drug is a prostaglandin analog or a prostamide analog.

106. 106. The method of claim 105, wherein the prostaglandin analog is latanoprost, travoprost, tafluprost, or unoprostone, and the prostamide analog is bimatoprost.

107. 106. The method of claim 105, wherein the second drug is a prostaglandin analog, and the prostaglandin analog is latanoprost.

108. 102. The method of any one of claims 99 to 101, wherein the second drug is a rho kinase inhibitor.

109. 109. The method of claim 108, wherein the rho kinase inhibitor is ripasudil or netarsudil.

110. 99. The method of claim 97 or 98, wherein the first drug is a prostaglandin analog or a prostamide analog.

111. 111. The method of claim 110, wherein the prostaglandin analog is latanoprost, travoprost, tafluprost, or unoprostone, and the prostamide analog is bimatoprost.

112. 112. The method of claim 111, wherein the first drug is a prostaglandin analog, and the prostaglandin analog is latanoprost.

113. 113. The method of any one of claims 110 to 112, wherein the second drug is a rho kinase inhibitor.

114. 114. The method of claim 113, wherein the rho kinase inhibitor is ripasudil or netarsudil.

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