Bioerodible ocular implant for treating conditions of eye

Abstract

The present disclosure relates to intraocular drug-eluting particulate implants and dry particulate formulations comprising a plurality of drug-eluting particulate implants for use in the treatment of conditions of the eye, wherein the implants are configured to deliver a drug to the eye without a carrier. The present disclosure also relates to methods of treating conditions of the eye by delivering one or more drugs from a drug eluting implant or dry particulate formulation to the anterior chamber, posterior chamber (e.g., ciliary sulcus), iris corneal horn, sclera, cornea, limbus, subconjunctival space, subcapsular space, and vitreous body.

Description

Technical Field

[0001] The present invention generally relates to bioerodible ocular implants (eg, drug eluting implants) for treating conditions of the eye and associated methods and systems for treating such conditions of the eye.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 63 / 428,389, filed on November 28, 2022. All applications are hereby incorporated by reference in their entirety. Background Art

[0004] Glaucoma is a group of optic neuropathy associated with specific structural changes in the optic nerve, which eventually leads to irreversible visual field loss. In many cases, this vision loss is progressive and, if left untreated, will lead 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 three million people in the United States were diagnosed with glaucoma. Worldwide, the number is 80,000,000 people. By 2040, it is expected that more than 110,000,000 people will suffer from this potential blinding disease ("Global Prevalence of Glaucoma and Projections of Glaucoma Burden through 2040", Ophthalmology 2014; 121: 2081-2090). Glaucoma is generally divided into two categories: open-angle glaucoma and angle-closure glaucoma. In both the United States and Europe, open-angle glaucoma is about seven times more common than the closed-angle form (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, leading to a constriction of the visual field. The ultimate result is permanent blindness. Because the disease is often asymptomatic until it has progressed significantly, early diagnosis through regular eye examinations and early treatment are crucial. Although the prevalence of glaucoma increases with age, the majority of undiagnosed glaucoma patients are under 60 years old (Shaikh Y, Yu F, Coleman AL. Am. J. Ophthalmol. 2014; 158(6): 1121-1129).

[0005] Risk factors associated with glaucoma include family history, ethnic origin, and age. Having a first-degree relative with glaucoma is associated with a significantly increased risk (Wolfs RC, Klaver CC, Ramrattan RS, van Duijn CM, Hofman A, de Jong PT. Arch Ophthalmol. 1998; 116(12): 1640-1645). Black and Hispanic individuals have a higher prevalence of open-angle glaucoma. Additionally, they are often diagnosed with more severe disease. Asian, Southeast Asian, Asian Indian, and Inuit individuals are more commonly diagnosed with angle-closure glaucoma (see, e.g., Varma R, Ying-Lai M, Franc Francis BA, et al.; Los Angeles Latino Eye Study Group. Ophthalmology 2004; 111(8):1439-1448; Tielsch JM, Sommer A, Katz J, Royall 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).

[0006] Angle-closure glaucoma is usually caused by an anatomical obstruction of the anterior chamber angle and its associated drainage channels. The anatomical obstruction prevents the aqueous humor from efficiently reaching the drainage channels, resulting in increased intraocular pressure. Compared to more palliative medical therapies such as cholinergic drugs (e.g., pilocarpine eye drops) used to relieve the obstruction caused by pupil constriction, surgical iridotomy, laser iridotomy, or lensectomy are generally considered to be more etiological surgical options.

[0007] Open-angle glaucoma (OAG) is more common in the United States, and it causes significantly more vision loss than angle-closure glaucoma. Although the exact pathophysiology of OAG is not fully understood, it has been shown that increased intraocular pressure (IOP) is associated with retinal ganglion cell death. There is a relationship between the ciliary body secreting aqueous humor and aqueous humor going out of the eye via conventional trabecular meshwork paths and unconventional uveoscleral paths. This relationship and any resulting imbalance determine the IOP. It is believed that the increased resistance to outflow in the trabecular meshwork or more distal aqueous collector channels is associated with the increased IOP in OAG. The increased IOP can cause mechanical stress on the lamina cribrosa where retinal ganglion cell axons leave the eye to coalesce into the optic nerve. The stress induced by the IOP at the lamina cribrosa can deform, damage and interfere with retinal axons, thereby causing irreversible damage and vision loss. Although the damage associated with this IOP usually occurs when pressure is higher than the group average pressure, it can occur at lower or "normal" pressures, depending on individual vulnerability. Conversely, many people with higher-than-average IOP never develop glaucoma. A growing number of studies are identifying genomic loci associated with glaucoma susceptibility. Therefore, patients whose intraocular pressure is relatively high for their individual susceptibility may develop glaucoma (see, for example, 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 does occur in glaucoma, characteristic changes in the optic nerve head and nerve fiber layer become apparent. This is ultimately associated with a characteristic pattern of visual field loss. Prompt referral to an eye care specialist is crucial for treating glaucoma and slowing 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 criteria include age, family history, ethnic background, IOP, corneal thickness, optical coherence tomography of various retinal tissues, optic nerve head appearance, and peripheral visual field testing.

[0008] The primary goal of treatment is to slow progressive optic nerve damage in order to preserve vision and quality of life. Given that visual loss is irreversible, early diagnosis and intervention are crucial. Treatment to lower IOP combined with serial diagnostic assessments of treatment efficacy are part of primary glaucoma care.

[0009] Initially, treatment usually consists of the minimum number of drugs needed to adequately lower IOP. Drugs include drugs from the following families of compounds: prostaglandins, prostaglandin analogs, beta-adrenergic blockers, alpha-adrenergic agonists, carbonic anhydrase inhibitors, Rho kinase (ROCK) inhibitors, and cholinergic drugs.

[0010] If medical therapy fails, is not tolerated, or is not possible, other forms of therapy may be added or substituted for medical therapy. For example, laser therapy may be performed on the eye in the form of trabeculoplasty, ring ablation (endoscopic or transscleral). In more advanced cases or in some circumstances, incisional surgery may be considered. Trabeculectomy, valves, or shunts may be used to help control IOP. Recently, minimally invasive glaucoma surgery, or MIGS, has become a popular surgical approach to treat glaucoma. Various techniques are used to lower IOP while reducing exposure to the surgical risks of more invasive treatments such as trabeculectomy or valve placement. In 2017, nearly 175,000 surgical procedures were performed. Surgical procedures included over 20,000 trabeculectomies, 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).

[0011] While medical therapy is the preferred initial treatment for OAG in the United States, it does present a number of problems. Eye drops can be prohibitively expensive for patients, and patients may forget to use them regularly. Furthermore, proper instillation into the conjunctival fornix can be more difficult, especially in the hands of the elderly or those with arthritis. Over-instillation (such as administering multiple drops) and subsequent drug waste are also a problem. However, even with proper eye drop instillation, drug waste occurs. For example, a typical eye drop volume may be 60 to 90 microliters, but the ocular surface typically retains no more than 10 microliters. The therapeutic ingredients and the preservatives they are often combined with can cause ocular surface disease, discomfort, inflammation, dry eye, and reduced corneal sensitivity, all of which can irritate the eye and further reduce compliance. Multiple eye drop medications can also lead to drug confusion and misuse. All of these factors combine to create problems for drug therapy, the primary glaucoma treatment. However, medications do avoid many of the more serious complications that can occur with surgery.

[0012] Surgical treatment for glaucoma is usually reserved as a second-line therapy in the United States. This is gradually changing as minimally invasive glaucoma surgery (MIGS) becomes more mainstream. However, glaucoma surgery has its own risks. One of the more problematic complications is bacterial endophthalmitis, which is a potential visually devastating eye infection. However, there are many other complications of glaucoma surgery, including failure, hypotonia, bleeding, malignant glaucoma, progression, hyphema, retinal detachment and many other complications. In addition, there are long-term complications of trabeculectomy plus antimetabolites and glaucoma drainage devices.

[0013] While glaucoma has been covered in more detail here, many other eye diseases are also being successfully treated with medications. In addition to being used medically to treat a variety of eye diseases, medications are often used as adjuncts to surgical treatment of eye diseases. Medications are used to treat diseases of the ocular surface, cornea, sclera, uvea, vitreous, and chorioretinal disorders.

[0014] Age-related macular degeneration (AMD) is a common cause of vision loss in the United States and is the third leading cause of blindness worldwide. It is associated with degeneration of the retinal pigment epithelium and Bruch's membrane. This in itself can lead to damage to the overlying retina and vision loss. Unlike the aforementioned "dry" degeneration, further degeneration and the resulting growth of new blood vessels from the underlying choriocapillaris layer can lead to significant vision loss. This latter process is known as "wet" macular degeneration. One of the more common forms of treatment is conventional intravitreal injections of antibodies or drugs that target vascular endothelial-derived growth factor (VEGF). Patients typically need to receive such injections of anti-VEGF drugs (usually antibody-derived therapeutics, including ranibizumab, aflibercept, or bevacizumab) every 4 to 8 weeks to control their wet macular degeneration. This primary treatment presents significant problems in terms of cost, complications, and associated morbidity.

[0015] Other retinal diseases that require medical treatment include macular edema, vascular occlusions, diabetic retinopathy, retinal degeneration, and retinal dystrophies. Uveal diseases can affect the choroid, ciliary body, and iris. Examples include iritis and other forms of uveitis that respond well to various medications, such as steroids. Steroids are typically given as an oral treatment or as a topical therapy. For more severe cases, such as Behçet's disease, more aggressive cytotoxic agents and chemotherapy are used.

[0016] The vitreous can also be a site of eye disease. The vitreous can harbor opacities or hemorrhages that obstruct vision. In other cases, such as vitritis, the vitreous can accumulate inflammatory cells, which can also lead to vision loss.

[0017] The lens in the eye is susceptible to a variety of conditions. The most common are age-related. Clouding of the lens, or cataracts, often requires surgical correction in the form of cataract surgery. While many medications have been used to slow cataract formation, none have proven significantly effective to date. Following cataract surgery, various medications are often used to reduce the likelihood of infection or inflammation.

[0018] The cornea may become opaque, scarred, or deformed due to disease (such as herpes zoster or simple infection, keratitis, keratoconus, various infectious diseases, or other corneal degeneration). Additionally, the transplanted cornea may suffer from immune-mediated rejection or recurrence of the primary eye disease.

[0019] Scleral diseases can be caused by immune processes or infections. Indeed, one of the most common ocular diseases is myopia, or nearsightedness, and the sclera is believed to play a key role in the axial length and refractive status of the eye. Diluted topical atropine, which acts by inducing ciliary muscle paralysis or paralysis of the ciliary body, has been shown to reduce the progression of axial myopia in children. Complex pathways may explain the development of myopia in children. Given the large proportion of the world's population affected, there is considerable interest in this area.

[0020] Dry eye disease (DED) encompasses a wide range of disease states and is defined by TFOSDEWSII (Ocul. Surf., 2017, 15(3), 269-650) as "a multifactorial disease of the ocular surface characterized by a loss of tear film homeostasis and associated ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play an etiological role." DED is generally divided into two categories: aqueous tear-deficient dry eye (ADDE) and evaporative dry eye (EDE), each of which can be further divided into subcategories. One of the main conditions associated with DED (and specifically EDE) is meibomian gland dysfunction (MGD), which itself is an umbrella term covering several disorders in which rupture and obstruction of the 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 (Suppl 11), S20-S26). There are approximately 20 to 40 meibomian glands in each eyelid, and they are responsible for producing meibum, which coats the tears and prevents premature tear evaporation. When the meibomian glands are healthy, unobstructed, and functioning properly, the meibum has a liquid, olive oil-like consistency. Each blink exerts squeezing force on the meibomian glands, and some of the clear, liquid meibum squeezes out of the gland pores and reinforces the outermost lipid layer of the tears. In MGD-based EDE, the development of an imbalance in natural lipids and lipid chemistry results in a higher meibum melting temperature, which ultimately causes the meibum to transform from a healthy, clear, liquid state to a turbid, semi-hardened state and then to a late-stage, pathological, hardened state. Ultimately, as the disease progresses and the lipid chemistry of the meibum deteriorates, the hardened meibum becomes unusable and non-extrudable, leading to a low-quality tear lipid layer and premature tear evaporation. In obstructive MGD, blinking results in little meibum expression, a damaged lipid layer, and accelerated tear evaporation due to the hardened physiochemical state and non-extrudability of the meibum.

[0021] Globally, the prevalence of dry eye disease (DED) is estimated to be between 5% and 20%, and approximately 16,000,000 Americans have been diagnosed. It is estimated that 86% of these DED patients suffer from MGD-associated EDE (Lemp et al., Cornea, 2012, 472-478). Those suffering from DED suffer from insufficient tear production, poor tear quality, or both, which leads to redness, stinging, burning, itching, light sensitivity, tearing, blurred vision, irregularities in the ocular surface, and damage to the corneal or conjunctival epithelium and tissue. It is believed that most dry eye patients have at least a certain degree of both aqueous and lipid deficiencies. Treatment is mainly palliative, and a widespread cure for DED has not yet been developed.

[0022] For these and other eye diseases, drugs can be administered in various ways. Although there are systemic administration routes such as oral or intravenous drug administration, the eye is particularly suitable for topical administration because it is located on the surface of the body. Therefore, in most cases, the topical drug administration route is preferred. This limits the exposure of the rest of the body to the drug and reduces the required amount of drug. Currently, the most common drug administration route for glaucoma is the topical eye drop route. Such topically applied drugs usually diffuse across the cornea and spread into the eye. For retinal diseases, drug injection is a common route.

[0023] Given the above-described difficulties in treating diseases such as, for example, glaucoma, age-related macular degeneration, and dry eye, there is a need for safer, more effective, and convenient treatments that address the shortcomings of current standards of care. Summary of the Invention

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

[0025] Also disclosed herein are methods for treating a condition of the eye of 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 condition of the eye. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 A cross-sectional view showing the anatomy of a normal human eye.

[0027] Figure 2 An exemplary drug eluting implant is shown.

[0028] Figures 3A to 3D An exemplary implant system is shown.

[0029] Figure 3E An alternative drive assembly for inclusion in the implant system is shown.

[0030] Figure 4 A flow chart illustrating a method in an embodiment for loading a dry implant formulation into a cannula of an implant system.

[0031] Figures 5A to 5B An exemplary method is shown in an embodiment of a dry implant formulation into a cannula of an implant system.

[0032] Figure 6A flow chart of a method for implanting a dry implant formulation is shown.

[0033] Figure 7 An exemplary method of implanting a dry implant formulation in an eye to treat an ocular condition is shown. DETAILED DESCRIPTION

[0034] Overview

[0035] Devices, systems and methods for treating disorders of the eye (e.g., glaucoma, dry eye, and other disorders described herein) are described herein. Typically, such devices are intended to be implanted in the eye (e.g., in the ciliary sulcus, posterior chamber, anterior chamber, vitreous body, suprachoroidal space, subretinal space, retrobulbar space, periocular space, intracapsular space, tenon's capsule, subtenon's capsule space, intrascleral space, subconjunctival space, intracapsular space of the lens, Bergey's space) to release one or more drugs to one or more regions affected by the disease or disorder of the eye. For example, a device described herein can be an intraocular implant.

[0036] The devices described herein may generally include intraocular drug eluting implants for treating one or more conditions of the eye. The drug eluting implant may include a drug eluting matrix configured to release one or more drugs into the eye. The implant and / or the drug eluting matrix of the implant may comprise a bioerodible material (e.g., a bioerodible polymer) that degrades over a predetermined period of days, weeks, months, or years, thereby delivering the one or more drugs within a portion or all of the same time period. Additionally or alternatively, the drug eluting implant and / or the drug eluting matrix of the implant may comprise a material that preferentially releases the one or more drugs when in an aqueous environment (such as in tears, body fluids, or serum) compared to a dry environment (e.g., when in the eye or a portion thereof). In some variations, the drug eluting implant may be a sphere (e.g., a microsphere), a spheroid, an ellipsoid, or an ovoid. The drug eluting implant may be roughly spherical. In some variations, the drug eluting implant may be needle-shaped or rod-shaped. In some variations, the drug eluting implant may be a cube. In some variations, the drug eluting implant can be a pellet or granule. In some variations, the drug eluting implant can be irregular in shape. The drug eluting implant can be a submillimeter ("sub-mm") drug eluting implant, the size of which is set so that the maximum linear dimension of the implant (e.g., the diameter if a sphere, the major axis if an ovoid, the spatial diagonal if a cuboid) is less than one millimeter. As used herein, a sub-mm drug eluting implant may be referred to as a "microparticle implant." The drug eluting implant may be a submicron drug eluting implant, the size of which is set so that the maximum linear dimension is less than one micron. As used herein, a submicron drug eluting implant may be referred to as a "nanoparticle implant."

[0037] Also described herein are implant preparations that can include multiple microparticle implants and an implant system configured to deliver implant preparations to the eyes of a subject. In some variations, the implant preparation can be a dry implant preparation without a liquid carrier, and the implant system can be configured to deliver the dry implant preparation without a liquid carrier to the eyes of a subject. In some variations, one or more microparticle implants (alternatively in the form of an implant preparation (e.g., dry implant preparation as described herein)) and one or more (e.g., two, three, four or more) implant devices or systems can be packaged as a kit. In some cases, one or more drug eluting implants or implant preparations (e.g., dry implant preparation as described herein) can be preloaded in a corresponding implant system, and in other variations, one or more implants can be provided separately from the implant system, and one or more implants can be loaded into the implant system (e.g., in the cannula of the implant system) or otherwise positioned in the implant system by a user. In some modifications in these modifications, one or more implants can be provided separately and can be prepared as implant preparations (for example, dry implant preparations), and implant preparations can be loaded into an implant system (for example, in the cannula of an implant system) or otherwise be positioned in the implant system. In some modifications, a plurality of implants or a plurality of implant preparations can be delivered in order. In some modifications, a plurality of implants or a plurality of implant preparations can be delivered simultaneously. For example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 50, 100 or more implants or implant preparations can be delivered in order or simultaneously.

[0038] Methods for treating a condition of the eye may generally include: advancing one or more drug eluting implants (e.g., microspheres) or an implant formulation comprising a plurality of implants (e.g., a dry implant formulation as disclosed herein) to a target location (e.g., an implantation site) in the eye; positioning the one or more drug eluting implants or implant formulations in the one or more target locations in the eye; and delivering one or more drugs from the implants to the target location and / or other locations in the eye to treat the condition of the eye and / or alleviate one or more symptoms associated with the condition of the eye. For example, in some variations, the target location may be the subconjunctival space, and the methods may generally 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) in the subconjunctival space; and delivering one or more drugs from the implants to the subconjunctival space to treat the condition of the eye and / or alleviate one or more symptoms of the condition of the eye. In some variations, the target location may be the anterior chamber, and the methods may generally comprise: advancing a drug eluting implant or 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 a condition of the eye and / or alleviate one or more symptoms of a condition of the eye. In some variations, the target location may be the vitreous, and the methods may generally comprise: advancing and positioning a drug eluting implant or implant formulation (e.g., a dry implant formulation as disclosed herein) into the vitreous to treat a condition of the eye and / or alleviate one or more symptoms of a condition of the eye. In some variations, the target location can be the suprachoroidal space, and the methods 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 abexterno approach or an ab interno approach through the anterior chamber angle, to treat a condition of the eye and / or alleviate one or more symptoms of a condition of the eye. Additionally or alternatively, an implant system may be used to advance such an implant or implant formulation (e.g., a dry implant formulation as disclosed herein). Conditions of the eye may include, but are not limited to, ocular surface diseases, corneal diseases, scleral diseases, uveal diseases, vitreous diseases, optic nerve diseases, choroidal diseases, and retinal diseases. Implantation of a drug eluting implant or implant formulation (e.g., a dry implant formulation as disclosed herein) can be performed by a general ophthalmologist in a doctor's office and, therefore, does not require expensive surgery to be performed by a specialist. Additionally or alternatively, implantation of a drug eluting implant or implant formulation (eg, a dry implant formulation as disclosed herein) can be performed in an operating room as a stand-alone procedure or in combination with other procedures (eg, cataract surgery).

[0039] Implants or implant formulations (e.g., dry implant formulations as disclosed herein) that reside in the posterior chamber (e.g., within the ciliary sulcus, within the ciliary sulcus, and partially extend into the rest of the posterior chamber) can utilize naturally occurring flows (e.g., forward-flowing flow, backward-flowing flow) that can deliver one or more drugs to different parts of the eye. For example, it has been shown that aqueous humor produced at the ciliary body and released into the ciliary sulcus and / or posterior chamber can travel forward into the anterior chamber, where it travels via convection. Additionally, the backward-flowing aqueous fluid can reach the retina and, thus, deliver drugs to the retina and choroid (e.g., anti-vascular endothelial growth factor antibodies for exudative macular degeneration).

[0040] Therefore, the devices, systems and methods described herein can provide effective treatment for many conditions of the eye while avoiding the cost and consequences of utilizing a regular operating room, reducing the total amount of medication required, reducing or eliminating systemic drug exposure by spatially targeted implantation, reducing or eliminating the need for frequent injections or daily eye drops, and increasing patient compliance with 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 less drug to the target tissue without compromising efficacy, and therefore can reduce drug and preservative side effects. For example, although timolol is potentially effective in treating elevated intraocular pressure, systemically available timolol is known in the art to cause cardiac and pulmonary complications. When using timolol eye drops to treat elevated intraocular pressure, this safety issue imposes restrictions on the dosage and frequency of administration. When compared to eye drops, dry delivery of a timolol eluting implant in the eye (e.g., in the subconjunctival space or subtenon space) would make it possible to deliver timolol at higher concentrations in the eye and at lower concentrations systemically (e.g., in the serum). For example, dorzolamide hydrochloride eye drops often cause pain and discomfort due to the low pH typically required to dissolve dorzolamide into solution. Dry delivery of dorzolamide hydrochloride, dorzolamide base, or brinzolamide eluting implants would eliminate the pH or solubility issues experienced with topical administration and reduce the pain and / or discomfort associated with dorzolamide or brinzolamide eye drops.

[0041] Anatomy

[0042] For context, Figure 1A partial cross-sectional view of the anatomy of a normal human eye is shown. The eye can be conceptualized as a fluid-filled sphere. Anteriorly, the eye is bounded by the cornea (100), a three-layered clear tissue that allows light to enter and acts like a protective window to the eye. The periphery of the cornea (100) is called the limbus ("limbus") (102), which defines the junction with the sclera (104). The limbus (102) contains the stem cells of the ocular surface, contains numerous aqueous outflow pathways, and is highly vascularized.

[0043] The sclera (104) is the opaque, tough, protective outer layer of the eye. Like the cornea, the sclera is essentially avascular. Overlying the sclera (104) is the conjunctiva (106), a thin, clear tissue that overlies the sclera (104) and the inside of the eyelids. The conjunctiva helps lubricate the surface of the eye by contributing to the production of mucus and tears. In addition, the conjunctiva is vascularized and helps contribute to the immune response of the eye. 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 protective layer for the eyeball. The sub-Tenon's capsule space (125) (which may also be called the episcleral space) is the space between the Tenon's capsule and the sclera. The sub-Tenon's capsule space contains loose connective tissue, blood vessels, and fat and allows smooth movement of the eyeball by providing a cushioning effect.

[0044] Behind the cornea is the iris (108), or the colored part of the eye. The iris is a ring-shaped structure that adjusts its opening (the pupil) to regulate the amount of light entering the eye. Bright light causes the pupil to constrict, limiting exposure to excess light or the resulting glare. In dim lighting, the pupil opens to capture more of the available light.

[0045] The anterior chamber angle (110) filled with aqueous humor resides between the iris and the cornea. At the periphery of the anterior chamber, there is an anterior chamber angle (110) where the aqueous fluid flows out of the eye through the trabecular meshwork and Schlemm's canal. The annular band of the ciliary body is seen during gonioscopy. This area provides an intra-anterior chamber pathway to the suprachoroidal space.

[0046] Behind the iris (108) is the lens (112). Normally, the lens is transparent and focuses light on the retina to create a clear image. With age or disease, the lens (112) may become cloudy, and this is called a cataract. The lens (112) is suspended in the eye by fibers called the zonular ligaments. One end of the zonular ligament is attached around the equator of the lens (112). The other end of the zonular ligament is attached to the ciliary body (114). Contraction and relaxation of the ciliary body changes the load on the zonular ligament, resulting in increased curvature of the lens (112) or flattening of the lens. This is the main mechanism our eyes use to focus.

[0047] The ciliary body (114) not only contains muscles that apply load to the suspensory ligament, but it is also responsible for secreting aqueous humor, which travels through the ciliary sulcus (116), which is the peripheral part of the posterior chamber. Implants or devices residing in the ciliary sulcus or the peripheral posterior chamber avoid the visual axis and therefore do not interfere with vision. The aqueous humor flows into the ciliary sulcus and the posterior chamber, then into the pupil, and finally into the anterior chamber (110). Studies have also shown that the aqueous humor flow can also drive fluids and substances through the vitreous body and through the retina. In other words, the flow is bidirectional. The posterior chamber is the gap in the eye behind the iris and in front of the lens. At the periphery of the posterior chamber, the posterior chamber is defined by the ciliary sulcus (116). The ciliary sulcus (116) is the gap between the front of the ciliary body (114) and the back surface of the iris. This part of the posterior chamber is typically 12 mm in diameter.

[0048] The vitreous humor (118) is a gel-like substance that fills the central cavity of the eye. Its volume is approximately 4 mL (milliliters) to 4.5 mL. It is bounded by the retina at the periphery and rear. In the front, it is bounded by the Bergey's space, which separates the vitreous cavity from the lens in the center, and the Poter's canal (also known as the zonular space), which separates the vitreous cavity from the lens at the periphery. The retina is the light-sensitive nerve layer lining the back of the eye. In humans, the retina has ten layers, of which the outermost layer or the layer closest to the sclera (104) is the retinal pigment epithelium. This layer is associated with macular degeneration.

[0049] Between the sclera and the retina is the portion of the uveal tract known as the choroid (120). The choroid is a high-flow, low-resistance layer of blood vessels that nourishes and oxygenates the outer two-thirds of the retina. The choroid has also been implicated in macular degeneration. The macula is the area of ​​the retina responsible for high-contrast, sharp vision. The macula is the functional center of the retina and gives humans their central vision. For example, the ability to read clearly or recognize faces depends on the macula. Macular degeneration affects this area and, therefore, can have a devastating effect on vision. The optic nerve is a collection of approximately 1 million retinal axons that carry visual information from the eye to the vision center in the brain.

[0050] Drug-eluting implants

[0051] Generally speaking, the devices, systems and formulations described herein include drug eluting implants for treating one or more conditions of the eye by delivering one or more drugs to the eye. Implants may include round shapes (e.g., spheres, roughly spheres, spheroids, ovoids, ellipsoids) and / or irregular shapes and may be configured to be implanted in one or more structures and / or cavities of the eye. For example, a drug eluting implant may be configured to reside partially or entirely in one or more of the subconjunctival space, anterior chamber, ciliary sulcus, posterior chamber, suprachoroidal space, subretinal space, or vitreous body of one or both eyes. In some variations, as will be discussed in more detail herein, the implant may be a microparticle implant, such as a microsphere.

[0052] In some variations, as will be discussed in more detail herein, an implant can 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) that serves as a medium for administering a pharmaceutical compound or pharmaceutical device. For example, an implant can be delivered without a carrier (i.e., dry), or it can be delivered with a carrier (e.g., one or more implants suspended in a fluid). It will be understood that, in accordance with the present disclosure, delivery of an implant with a non-fluid additive or composition, such as a binder (e.g., sucrose, gelatin, or cellulose), will be considered dry delivery.

[0053] The implant may comprise one or more drugs and may be configured to release or elute one or more drugs over time (e.g., over a predetermined time period). In some variations, the implant may be configured or formulated to preferentially release one or more drugs in an aqueous environment (e.g., in tears, body fluids, interstitial fluid, or serum) compared to a dry environment (e.g., when in the eye or a portion thereof). In variations in which the drug eluting implant is a microparticle implant (e.g., microspheres), the microparticle implant may comprise one or more drugs, such as in a coating layer on the outer surface and / or in a drug eluting matrix forming the microparticle implant. In any case, the implant may be drug eluting or otherwise configured to deliver, administer, or provide one or more drugs to the eye.

[0054] Figure 2 Depicted are exemplary drug eluting implants described herein, wherein a plurality of drug eluting implants (202) reside within the wall of the sclera, wherein a plurality of drug eluting implants (204) reside within the subconjunctival space, wherein a plurality of drug eluting implants (206) reside within the ciliary sulcus, and wherein a plurality of drug eluting implants (208) reside within the subtenon space.

[0055] like Figure 2 As shown, the drug eluting implant may include a rounded shape and may be, for example, a microsphere, a microsphere, a microovoid, a microellipsoid, etc. Therefore, in some variations, the circular drug eluting implant described herein may have a variety of cross-sectional shapes, including, for example, annular, oval, elliptical, etc. In some variations, the drug eluting implant may be any other shape as discussed above, such as a needle-shaped, rod-shaped, cubic, or irregular shape. Typically, 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 outer surface of the implant may be coated with a 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 a drug eluting matrix. In some variations, the drug eluting implant may include a drug eluting matrix and one or more additional substances that control the elution rate, control the degradation rate, or provide biocompatibility. 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, a uniformly dispersed mixture) of one or more drugs and one or more bioerodible polymers.

[0056] In some variations, the microparticle implants described herein may be characterized by a maximum linear dimension (diameter if spherical, major axis if ovoid). The maximum linear dimension may be between about 0.1 μm and about 500 μm.In some variations, the implants may independently have a diameter between about 0.1 μm and about 40 μm, between about 0.1 μm and about 30 μm, between about 0.1 μm and about 20 μm, between about 0.1 μm and about 10 μm, between about 0.1 μm and about 1 μm, between about 0.1 μm and about 400 μm, between about 0.1 μm and about 300 μm, between about 0.1 μm and about 200 μm, between about 0.1 μm and about 100 μm, between about 0.1 μm and about 10 μm, between about 0.5 μm and about 40 μm, between about 0.5 μm and about 30 μm, between about 0.5 μm and about 20 μm, between about 0.5 μm and about 10 μm, between about 1 μm and about 400 μm, between about between 1 μm and about 300 μm, between about 1 μm and about 200 μm, between about 1 μm and about 100 μm, between about 1 μm and about 10 μm, between about 1 μm and about 5 μm, between about 5 μm and about 100 μm, between about 10 μm and about 100 μm, between about 10 μm and about 90 μm, between about 10 μm and about 80 μm, between about 10 μm and about 70 μm, between about 10 μm and about 60 μm, between about 10 μm and about 50 μm, between about 10 μm and about 40 μm, between about 10 μm and about 30 μm, between about 10 μm and about 20 μm, between about 20 μm and about 100 μm, between about 20 μm and about 90 μm, and about 20 μm and about 80 μm. between about 20 μm and about 70 μm, between about 20 μm and about 60 μm, between about 20 μm and about 50 μm, between about 20 μm and about 40 μm, between about 20 μm and about 30 μm, between about 40 μm and about 100 μm, between about 30 μm and about 90 μm, between about 30 μm and about 80 μm, between about 30 μm and about 70 μm, between about 30 μm and about 60 μm, between about 30 μm and about 50 μm, between about 30 μm and about 40 μm, between about 40 μm and about 100 μm, between about 40 μm and about 90 μm, between about 40 μm and about 80 μm, between about 40 μm and about 70 μm, between about 40 μm and about 60 μm, and about 40 μm. or a maximum linear dimension of between about 90 μm and about 100 μm, between about 50 μm and about 90 μm, between about 50 μm and about 80 μm, between about 50 μm and about 70 μm, between about 50 μm and about 60 μm, between about 60 μm and about 100 μm, between about 60 μm and about 90 μm, between about 60 μm and about 80 μm, between about 60 μm and about 70 μm, between about 70 μm and about 100 μm, between about 70 μm and about 90 μm, between about 70 μm and about 80 μm, between about 80 μm and about 100 μm, between about 80 μm and about 90 μm; or between about 90 μm and about 100 μm, including all subranges and values ​​therein.In some variations, the implant may have a maximum linear dimension of approximately 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.

[0057] In some variations, a mixture of implants described herein (e.g., implants of different sizes, implants of different shapes, implants with different drugs) can be delivered. In some cases, it can be beneficial to administer a mixture of implants described herein, wherein the mixture comprises implants of similar size (e.g., a majority of the implants have a maximum linear dimension within 5%, 10%, 15%, or 20% of the average maximum linear dimension of the implants in the mixture, which maximum linear dimension can be a diameter in the case of microsphere implants). Without being bound by theory, for example, using similarly sized implants in dry implant formulations can help prevent lattice formation between individual implants, and this prevention of lattice formation can reduce or prevent clogging of an implant system loaded with multiple implants or dry implant formulations.

[0058] When two or more implants are delivered (eg, as an implant formulation), they may collectively have an average maximum linear dimension. For example, in some variations, two or more implants may have an average maximum linear dimension between about 0.1 μm and about 500 μm.In some variations, the implants may collectively have a diameter between about 0.1 μm and about 40 μm, between about 0.1 μm and about 30 μm, between about 0.1 μm and about 20 μm, between about 0.1 μm and about 10 μm, between about 0.1 μm and about 1 μm, between about 0.1 μm and about 400 μm, between about 0.1 μm and about 300 μm, between about 0.1 μm and about 200 μm, between about 0.1 μm and about 100 μm, between about 0.1 μm and about 10 μm, between about 0.5 μm and about 40 μm, between about 0.5 μm and about 30 μm, between about 0.5 μm and about 20 μm, between about 0.5 μm and about 10 μm, between about 1 μm and about 400 μm, or between about 1 μm. between about 1 μm and about 300 μm, between about 1 μm and about 200 μm, between about 1 μm and about 100 μm, between about 1 μm and about 10 μm, between about 1 μm and about 5 μm, between about 5 μm and about 100 μm, between about 10 μm and about 100 μm, between about 10 μm and about 90 μm, between about 10 μm and about 80 μm, between about 10 μm and about 70 μm, between about 10 μm and about 60 μm, between about 10 μm and about 50 μm, between about 10 μm and about 40 μm, between about 10 μm and about 30 μm, between about 10 μm and about 20 μm, between about 20 μm and about 100 μm, between about 20 μm and about 90 μm, between about 20 μm and about 80 μm , between about 20 μm and about 70 μm, between about 20 μm and about 60 μm, between about 20 μm and about 50 μm, between about 20 μm and about 40 μm, between about 20 μm and about 30 μm, between about 40 μm and about 100 μm, between about 30 μm and about 90 μm, between about 30 μm and about 80 μm, between about 30 μm and about 70 μm, between about 30 μm and about 60 μm, between about 30 μm and about 50 μm, between about 30 μm and about 40 μm, between about 40 μm and about 100 μm, between about 40 μm and about 90 μm, between about 40 μm and about 80 μm, between about 40 μm and about 70 μm, between about 40 μm and about 60 μm, an average maximum linear dimension of between about 50 μm, between about 50 μm and about 100 μm, between about 50 μm and about 90 μm, between about 50 μm and about 80 μm, between about 50 μm and about 70 μm, between about 50 μm and about 60 μm, between about 60 μm and about 100 μm, between about 60 μm and about 90 μm, between about 60 μm and about 80 μm, between about 60 μm and about 70 μm, between about 70 μm and about 100 μm, between about 70 μm and about 90 μm, between about 70 μm and about 80 μm, between about 80 μm and about 100 μm, between about 80 μm and about 90 μm; or between about 90 μm and about 100 μm, including all subranges and values ​​therein.In some variations, the implants may collectively have an average maximum linear dimension of approximately 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.

[0059] The implants described herein (e.g., microparticles, such as microspheres) may include a drug eluting matrix. As used herein, a "drug eluting matrix" refers to a material impregnated with a drug, wherein when positioned in the eye, the drug is released from the material. In some variations, the drug can be slowly released from the material over a set time period. The drug eluting matrix may, for example, comprise a polymer impregnated with a drug, wherein when implanted in the eye, the drug is released from the polymer. In certain embodiments, the drug eluting matrix may be erodible so that it safely dissolves or breaks into non-toxic or biocompatible components within a predetermined time period within the subject. In some embodiments, the entire microsphere is composed of the drug eluting matrix. The drug eluting matrix described herein may form a coating on the structure of the drug eluting implant described herein or form a filler within the structure. For example, in some embodiments, the microsphere may include a hollow internal chamber that accommodates the drug eluting matrix, and the microsphere may also include a window (e.g., opening) that passes through the wall of the microsphere to deliver the drug from the drug eluting matrix in the internal 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.

[0060] Implants described herein (e.g., microparticles, such as microspheres) 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-ε-caprolactone (PCL), high-density polyethylene (HDPE), poly(styrene-block-isobutylene-block-styrene) (SIBS), polyurethane, polycarbonate, polypropylene, polymethyl methacrylate (PMMA), polybutyl methacrylate, polyester, polytetrafluoroethylene (PTFE), silicone, acrylic polymers, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl chloride, ethyl vinyl acetate, collagen, collagen derivatives, flexible fused silica, polyolefins, Polymers, polyimides, polyacrylamides, fluorinated elastomers and their copolymers and blends. In some variations, the biocompatible polymer can be a thermosensitive polymer, such as poly (N-isopropylacrylamide) (PNIPAM). The implant (e.g., microsphere) can be completely or partially bioerodible (e.g., biodegradable) and can, for example, comprise 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., entire microsphere) can be completely bioerodible (e.g., biodegradable). The rate of elution of the drug from the erodible implants (e.g., microspheres) described herein can be controlled by selecting an appropriate erodible material (e.g., polymer) with predictable release characteristics (e.g., release rate). In some embodiments, the implant (e.g., microsphere) can include an erodible drug eluting matrix with a variable erosion rate. For example, in some variations, a first portion of an implant may have a first erosion rate (e.g., the rate at which a drug eluting matrix is ​​degraded or absorbed), and a second portion of the implant may have a second, different erosion rate. Thus, the elution of a drug from an implant described herein (e.g., a microsphere) 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, an implant may include one or more layers, each layer including an erodible drug eluting matrix. These layers may have the same erosion rate, or one or more layers may have different erosion rates. In some variations, an implant may contain a drug or an erodible drug eluting matrix. In some embodiments, an implant may include an erodible material (e.g., a polymer), the erosion rate of which can be tuned by selecting an appropriate material (e.g., a polymer). In some variations, an implant may have a first erosion rate (e.g., the rate at which an outer portion of the implant is degraded or absorbed), and the contained drug eluting matrix 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 higher than the first erosion rate. Therefore, the drug eluting matrix can elute faster than the outer portion erodes.

[0061] Dry implant preparations

[0062] As described herein, a plurality of implants can be formulated for being implanted in, for example, an eye as a dry implant formulation without a liquid carrier. In some variations, the dry implant formulation can be formulated as a semisolid mass that is stretchable but not easily dissociated into a separate implant, and can be delivered together as a unit. For a variety of reasons, utilizing a dry implant formulation as a semisolid mass can be advantageous. By way of example, the dry implant formulation formulated as a semisolid mass can promote the use of an implant system (for example, the cannula of an implant system) to load and / or deliver the dry implant formulation. In some variations, the formulation can be fully stretchable so as not to be blocked in the lumen of an implant system (for example, the cannula). Additionally or alternatively, utilizing this dry implant formulation can also prevent accidental or premature ejection from an implant system (for example, the cannula of an implant system) due to, for example, gravity or during the intubation advancing through tissue towards the target position.

[0063] The dry implant formulation can be, for example, imparted with semisolid properties by the presence of adhesion (inter-implant adhesion) between the individual implants without the use of a liquid carrier. In some variations, most of the implants (e.g., approximately 51%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%) in the implant of the dry implant formulation can adhere to at least one other implant. The basis of inter-implant adhesion can be electrostatic adhesion, adhesion by molecular intermediates and / or adhesion by the ductility of an individual implant and the surface of an implant against the partial deformation of one or more other implants.

[0064] In some variations, a dry implant formulation may include a plurality of drug eluting implants and one or more binders that serve as a cohesive molecular intermediate between the individual implants. In some variations, the binder may be selected from a sugar, gelatin, collagen, polyethylene glycol (PEG), starch, cellulose, alginate, chitosan, or a combination thereof.

[0065] In some modifications, at least most of the implants in the implant can be heated to the corresponding glass transition temperature higher than one or more polymers included in the independent implant, and alternatively it is compressed (in the heating period or after heating soon, at the temperature of most of the implants in the implant is reduced to before being lower than the corresponding glass transition temperature).The glass transition temperature is that amorphous polymer changes into soft / leather state or conversely the temperature from hard / glass state. When not bound by theory, be heated to higher than glass transition temperature, alternatively be combined in the heating period or after heating soon, at least most of the implants in the implant when higher than glass transition temperature (this can be approximately 1 minute, approximately 2 minutes, approximately 5 minutes or approximately 10 minutes) and compress, the surface of the independent implant can be induced to be partially deformed against adjacent implant. In some modifications, between the implants, adhesion can be weakened in an aqueous environment (for example, in eyes) so that independent implant can be more easily dispersed after implanting.

[0066] A dose of an implant formulation (e.g., a dry implant formulation as disclosed herein) for a single implant into the eye may be referred to herein as an "implant dose" or "implant unit" of the dry implant formulation. An implant unit of an implant formulation (e.g., a dry implant formulation as disclosed herein) may include between about 1 and about 100, between about 100 and about 1,000, between about 1,000 and about 10,000, or more implants. In some embodiments, an implant formulation (e.g., a dry implant formulation as disclosed herein) of implant units may include between about 100 and about 200, between about 100 and about 300, between about 100 and about 400, between about 100 and about 500, between about 100 and about 600, between about 100 and about 700, between about 100 and about 800, between about 100 and about 900, between about 100 and about 10 ... between about 200 and about 300, between about 200 and about 400, between about 200 and about 500, between about 200 and about 600, between about 200 and about 700, between about 200 and about 800, between about 200 and about 900, between about 200 and about 1000, between about 300 and about 400, between about 300 and about 500, between about 300 and about 600, between about 300 and about 700, between about 300 and about 800, between about 200 and about 900, between about 200 and about 1000, between about 300 and about 400, between about 300 and about 500, between about 300 and about 600, between about 300 and about 700, between about 300 between about 400 and about 800, between about 400 and about 900, between about 400 and about 1000, between about 500 and about 600, between about 400 and about 700; between about 400 and about 800, between about 400 and about 900, between about 400 and about 1000, between about 500 and about 600, between about 500 and about 700, between about 500 and about 800, between about 500 and about 1000, between about 500 and about 600, between about 500 and about 700, between about 500 and about 800, between about 500 and about 900, between about 500 and about 1000, between about 600 and about 700, between about 600 and about 800, between about 600 and about 900, between about 600 and about 1000, between about 700 and about 800, between about 700 and about 900, between about 700 and about 1000, between about 800 and about 900, between about 800 and about 1000, and between about 900 and about 1000 implants.In some embodiments, an implant formulation (e.g., a dry implant formulation as disclosed herein) of an implant unit may include between about 1000 and about 2000, between about 1000 and about 3000, between about 1000 and about 4000, between about 1000 and about 5000, between about 1000 and about 6000, between about 1000 and about 7000, between about 1000 and about 8000, between about 1000 and about 9000, between about 1000 and about 10000, about 2000 and about 3,000, between about 2,000 and about 4,000, between about 2,000 and about 5,000, between about 2,000 and about 6,000, between about 2,000 and about 7,000, between about 2,000 and about 8,000, between about 2,000 and about 9,000, between about 2,000 and about 10,000, between about 3,000 and about 4,000, between about 3,000 and about 5,000, between about 3,000 and about 6,000, between about 3,000 and about 7,000, between about 3,000 and about 10,000. between about 8,000, between about 3,000 and about 9,000, between about 3,000 and about 10,000, between about 4,000 and about 5,000, between about 4,000 and about 6,000, between about 4,000 and about 7,000; between about 4,000 and about 8,000, between about 4,000 and about 9,000, between about 4,000 and about 10,000, between about 5,000 and about 6,000, between about 5,000 and about 7,000, between about 5,000 and about 8,000, Between about 9,000, between about 5,000 and about 10,000, between about 6,000 and about 7,000, between about 6,000 and about 8,000, between about 6,000 and about 9,000, between about 6,000 and about 10,000, between about 7,000 and about 8,000, between about 7,000 and about 9,000, between about 7,000 and about 10,000, between about 8,000 and about 9,000, between about 8,000 and about 10,000, and between about 9,000 and about 10,000 implants.

[0067] The volume of an implant formulation (eg, a dry implant formulation as disclosed herein) of an implant unit will depend on the number and size of implants included therein, as well as the amount of binder (if any) in the formulation. Taking the above factors into account, the volume of the implant unit can be, for example, between about 1 μl (microliter) and about 500 μl, between about 1 μl and about 50 μl, between about 1 μl and about 100 μl, between about 1 μl and about 200 μl, between about 1 μl and about 300 μl, between about 1 μl and about 400 μl, between about 1 μl and about 40 μl, between about 2 μl and about 50 μl, between about 2 μl and about 100 μl, between about 2 μl and about 200 μl, between about 2 μl and about 300 μl, between about 2 μl and about 400 μl, between about 2 μl and about 500 μl, between about 4 μl and about 50 μl, between about 4 μl and about 100 μl, or between about 4 μl and about 100 μl. between about 4 μl and about 200 μl, between about 4 μl and about 300 μl, between about 4 μl and about 400 μl, between about 4 μl and about 500 μl, between about 10 μl and about 50 μl, between about 10 μl and about 100 μl, between about 10 μl and about 200 μl, between about 10 μl and about 300 μl, between about 10 μl and about 400 μl, between about 10 μl and about 500 μl, between about 50 μl and about 100 μl, between about 50 μl and about 200 μl, between about 50 μl and about 300 μl, between about 50 μl and about 400 μl, between about 50 μl and about 500 μl. In some 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 some variations, an implant formulation (e.g., a dry implant formulation as disclosed herein) may include two or more subsets of implants. In these variations, a first subset of implants may contain a first drug, and a second subset of implants may contain a second, different drug. The first and second subsets of implants may be mixed uniformly or unevenly throughout the implant formulation such that the combined implant formulation is capable of eluting both drugs. For example, a first subset of implants may contain timolol (e.g., timolol maleate or timolol hemihydrate), and a second subset of implants may contain dorzolamide (e.g., dorzolamide hydrochloride or dorzolamide base) or brinzolamide. In another example, a first subset of implants may contain timolol (e.g., timolol maleate or timolol hemihydrate) and a second subset of implants may contain a prostamide analog (e.g., bimatoprost) or a prostaglandin analog (e.g., latanoprost).In another example, a first subset of implants may contain timolol (e.g., timolol maleate or timolol hemihydrate), and a second subset of implants may contain a rho-kinase inhibitor (e.g., ripasudil or netarsudil). In another example, a first subset of implants may contain a prostamide analog (e.g., bimatoprost) or a prostaglandin analog (e.g., latanoprost), and a second subset of implants may contain a rho-kinase inhibitor (e.g., ripasudil or netarsudil). Additionally or alternatively, in some variations, each individual implant may contain 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 as disclosed herein) may include a first subset of implants containing a first drug and one or more subsets (e.g., two, three, four, five, six, or more subsets) of implants containing one or more drugs. For example, an implant formulation (e.g., a dry implant formulation as disclosed herein) may include a first subset of implants containing a first drug, and a second subset of implants, wherein each implant in the second subset contains a second drug and a third drug. In some variations, the first drug may be the same as one of the second and third drugs, while in other variations, each of the first, second, and third drugs may be a different drug. In this way, precise amounts of one or more drugs (e.g., two, three, four, five, six, or more) can be delivered together to the implanted site. Drugs.

[0068] The drug eluting implants described herein contain one or more drugs (e.g., two, three, four, five or more) that can be used to treat a condition of the eye. In some embodiments, the condition of the eye can be glaucoma, dry eye, AMD, a retinal disease (e.g., a retinal vascular disease), a neurological disease, a corneal disease, a lens disease, a uveal disease, a vitreous disease, a surface disease, an eyelid disease, or an eye infection. In some embodiments, the one or more drugs can include drugs suitable for treating glaucoma and diseases of the retina, lens, cornea, uveal tract, vitreous body, iris, ciliary body, sclera, or ocular surface. Such drugs include, but are not limited to:

[0069] Corticosteroids, such as prednisolone, prednisone, cortisone, cortisol, or trimethoprim-sulfamethoxazole

[0070] Anxilong;

[0071] Anti-VEGF agents, such as ranibizumab, aflibercept, bevacizumab, or bucizumab

[0072] β-Azolomide;

[0073] growth factors, such as nerve growth factor or insulin-like growth factor;

[0074] prostaglandins or prostaglandin analogs, such as latanoprost, travoprost, tafluprost, or unoprostone;

[0075] prostamides or prostamide analogs, such as bimatoprost;

[0076] nitric oxide-releasing drugs and nitric oxide donors;

[0077] alpha-1 adrenergic agonists, such as epinephrine and dipivefrin;

[0078] Alpha-2 adrenergic agonists, such as epinephrine, dipivefrin, and brimonide

[0079] Apraclonidine or Apraclonidine;

[0080] Beta-adrenergic blocking drugs ("beta blockers"), such as levobunolol, timolol

[0081] lol, betaxolol, carteolol, or metipranolol;

[0082] miotics, such as pilocarpine;

[0083] Carbonic anhydrase inhibitors, such as acetazolamide, methazolamide, dorzolamide, and bolifenesin

[0084] zolamide, desclofenamide, esoxazolidone, or zonisamide;

[0085] Rho kinase (ROCK) inhibitors, such as rosudil or nesudil;

[0086] parasympathomimetic drugs;

[0087] sympathomimetics, such as muscarinic antagonists (e.g., atropine);

[0088] antimetabolites, such as fluorouracil and mitomycin C;

[0089] antibiotic;

[0090] Nonsteroidal anti-inflammatory drugs, such as NSAIDs;

[0091] antifungal agents;

[0092] immunosuppressants, such as cyclosporine, sirolimus, everolimus, or tacrolimus;

[0093] Vitreous hemorrhage medication;

[0094] collagenase;

[0095] Vitreous floater treatments;

[0096] pupil dilators;

[0097] pupillary constrictors;

[0098] anticoagulants (e.g., heparin);

[0099] fibrinolytic compounds;

[0100] monoclonal antibodies or other biologics;

[0101] and their combinations.

[0102] 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 drug is used to reduce intraocular pressure. In certain variations, the drug can inhibit the production of aqueous humor. In some variations, the drug can increase the drainage of aqueous humor through the trabecular canalicular pathway and / or the uveoscleral pathway.

[0103] The amount of drug within 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 as 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 as disclosed herein) can contain between about 1 μg and about 500 μg of drug or between about 30 ng and about 90 mg of drug. In some variations, an implant or implant unit of an implant formulation (e.g., a dry implant formulation as disclosed herein) may have a dosage of between about 1 μg and about 400 μg, between about 1 μg and about 300 μg, between about 1 μg and about 200 μg, between about 1 μg and about 100 μg, between about 1 μg and about 10 μg, between about 1 μg and about 5 μg, between about 5 μg and about 10 μg, between about 5 μg and about 100 μg, between about 10 μg and about 100 μg, between about 10 μg and about 90 μg, between about 10 μg and about 80 μg, between about 10 μg and about 70 μg, or between about 10 μg and about 70 μg. between about 0 μg, between about 10 μg and about 60 μg, between about 10 μg and about 50 μg, between about 10 μg and about 40 μg, between about 10 μg and about 30 μg, between about 10 μg and about 20 μg, between about 20 μg and about 100 μg, between about 20 μg and about 90 μg, between about 20 μg and about 80 μg, between about 20 μg and about 70 μg, between about 20 μg and about 60 μg, between about 20 μg and about 50 μg, between about 20 μg and about 40 μg, between about 20 μg and about 30 μg, between about 40 μg and about 100 μg between about 30 μg and about 90 μg, between about 30 μg and about 80 μg, between about 30 μg and about 70 μg, between about 30 μg and about 60 μg, between about 30 μg and about 50 μg, between about 30 μg and about 40 μg, between about 40 μg and about 100 μg, between about 40 μg and about 90 μg, between about 40 μg and about 80 μg, between about 40 μg and about 70 μg, between about 40 μg and about 60 μg, between about 40 μg and about 50 μg, between about 50 μg and about 100 μg, between about 50 μg and about 90 μg, between about 5 or about 90 μg to about 100 μg, including all subranges and values ​​therein.In some embodiments, the implant (e.g., microsphere) or implant unit of the implant formulation (e.g., a dry implant formulation as disclosed herein) may have about 1 μg, 2 μg, 3 μg, 4 μg, 5 μg, 6 μg, 7 μg, 8 μg, 9 μg, 10 μg, 15 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 150 μg, 200 μg, 250 μg, 300 μg, 350 μg, 400 μg, 450 μg, or 500 μg of the drug.In some variations, an implant or implant unit of an implant formulation (e.g., a dry implant formulation as disclosed herein) may have a dosage of between about 30 ng and about 90 mg, between about 30 ng and about 80 mg, between about 30 ng and about 70 mg, between about 30 ng and about 60 mg, between about 30 ng and about 50 mg, between about 30 ng and about 40 mg, between about 30 ng and about 30 mg, between about 30 ng and about 20 mg, between about 30 ng and about 10 mg, between about 30 ng and about 5 mg, between about 30 ng and about 1 mg, between about 30 ng and about 500 μg, between about 30 ng and about 10 mg, or between about 30 ng and about 500 μg. 0 μg, between about 30 ng and about 900 ng, between about 30 ng and about 800 ng, between about 30 ng and about 700 ng, between about 30 ng and about 600 ng, between about 30 ng and about 500 ng, between about 30 ng and about 400 ng, between about 30 ng and about 300 ng, between about 30 ng and about 200 ng, between about 30 ng and about 100 ng, between about 30 ng and about 50 ng, between about 100 ng and about 90 mg, between about 100 ng and about 80 mg, between about 100 ng and about 70 mg, between about 100 ng and about 60 μg, about 100 between about 100 ng and about 50 μg, between about 100 ng and about 40 μg, between about 100 ng and about 30 mg, between about 100 ng and about 20 mg, between about 100 ng and about 10 mg, between about 100 ng and about 5 mg, between about 100 ng and about 1 mg, between about 100 ng and about 500 μg, between about 100 ng and about 100 μg, between about 200 ng and about 90 mg, between about 200 ng and about 80 mg, between about 200 ng and about 70 mg, between about 200 ng and about 60 mg, between about 200 ng and about 50 mg, between about 200 ng and about 40 mg The present invention relates to a drug having an amount of at least one pharmaceutical composition comprising: about 200 ng and about 30 mg, about 200 ng and about 20 mg, about 200 ng and about 10 mg, about 200 ng and about 5 mg, about 200 ng and about 1 mg, about 200 ng and about 500 μg, about 200 ng and about 100 μg, about 200 ng and about 900 ng, about 200 ng and about 800 ng, about 200 ng and about 700 ng, about 200 ng and about 600 ng, about 200 ng and about 500 ng, about 200 ng and about 400 ng, including all subranges and values ​​therein.

[0104] In some variations, an implant or multiple implants (e.g., an implant unit of an implant formulation (e.g., a dry implant formulation as disclosed herein)) may have a dosage of between about 1 μg and about 90 mg, between about 1 μg and about 70 mg, between about 1 μg and about 50 mg, between about 1 μg and about 40 mg, between about 1 μg and about 30 mg, between about 1 μg and about 20 mg, between about 1 μg and about 15 mg, between about 1 μg and about 10 mg, between about 1 μg and about 5 mg, between about 1 μg and about 1 mg, between about 5 μg and about 90 mg, between about 5 μg and about 70 mg, between about 5 μg and about 50 mg, between about 5 μg and about 40 mg, between about 5 μg and about 30 mg, between about 5 μg and about 20 mg, between about 1 μg and about 15 mg, between about 1 μg and about 10 mg, between about 1 μg and about 5 mg, between about 1 μg and about 1 mg, between about 5 μg and about 90 mg, between about 5 μg and about 70 mg, between about 5 μg and about 50 mg, between about 5 μg and about 40 mg, between about 5 μg and about 30 mg, between about 5 μg and about g and about 20 mg, between about 5 μg and about 15 mg, between about 5 μg and about 10 mg, between about 5 μg and about 5 mg, between about 5 μg and about 1 mg, between about 10 μg and about 90 mg, between about 10 μg and about 70 mg, between about 10 μg and about 50 mg, between about 10 μg and about 40 mg, between about 10 μg and about 30 mg, between about 10 μg and about 20 mg, between about 10 μg and about 15 mg, between about 10 μg and about 10 mg, between about 10 μg and about 5 mg, between about 10 μg and about 1 mg, between about 20 μg and about 90 mg, between about 20 μg and about 70 mg, between about 20 μg and about 50 mg, between about 20 μg and about 40 mg g, between about 20 μg and about 30 mg, between about 20 μg and about 20 mg, between about 20 μg and about 15 mg, between about 20 μg and about 10 mg, between about 20 μg and about 5 mg, between about 20 μg and about 1 mg, between about 40 μg and about 90 mg, between about 40 μg and about 70 mg, between about 40 μg and about 50 mg, between about 40 μg and about 40 mg, between about 40 μg and about 30 mg, between about 40 μg and about 20 mg, between about 40 μg and about 15 mg, between about 40 μg and about 10 mg, between about 40 μg and about 5 mg, between about 40 μg and about 1 mg, between about 60 μg and about 90 mg, between about 60 μg and about 70 mg. between about 60 μg and about 50 mg, between about 60 μg and about 40 mg, between about 60 μg and about 30 mg, between about 60 μg and about 20 mg, between about 60 μg and about 15 mg, between about 60 μg and about 10 mg, between about 60 μg and about 5 mg, between about 60 μg and about 1 mg, between about 80 μg and about 90 mg, between about 80 μg and about 70 mg, between about 80 μg and about 50 mg, between about 80 μg and about 40 mg, between about 80 μg and about 30 mg, between about 80 μg and about 20 mg, between about 80 μg and about 15 mg, between about 80 μg and about 10 mg, between about 80 μg and about 5 mg, between about 80 μg and about 1 mg,Between about 100 μg and about 90 mg, between about 100 μg and about 70 mg, between about 100 μg and about 50 mg, between about 100 μg and about 40 mg, between about 100 μg and about 30 mg, between about 100 μg and about 20 mg, between about 100 μg and about 15 mg, between about 100 μg and about 10 mg, between about 100 μg and about 5 mg, or between about 100 μg and about 1 mg, including all subranges and values ​​therein.

[0105] In some embodiments, an implant (e.g., a microsphere) or a plurality of implants (e.g., an implant unit of an implant formulation as described herein (e.g., a dry implant formulation as disclosed herein)) can have about 30 ng, 40 ng, 50 ng, 60 ng, 70 ng, 80 ng, 90 ng, 100 ng, 150 ng, 200 ng, 250 ng, 300 ng, 350 ng, 400 ng, 450 ng, 500 ng, 600 ng, 700 ng, 800 ng, 900 ng, or 1000 ng of drug, or about 1 μg, 2 μg, 3 μg, 4 μg, 5 μg, 6 μg, 7 μg, 8 μg, 9 μg , 10μg, 15μg, 20μg, 30μg, 40μg, 50μg, 60μg, 70μg, 80μg, 90μg, 100μg, 150μg, 200μg, 250μg, 300μg, 350μg, 400μg, 450μg, 500μg, 600μg, 700μg, 800μg, 900μg or 1000μg of the drug, or about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 90 mg of the drug.

[0106] Implants disclosed herein can elute drugs at a rate determined by their composition, size, and / or implant location. Thus, by adjusting the properties of the implant (e.g., microparticle implants or microspheres), an appropriate dose of drug can be administered to the eye. In some embodiments of the implants described herein, the drug eluting implant or implant formulation of the implant unit (e.g., a dry implant formulation as disclosed herein) can be between about 1 ng / day and about 3000 ng / day, between about 1 mg / day and about 300 mg / day, or between about 1 ng / day and about 300 mg / day. One or more drugs are delivered to the eye at a rate between about 1 ng / day and about 300 mg / day. In certain embodiments, the implant formulation of the drug eluting implant or implant unit (e.g., a dry implant formulation as disclosed herein) can be between about 1 ng / day and about 2000 ng / day, between about 1 ng / day and about 1000 ng / day, between about 1 ng / day and about 500 ng / day, between about 1 ng / day and about 400 ng / day, between about 1 ng / day and about 300 ng / day, between about 1 ng / day and about 200 ng / day, between about 1 ng / day and about 100 ng / day, between about 1 ng / day and about 5 ...50 ng / day, between about 1 ng / day and about 60 ng / day, between about 1 ng / day and about 70 ng / day, between about 1 ng / day and about 100 ng / day, between about 1 ng / day and about 50 ng / day, between about 1 ng / day and about 60 ng / day, between about 1 ng / day and about 70 ng / day, between about 1 ng / day and about 80 ng / day, between about 1 ng / day and about 100 ng / day, between about 1 ng / day and about 150 ng / day, between about 1 ng / day and about 100 ng / day, between about 1 ng / day and about 150 ng / day, between about 1 ng / day and between about 5 ng / day and about 3000 ng / day or more, between about 5 ng / day and about 2000 ng / day, between about 5 ng / day and about 1000 ng / day, between about 5 ng / day and about 500 ng / day, between about 5 ng / day and about 400 ng / day, between about 5 ng / day and about 300 ng / day, between about 5 ng / day and about 200 ng / day, between about 5 ng / day and about 100 ng / day, between about 5 ng / day and about 50 ng / day, between about 10 ng / day and about 3000 ng / day or more, between about 10 ng / day and about 1500 ng / day, between about 1500 ng / day and about 2000 ng / day, between about 10 ng / day and about 3000 ng / day or more, between about 10 ng / day and about 500 ng / day day and about 2000 ng / day, between about 10 ng / day and about 1000 ng / day, between about 10 ng / day and about 500 ng / day, between about 10 ng / day and about 400 ng / day, between about 10 ng / day and about 300 ng / day, between about 10 ng / day and about 200 ng / day, between about 10 ng / day and about 100 ng / day, between about 10 ng / day and about 50 ng / day, between about 50 ng / day and about 3000 ng / day or more, between about 50 ng / day and about 2000 ng / day, about 50 ng / day / day and about 1000 ng / day, between about 50 ng / day and about 500 ng / day, between about 50 ng / day and about 400 ng / day, between about 50 ng / day and about 300 ng / day, between about 50 ng / day and about 200 ng / day, between about 50 ng / day and about 100 ng / day, between about 100 ng / day and about 3000 ng / day or more, between about 100 ng / day and about 2000 ng / day, between about 100 ng / day and about 1000 ng / day, between about 100 ng / day and about 500 ng / day,The drug is delivered to the eye at a rate of between about 100 ng / day and about 400 ng / day, between about 100 ng / day and about 300 ng / day, between about 100 ng / day and about 200 ng / day, between about 200 ng / day and about 300 ng / day, between about 300 ng / day and about 400 ng / day, between about 400 ng / day and about 500 ng / day, between about 500 ng / day and about 1000 ng / day, between about 1000 ng / day and about 1500 ng / day, between about 1500 ng / day and about 2000 ng / day, between about 2000 ng / day and about 2500 ng / day, between about 2500 ng / day and about 3000 ng / day, including all subranges and values ​​of any of the foregoing. In certain embodiments, the implant formulation of the drug eluting implant or implant unit (e.g., a dry implant formulation as disclosed herein) can be about 1 ng / day, 2 ng / day, 3 ng / day, 4 ng / day, 5 ng / day, 6 ng / day, 7 ng / day, 8 ng / day, 9 ng / day, 10 ng / day, 11 ng / day, 12 ng / day, 13 ng / day, 14 ng / day, 15 ng / day, 16 ng / day, 17 ng / day, 18 ng / day, 19 ng / day, 20 ng / day, 21 ng / day, 22 ng / day, 23 ng / day, 24 ng / day, 25 ng / day, 26 ng / day, 27 ng / day, 28 ng / day, 29 ng / day, 30 ng / day The one or more drugs are delivered to the eye at a rate of 100 ng / day, 200 ng / day, 250 ng / day, 300 ng / day, 350 ng / day, 400 ng / day, 450 ng / day, 500 ng / day, 550 ng / day, 600 ng / day, 650 ng / day, 700 ng / day, 750 ng / day, 800 ng / day, 850 ng / day, 900 ng / day, 950 ng / day, 1000 ng / day, 1500 ng / day, 2000 ng / day, 2500 ng / day or 3000 ng / day.

[0107] In certain embodiments, the dosage of a drug eluting implant or implant unit (e.g., a dry implant formulation as disclosed herein) may be between about 1 mg / day and about 300 mg / day, between about 1 mg / day and about 200 mg / day, between about 1 mg / day and about 100 mg / day, between about 1 mg / day and about 50 mg / day, between about 1 mg / day and about 20 mg / day, between about 1 mg / day and about 10 mg / day, between about 10 mg / day and about 10 .... The drug is delivered to the eye at a rate of between about 10 mg / day and about 300 mg / day, between about 10 mg / day and about 200 mg / day, between about 10 mg / day and about 100 mg / day, between about 10 mg / day and about 50 mg / day, between about 10 mg / day and about 20 mg / day, between about 100 mg / day and about 300 mg / day, between about 100 mg / day and about 200 mg / day, including all subranges and values ​​of any of the foregoing. In certain embodiments, the drug eluting implant or implant unit of the implant formulation (e.g., a dry implant formulation as disclosed herein) can be about 1 mg / day, 2 mg / day, 3 mg / day, 4 mg / day, 5 mg / day, 6 mg / day, 7 mg / day, 8 mg / day, 9 mg / day, 10 mg / day, 11 mg / day, 12 mg / day, 13 mg / day, 14 mg / day, 15 mg / day, 16 mg / day, 17 mg / day, 18 mg / day, 19 mg / day, 20 mg / day, 21 mg / day, 22 mg / day, 23 mg / day, 24 mg / day, 25 mg / day, 26 mg / day, 27 mg / day, 28 mg / day, 29 mg / day, 30 mg / day, 31 mg / day, 32 mg / day, 33 mg / day, 34 mg / day, 35 mg / day, 36 mg / day, 37 mg / day, 38 mg / day, 39 mg / day, 40 mg / day, 41 mg / day, 42 mg / day, 43 mg / day, 44 mg / day The one or more drugs are delivered to the eye at a rate of 0 mg / day, 21 mg / day, 22 mg / day, 23 mg / day, 24 mg / day, 25 mg / day, 26 mg / day, 27 mg / day, 28 mg / day, 29 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 60 mg / day, 70 mg / day, 80 mg / day, 90 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day or 300 mg / day.

[0108] In certain embodiments, the implant formulation of the drug eluting implant or implant unit (e.g., a dry implant formulation as disclosed herein) can be between about 1 ng / day and about 300 mg / day, between about 1 ng / day and about 200 mg / day, between about 1 ng / day and about 100 mg / day, between about 1 ng / day and about 50 mg / day, between about 1 ng / day and about 20 mg / day, between about 1 ng / day and about 10 mg / day, between about 10 ng / day and about 300 mg / day, between about 10 ng / day and about 200 mg / day, between about 10 ng / day and about 100 mg / day, between about 10 ng / day and about 50 mg / day between about 10 ng / day and about 20 mg / day, between about 10 ng / day and about 10 mg / day, between about 10 ng / day and about 1 mg / day, between about 20 ng / day and about 200 mg / day, between about 20 ng / day and about 100 mg / day, between about 20 ng / day and about 50 mg / day, between about 20 ng / day and about 20 mg / day, between about 20 ng / day and about 10 mg / day, between about 20 ng / day and about 1 mg / day, between about 30 ng / day and about 200 mg / day, between about 30 ng / day and about 100 mg / day, between about 30 ng / day and about 50 mg / day, between about 30 ng / day and about 20 mg / day, between about 30 ng / day and about 10 mg / day, between about 30 ng / day and about 1 mg / day, between about 50 ng / day and about 200 mg / day, between about 50 ng / day and about 100 mg / day, between about 50 ng / day and about 50 mg / day, between about 50 ng / day and about 20 mg / day, between about 50 ng / day and about 10 mg / day, between about 50 ng / day and about 1 mg / day, between about 100 ng / day and about 300 mg / day, between about 100 ng / day and about 200 mg / day, between about 100 ng / day and about 100 mg / day, between about 100 ng / day and about 50 The drug is delivered to the eye at a rate between about 100 ng / day and about 20 mg / day, between about 100 ng / day and about 10 mg / day, between about 100 ng / day and about 1 mg / day, between about 200 ng / day and about 300 mg / day, between about 200 ng / day and about 200 mg / day, between about 200 ng / day and about 100 mg / day, between about 200 ng / day and about 50 mg / day, between about 200 ng / day and about 20 mg / day, between about 200 ng / day and about 10 mg / day, between about 200 ng / day and about 1 mg / day, including all subranges and values ​​of any of the foregoing.

[0109] As described below, the drug suitable for being delivered by the implant described herein can diffuse from the implant position in one part / position of the eye (e.g., vitreous body, subconjunctival space) to another part / position in the eye (e.g., anterior chamber, posterior chamber), or vice versa. In order to enhance this diffusion from the implant position to another position in the eye, the drug described herein can be applied together with the application of one or more penetration enhancers. Penetration enhancers can include, for example, compounds such as cyclodextrins, chelating agents, crown ethers, bile acids, bile salts, surfactants, cell penetrating peptides, and amphiphilic compounds. Such penetration enhancers can be combined with the drug for treating the disease of the eye being applied by the drug eluting implant described herein, or they can be applied separately. In some variations, the first drug eluting implant delivers the drug for treating the disease of the eye, and the second drug eluting implant delivers the penetration enhancer. In other variations, a drug eluting implant delivers both the drug for treating the disease of the eye and the penetration enhancer. The penetration enhancer can also be a non-compound penetration enhancer that is applied separately and as a supplement to the implant. For example, non-compound penetration enhancers can include electric current, iontophoresis, ultrasound or microneedles. These can, for example, be applied to the tissue of the eye to enhance the penetration of the drug delivered by the drug eluting implant described herein. The selection of suitable penetration enhancers can depend on the properties (e.g., molecular weight, hydrophobicity / lipophilicity) of the drug being administered. Suitable penetration enhancers can be selected to enhance the penetration of drugs through specific tissues (e.g., cornea, sclera).

[0110] In some embodiments, the drug is delivered to eyes in a predetermined time period such as 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 values ​​and subranges therein). For example, in some variations, the drug eluting implant is configured for sustained release of drug to the eye for between about 1 month and about 3 months, between about 2 months and about 4 months, between about 1 month and about 6 months, between about 6 months and about 9 months, between about 6 months and about 12 months, between about 12 months and about 18 months, between about 12 months and about 24 months, between about 24 months and about 36 months, between about 12 months and about 72 months, or between about 1 month and about 72 months. In certain embodiments, the time period is between about 0 months and 1 month, between about 0 months and about 2 months, between about 0 months and about 3 months, between about 0 months and about 4 months, between about 0 months and about 5 months, between about 0 months and about 6 months, between about 0 months and about 7 months, between about 0 months and about 8 months, between about 0 months and about 9 months, between about 0 months and about 10 months, between about 0 months and about 11 months, between about 0 months and about 12 months, between about 1 month and about 2 months, between about 1 month and about 3 months, between about 1 month and about 4 months, between about 1 month and about 5 months, between about 1 month and about 6 months, between about 1 month and about 7 months, between about 1 month and about 8 months, between about 1 month and about 9 months, between about 1 month and about 10 months, between about 1 month and about 11 months, between about 0 months and about 12 months. between 1 month and about 12 months, between about 2 months and about 3 months, between about 2 months and about 4 months, between about 2 months and about 5 months, between about 2 months and about 6 months, between about 2 months and about 7 months, between about 2 months and about 8 months, between about 2 months and about 9 months, between about 2 months and about 10 months, between about 2 months and about 11 months, between about 2 months and about 12 months, between about 3 months and about 4 months, between about 3 months and about 5 months, between about 3 months and about 6 months, between about 3 months and about 7 months, between about 3 months and about 8 months, between about 3 months and about 9 months, between about 3 months and about 10 months, between about 3 months and about 11 months, between about 3 months and about 12 months, between about 4 months and about 5 months, between about 4 months and about 6 months, between about 4 months and about 7 months,between about 4 months and about 8 months, between about 4 months and about 9 months, between about 4 months and about 10 months, between about 4 months and about 11 months, between about 4 months and about 12 months, between about 5 months and about 6 months, between about 5 months and about 7 months, between about 5 months and about 8 months, between about 5 months and about 9 months, between about 5 months and about 10 months, between about 5 months and about 11 months, between about 5 months and about 12 months, between about 6 months and about 7 months, between about 6 months and about 8 months, between about 6 months and about 9 months, between about 6 months and about 10 months, between about 6 months and about 11 months, between about 6 months and about 12 months, between about 7 months and about 8 months, between about Between 7 months and about 9 months, between about 7 months and about 10 months, between about 7 months and about 11 months, between about 7 months and about 12 months, between about 8 months and about 9 months, between about 8 months and about 10 months, between about 8 months and about 11 months, between about 8 months and about 12 months, between about 9 months and about 10 months, between about 9 months and about 11 months, between about 9 months and about 12 months, between about 10 months and about 11 months, between about 10 months and about 12 months, between about 11 months and about 12 months, between about 10 months and about 24 months, between about 10 months and about 36 months, between about 12 months and about 24 months, or between about 12 months and about 36 months. In certain embodiments, the time period is at least about 1 year, 2 years, 3 years, 4 years, 5 years, 10 years, 15 years, 20 years, or between about 1 year and about 5 years, about 1 year and about 10 years, about 5 years and about 10 years, about 5 years and about 15 years, about 10 years and about 20 years, about 5 years and about 20 years, or about 1 year and about 20 years. As used above, "about 0 months" refers to the approximate time of implantation of an implant or implants.

[0111] In some modifications, multiple implants or multiple subsets of (for example, in implant preparations) implants can have similar or identical delivery periods. In some modifications, multiple implants or multiple subsets of (for example, in implant preparations) implants can have independent delivery periods (for example, predetermined time periods as described above). Only by way of example, two subsets of (for example, in implant preparations) implants can be used to experimenter, wherein the first subset has the time period between about 0 month and about 3 months, and the second subset has the time period between about 4 months and about 9 months. It should be understood that each implant or each subset of implants can independently have any delivery period in the delivery period described above.

[0112] As discussed, the drug eluting implants described herein can be at least partially bioerodible. In some variations, when one or more implanted implants degrade in the eye, one or more new implants (e.g., replacement implants) can be delivered to one or more locations in the eye. For example, a new implant can replace a partially or completely degraded implant every month, every 2 months, every 3 months, every 6 months, every 12 months, every 18 months, every 2 years, every 3 years, or every longer time, or any interval therein.

[0113] As previously discussed, in the variant in which the implant (e.g., microparticles, such as microspheres) is at least partially positioned in the posterior chamber (e.g., the rest of the ciliary sulcus, the posterior chamber), the drug delivered from the drug eluting implant can be carried by the stream flowing forward and / or the stream flowing backward so that the drug can be delivered to the anterior chamber and / or the posterior chamber of the eye. In some variations, the drug can be delivered to the anterior chamber, the posterior chamber (e.g., the rest of the ciliary sulcus and / or the posterior chamber), the cornea, the iris, the lens, the pupil, the retina, or the vitreous body. In the variant in which the implant is positioned in the wall (e.g., entirely embedded in or positioned in one or more tissues of the eye), the drug can 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 can be delivered through the conjunctiva to the subconjunctival space or through the conjunctiva and the Tenon's capsule to the subtenon's capsule space. In some variations, the implant is positioned in the ciliary sulcus, and posterior chamber flow delivers the eluted drug to the retina and / or choroid.

[0114] Implants described herein (e.g., microparticles, such as microspheres) may be advantageous in comprising at least one imaging agent, which may contribute to visualization of the implant and / or drug during and / or after implantation. In variations comprising an imaging agent, the imaging agent may be released along with the degradation of the bioerodible implant, which may further contribute to visualization and / or quantification of how much drug remains in the initial implant dose at any given time point and / or within a certain time period (e.g., days, weeks, years). In other words, the imaging agent serves as a substitute for drug elution. In some variations, the imaging agent may be one or more of a dye, a radiolabel, and a fluorescent marker. In certain embodiments, the imaging agent may be fluorescein. In some variations of implants described herein, the implant may comprise a drug and an imaging agent, and the implant may be configured to deliver the drug and the imaging agent to the eye at the same delivery rate (e.g., elution rate). In other variations, the implant may be configured to deliver the drug and the imaging agent to the eye at different delivery rates. In some cases, a medical professional can visualize an imaging agent to estimate or otherwise quantify the amount of drug delivered, and can personalize treatment based on this determination. For example, a medical professional can determine the characteristics of a future procedure (e.g., the number or volume of implants, the type of drug, the amount of drug, the time of the next implant, the amount of time the next implant should remain in the eye) based on the visualization data of the imaging agent and / or the estimate or quantification of the amount of drug delivered.

[0115] The implants described herein (e.g., microparticles, such as microspheres) can be configured for placement within the eye. For example, in some variations, the microspheres can reside partially or completely in the subconjunctival space, the Tenon's capsule, the subtenon's capsule space, the anterior chamber (including the iridocorneal angle), the posterior chamber (including the ciliary sulcus), or the vitreous body.

[0116] Implant location

[0117] Drug eluting implants described herein can be configured to reside in any suitable position in the eye. For example, implants described herein can reside in the subconjunctival space, the Tenon's capsule, the space below the Tenon's capsule, the suprachoroidal space (the suprachoroidal space can be entered via an external approach or through the internal approach of the anterior chamber angle to implant), the subretinal space, the sclera, the cornea, the limbus, the anterior chamber, the posterior chamber (including the remainder of the ciliary sulcus and the posterior chamber) and the vitreous body. Implants can be delivered to a plurality of different implantation sites. In these cases, the implant in one part of the eye can have one or more different drugs and / or can have different delivery rates (for example, elution rate, dissolution rate) compared to the implant in another part of the eye. By way of example, the first implant or a first subset of implants can be configured to reside in the first position, and the second implant or a second subset of implants can be configured to reside in the second position. In some embodiments, a first implant or a first subset of implants that can be configured to reside in a first location can include a first drug, and a second implant or a second subset of implants that can be configured to reside in a second location can include the same or a different drug. In some embodiments, a first implant or a first subset of implants that can be configured to reside in a first location can have a first drug delivery rate, and a second implant or a second subset of implants that can be configured to reside in a second location can have the same or a different drug delivery rate.

[0118] The drug eluting implant may also reside completely within the wall (e.g., entirely embedded or positioned within one or more tissues of the eye), such as, for example, the cornea, the sclera, the limbus, or a combination thereof. In certain variations, one or more implants may reside completely within the cornea, completely within the sclera, or completely within the limbus.

[0119] Implant system

[0120] As described herein, implants and / or implant formulations (e.g., dry implant formulations as disclosed herein) can be implanted, for example, in the eye using an implant system that is configured to enter a target location in the eye of a subject and implant one or more implants or a desired amount (e.g., an implant unit) of an implant formulation as described herein into the target location. In some embodiments, an implant system can be configured to implant the implant or dry implant formulation as disclosed herein without a carrier.

[0121] In some variations, the implant system may include an implant device comprising a handle and a cannula coupled to the distal end of the handle. The size and shape of the handle may be configured to allow the user to comfortably grip and manipulate the cannula to advance the cannula or a portion thereof toward the target location in the eye. In some variations, the lumen of the cannula or a portion thereof may be loaded (e.g., preloaded) with one or more implants, such as, for example, an implant formulation (e.g., a dry implant formulation as disclosed herein) of an implant unit. In some variations, the implant system may also include a plunger or push rod slidably positioned within the lumen of the cannula. In some variations, the handle may include an actuator that controls the implant system (e.g., controls the plunger or push rod) for the user to eject the implant formulation from the cannula so that the implant is delivered to the target location in the eye.

[0122] The cannula may include a distal portion configured to be inserted into a target location in 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 a distal tip and terminate at the distal tip, wherein the lumen terminates as a distal opening in the distal tip. One or more implants, such as, for example, an implant formulation (e.g., a dry implant formulation as disclosed herein), may be positioned within the lumen of the cannula. The distal tip may be sharp enough to penetrate tissue and / or membranes in the eye. By way of example, the distal tip of the cannula may have a beveled edge. Additionally or alternatively, the distal portion comprising the distal tip may be tapered so that the outer diameter of the cannula gradually decreases toward the distal tip, and the outer diameter of the distal tip is 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. A transparent cannula advantageously provides for visualization of the implant or implant formulation (eg, a dry implant formulation as disclosed herein) loaded into the lumen as well as visual control of the implantation process.

[0123] In some variations, the implant device may be a syringe operatively coupled to a cannula loaded with one or more implants or implant formulations (eg, dry implant formulations as disclosed herein), and the actuator may be the plunger of the syringe.

[0124] In some variations, the actuator may be or may include one or more of the following: a wheel, a switch, a button, a knob, a lever, a slider, a touchpad, a capacitive touch sensor, etc. In some variations, the distal tip of the push rod or plunger may contact at least a portion of one or more implants, or an implant formulation (e.g., a dry implant formulation as disclosed herein). In some variations, the actuator may have markings or colors to indicate the degree or direction of advancement.

[0125] In some modifications, the actuator is operably coupled to the plunger or push rod and can be operated to move the push rod relative to the handle and the cannula so that the end of the push rod is advanced toward the distal opening of the cannula. In some modifications, the actuator is operably coupled to the cannula and can be operated to move the cannula relative to the handle and the push rod so that the distal opening of the cannula is retracted toward the distal end of the push rod. In some modifications, the actuator is operably coupled to the plunger or push rod and the cannula. The actuator can be operated to move the push rod and the cannula in opposite directions. That is, the actuator can be operated to move the push rod relative to the handle and the cannula so that the end of the push rod is advanced toward the distal opening of the cannula, and can be operated to move the cannula relative to the handle and the push rod so that the distal opening of the cannula is retracted toward the end of the push rod.

[0126] In some variations, the handle may include a drive assembly that converts rotational movement into linear motion of the pushrod, 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 cause one or more components of the drive assembly (e.g., a circular gear) to rotate, which may result in linear movement of the pushrod, as will be described in greater detail herein.

[0127] For example, a 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. The at least one elongated member may be connected to the pushrod and / or cannula. The elongated member may be configured to engage with the pinion such that rotational motion of the pinion is converted into linear motion of the elongated member. In some variations, the elongated member may be a linear gear having teeth on its surface that engage corresponding teeth on the pinion. The drive assembly may include one or more idler gears that engage with the elongated member and / or the pinion to provide a desired direction of movement of the elongated member relative to the direction of rotation of the pinion. The at least one pinion may also be coupled (e.g., coaxially or tangentially) to a wheel. This coupling may be achieved, for example, by a pin that may be coupled (e.g., via threads, etc.) to a central opening in the rotatable member and the pinion. Mechanical or other fasteners (e.g., nuts) may be used to secure the rotatable member and the pinion such that rotation of the rotatable member also rotates the pinion, or vice versa. The wheel may be attached to the pinion in any suitable manner. For example, in some variations, the wheel may be positioned (e.g., slid) onto the pinion and may be secured to the pinion (e.g., using an adhesive or other mechanical fastening technique, such as a compression fit, press fit, etc.). In other variations, the wheel and pinion may be integrally formed (e.g., molded as one part using plastic injection molding techniques). 2) Regardless of how the wheel may be coupled to the pinion, the wheel and pinion may rotate coaxially or tangentially in the same direction and at the same angular rate.

[0128] In some variations, the cannula and the pushrod may be configured to move linearly in opposite directions when the actuator is engaged. In these variations, the drive assembly may include: a first pinion gear that is coupled (e.g., coaxially or tangentially) to the actuator (e.g., a wheel) and configured to engage with a first elongated member connected to the pushrod; and a second pinion gear that is coupled (e.g., coaxially or tangentially) to the actuator and configured to engage with a second elongated member connected to the cannula. In addition, the drive assembly may include an idler gear located between the first pinion gear and the first elongated member or between the second pinion gear and the second elongated member, such that when the actuator moves in a given direction (e.g., the wheel rotates), the first elongated member and the second elongated member can move in opposite directions.

[0129] Now turn Figures 3A to 3B , shows an implant system 300 configured to deliver an implant or implant formulation (e.g., a dry implant formulation as disclosed herein). Figures 3A to 3B In the variation shown, the implant system 300 is constructed to move both the cannula and the push rod during the implantation procedure. In this variation, the implant system 300 may include a cannula 310, a push rod 320, and a handle 330. The cannula 310 may include a distal portion 312, a distal end 313 having a beveled edge, and a proximal portion 314. The push rod 320 may be slidably positioned in the lumen of the cannula 310. The handle 330 may include: a housing 332 that is shaped to be comfortably gripped by a user (not shown) (e.g., in a single handle of the user); and an actuator 334 in the form of a wheel for moving the cannula 310 and the push rod 320 in opposite directions when actuated (e.g., rotated) by the user. Additionally, handle 330 may further include (e.g., at least partially housed therein) a drive assembly 340 that translates movement (e.g., rotational movement) of actuator 334 into opposing linear movement of cannula 310 and pushrod 320. Housing 332 of handle 330 is depicted as being partially cut away to provide a view of drive assembly 340 and its components, which, in this variation, are entirely housed within an interior portion of housing 332 of handle 330.

[0130] Figure 3C Shown Figure 3A and Figure 3B357. A top view of implant system 300 is shown in FIG. 35, wherein housing 332 of handle 330 is removed to provide a better view of drive assembly 340 and its connection to cannula 310 and pushrod 320. As can be more easily seen in this figure, proximal portion 324 of pushrod 320 can be fixedly connected to linear gear 346 via pushrod retainer 347, proximal portion 314 of cannula 310 can be fixedly connected to linear gear 356 via handle 357, and distal portion of pushrod 320 can be slidably positioned within the lumen of cannula 310.

[0131] Figure 3E Another variation of a drive assembly 1340 that can be housed in housing 332 is shown, which converts movement (e.g., rotational movement) of an actuator (e.g., actuator 1334) into opposing linear movement of a cannula (not shown) and a push rod (not shown) for delivering an implant or implant formulation (e.g., a dry implant formulation) loaded in the cannula. In this variation, drive assembly 1340 can include a first linear gear 1346 fixedly coupled to the push 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 can engage with each other via an idler gear 1357. Thus, drive assembly 1340 can be configured to move the push rod (via first linear gear 1346) and the cannula (via second linear gear 1356) in opposing linear directions.

[0132] Implant system 330 can be configured such that when cannula 310 is retracted and pushrod 320 is advanced via engagement (eg, rotation) of actuator 334 , dry implant formulation 360 is ejected through distal opening 318 of lumen 316 . Figure 3D yes Figures 3A to 3C FIG3 is a close-up view of the distal portion of the implant system 300. In addition, the cannula 310 is depicted as transparent to illustrate the implant or dry implant formulation 360 loaded into the lumen 316 of the cannula 310, and the distal tip 322 of the push rod 320 inserted within the lumen 316 and contacting the implant or dry implant formulation 360. Thus, when the push rod 320 is advanced through the lumen 316 and the cannula 310 is retracted, the implant or dry implant formulation 360 is ejected through the distal opening 318.

[0133] Method for loading a cannula preloaded with a dry implant formulation

[0134] Due to the size and characteristics of the implants and / or dry implant formulations as described herein and the size and configuration of the implant system (e.g., the narrow lumen of a cannula), loading one or more implants and / or dry implant formulations into an implant system can be challenging. Therefore, in some variations, one or more specialized methods and / or loading tools may be utilized to facilitate loading 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, wherein a groove is formed on the flat surface and is configured to receive a cannula (e.g., a cannula of an implant system as described herein), a plurality of implants or dry implant formulations as described herein, and a tamping device or push rod. The loading block may be configured to heat, cool, and / or apply an electrostatic discharge at or near the groove to facilitate implant installation. For example, Figure 4 A flow chart is provided for a method 400 for loading an implant or dry implant formulation (or specifically in the variation provided in FIG. 5 , a dry implant formulation) into a lumen of a cannula of an implant system. Figure 4 As shown, the production method 400 may include: in step 402, loading a cannula in a first portion of a groove sized to fit the cannula; in step 404, loading a dry implant formulation (or one or more implants) in a second portion of the groove near the proximal end of the cannula; in step 406, loading a push rod in a third portion of the push rod such that the loaded dry implant formulation (or one or more implants) is placed between the proximal end of the cannula and the distal end of the push rod.

[0135] After positioning the cannula, implant and / or dry implant formulation, and push rod in the groove, method 400 may further include, at step 408, advancing the push rod toward the cannula to force the implant and / or dry implant formulation into the lumen of the cannula through the proximal opening of the lumen. The push rod may be advanced such that the distal end of the push rod enters the lumen of the cannula. In some variations, the push rod may be advanced until a portion of the implant or dry implant formulation is positioned proximate the distal opening of the cannula.

[0136] In some variations, such as those using a dry implant formulation (which may or may not include a binder), after positioning the dry implant formulation within the lumen of the cannula, the method may include, in step 410, treating the dry implant formulation to enhance inter-implant adhesion between at least a majority of the implants in the dry implant formulation. In some variations, treating may include heating at least a majority of the implants to a temperature above the corresponding glass transition temperature of one or more polymers included in the drug eluting matrix of the individual implants. The glass transition temperature of the implant is based on the substances included therein, such as a bioerodible polymer included in the drug eluting matrix of the implant. In some variations, the glass transition temperature of the implant may be between about 35 degrees Celsius (°C) and about 45°C, between about 40°C and about 45°C, or between about 37°C and about 40°C. In some variations, treating may include compressing the dry implant formulation within the lumen of the cannula using, for example, a separate tamping device and / or a push rod of the implant system. In some modifications, processing can include heating and compression.For example, in some modifications, the intubation that can be heated to accommodate dry implant preparation is made to heat at least most of the implants in the implant of dry implant preparation to the glass transition temperature higher than their corresponding polymer, and can (during heating or soon after heating, before the temperature of at least most of the implants in the implant is lower than the corresponding glass transition temperature) by inserting tamping device into the lumen of intubation, and / or by advancing push rod or tamping device so that implant is compressed between push rod or tamping device and cap when intubation is capped (for example, utilizing the removable cap positioned on the distal end of intubation), compress the implant of dry implant preparation.Without being bound by theory, be heated to higher than glass transition temperature, apply compression or heating and during heating or after heating, compression combination soon induces the surface of independent implant to partially deform against adjacent implant.

[0137] Figure 5ASchematically depict an exemplary method for loading one or more implants and / or dry implant formulations into a cannula using a loading block 500 that includes a groove 502 sized to fit the cannula of an implant system as described herein. In the exemplary variation depicted, the distal portion of the cannula 550 is positioned within a first portion 504 of the groove, and the implant and / or dry implant formulation comprising a plurality of microparticle implants is positioned in a second portion of the groove 506 near (e.g., adjacent) the proximal end 602 of the cannula 550. A push rod or tamping device 570 is positioned within a third portion 508 of the groove 502 near the implant and / or dry implant formulation. In this way, the implant and / or dry implant formulation 560 is positioned between the proximal end 552 of the cannula and the distal end 572 of the push rod or tamping device 570. The push rod or tamping device 570 is then advanced toward the cannula (schematically shown in the direction of block arrow 640), thereby pushing the implant and / or dry implant formulation 560 into the lumen of the cannula 550 through the proximal opening 554 of the lumen of the cannula 550. In other variations, the cannula 550 may be reversely loaded into the loading block 500 so that the implant and / or dry implant formulation 560 is loaded through the distal opening 556 of the cannula 560 in a similar manner. In some variations, the loading block 500 may be heated so that at least a majority of the particulate implants in the dry implant formulation are heated to above the glass transition temperature, as described in more detail herein. In some variations, although Figure 5A 510. In some embodiments, the implant and / or dry implant preparation are not described in detail, but during the loading of the implant and / or dry implant preparation, the top cover can be removably positioned on the end (e.g., distal end) of the cannula 510. In a modification in which compression is accompanied by or replaces heating, a push rod or tamping device 570 can be advanced until enough compressive forces are applied to the implant and / or dry implant preparation. For example, a push rod or tamping device 570 can be advanced so that the distal end of the implant and / or dry implant preparation contacts the top cover, and the proximal end of the implant and / or dry implant preparation continues to advance distally, thereby compressing the implant and / or dry implant preparation. In some modifications, in addition to or in place of a push rod or tamping device 570, the push rod of the implant system can be used to apply compressive force to the implant and / or dry implant preparation.

[0138] Figure 5BThe cannula 550 loaded with the dry implant formulation 560 is shown after compression has been applied by a push rod or tamping device 570. The cannula 550 has a cap 580 that is releasably coupled to the distal opening 556 of the cannula 550. When coupled to the cannula 550, the cap 580 can be positioned over the distal opening 556 of the cannula 550. The cap 580 can further provide protection to the distal end 556 before the cannula is used in an implantation procedure, such as during shipping and storage, and can be removed by a user before the implantation procedure.

[0139] Methods of treating eye diseases

[0140] Also provided are methods for treating a condition of a subject's eye using an implant or one or more implant formulations (e.g., a dry implant formulation as disclosed herein). Generally speaking, the methods described herein may include implanting at least one drug eluting implant or implant formulation (e.g., a dry implant formulation as disclosed herein) (including multiple implants or multiple collections or groups of implants) into the subject's eye. The methods described herein may involve implanting one or more implants or implant formulations described herein (e.g., a dry implant formulation) with or without a carrier. When administered with a carrier / vehicle, saline, water, or other non-toxic aqueous media may be used as a carrier / vehicle. A 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. Implanting a drug eluting implant without the use of a liquid carrier may be referred to herein as a "dry" implant. Dry implants limit or eliminate dangerous intraocular pressure changes that may occur in the eye when a liquid carrier is injected. Additionally, due to at least the size, shape and structure of the implant and the properties of the implant formulation disclosed herein (e.g., dry implant formulation), multiple implants can be implanted closely to each other, and their movement in the eye can be more limited than with implants administered using aqueous solutions, which can help avoid the extravasation typically experienced in aqueous solutions. Other advantages of administering without a carrier are that the drug dose injected per unit volume is higher, and the need for refrigerated or frozen shipment of drug implant devices is eliminated. The dose can be deployed immediately without the need for additional steps or the chance of mixing errors. Additionally, dry implantation allows implants to aggregate in one area, thereby increasing visibility to physicians to determine the presence of the drug in a specific part of the eye and therefore elution. In addition, 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.

[0141] Implant location

[0142] Generally speaking, the drug can be delivered from at least one drug eluting implant (optionally as an implant formulation, such as a dry implant formulation as described herein) to structures of the eye to alleviate symptoms of a disorder of the eye, as previously described. In some embodiments, the methods may include: implanting at least one drug eluting implant or implant formulation (e.g., a dry implant formulation as disclosed herein) in the anterior chamber; and delivering the drug from the implant to the anterior chamber and / or another location in the eye (e.g., the posterior chamber, sclera, vitreous, subconjunctival space, Tenon's capsule, subtenon's capsule) to treat a disorder of the eye and / or alleviate one or more symptoms of a disorder of the eye. In some embodiments, the method may include: implanting at least one drug eluting implant or implant formulation (e.g., a dry implant formulation as disclosed herein) in the vitreous; and delivering the drug from the at least one implant or implant formulation (e.g., a dry implant formulation as disclosed herein) to the vitreous and / or another location in the eye (e.g., the posterior chamber, the sclera, the anterior chamber, the subconjunctival space) to treat a condition of the eye and / or alleviate one or more symptoms of a condition of the eye. In some embodiments, the method may include: implanting at least one drug eluting implant or implant formulation (e.g., a dry implant formulation as disclosed herein) in the subconjunctival space; and delivering the drug from the implant or implant formulation (e.g., a dry implant formulation as disclosed herein) to the subconjunctival space and / or another location in the eye (e.g., the posterior chamber, the sclera, the anterior chamber, the vitreous, the Tenon's capsule, the subconjunctival space) to treat a condition of the eye and / or alleviate one or more symptoms of a condition of the eye. In some embodiments, the method may include: implanting at least one drug eluting implant or implant formulation (e.g., a dry implant formulation as disclosed herein) in the Tenon's capsule or subtenon's space; and delivering the drug from the implant or implant formulation (e.g., a dry implant formulation as disclosed herein) to the Tenon's capsule or subtenon's space and / or another location in the eye (e.g., the posterior chamber, sclera, anterior chamber, vitreous, subconjunctival space) to treat a disorder of the eye and / or alleviate one or more symptoms of a disorder of the eye. In some embodiments, the method may include: implanting at least one drug eluting implant or implant formulation (e.g., a dry implant formulation as disclosed herein) in the posterior chamber (including in the ciliary sulcus and / or in the remainder of the posterior chamber); and delivering the drug from the at least one drug eluting implant or implant formulation (e.g., a dry implant formulation as disclosed herein) to the posterior chamber and / or another location in the eye (e.g., the subconjunctival space, the sclera, the anterior chamber, the vitreous) to treat a disorder of the eye and / or alleviate one or more symptoms of a disorder of the eye.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 as disclosed herein) completely within the wall; and delivering the drug from the implant or implant formulation to another location of the eye (e.g., anterior chamber, posterior chamber, vitreous body) to alleviate the symptoms of the disorder of the eye. Any of the above-mentioned drug eluting implants or implant formulations (e.g., dry implant formulations as disclosed herein) and implant systems are suitable for use with the methods described herein.

[0143] anaesthetization

[0144] Prior to administering the drug-eluting implant, the eye may be anesthetized and one or more antimicrobial agents may be applied to the eye to prepare it for the implant procedure. Anesthesia may include one or a combination of the following types of anesthesia: topical, subconjunctival, tenon's capsule, subtenon's capsule space, periocular, and retrobulbar. In some cases, a lid speculum may be applied to expose the ocular surface and prevent the eyelid from closing. In some cases, dilating the pupil may be advantageous. The procedure may also be performed under a slit lamp with the patient sitting upright, or under a microscope with the patient lying supine. In some embodiments, a magnifying glass, slit lamp, or surgical microscope may be used to advance and / or position the implant. The procedure may be performed in an operating room, but advantageously, the methods described herein are suitable for use in a doctor's office or in a small operating room, for example, using a slit lamp, under direct visualization, under magnification, or under a microscope. The methods described herein may be performed with or without gonioscopy or minimally invasive glaucoma surgery (MIGS) type implantation. In contrast, many of the methods described herein allow for injection into the tissues of the eye, which is performed by an ophthalmologist or optometrist under a slit lamp or in an office-based setting. While these procedures can be performed in an operating room, there are many advantages to performing these procedures in an office-based setting (e.g., cost savings, patient convenience, increased appointment availability and / or opportunities).

[0145] Implantation process

[0146] In some variations, a cannula preloaded with one or more implants or implant formulations (e.g., dry implant formulations as disclosed herein) may be advanced through external tissue (e.g., sclera, conjunctiva, cornea) to a desired or target location or position within the eye. The implant formulation may then be ejected or otherwise released from the implant system into the target location. In some variations, such as Figure 6As shown, an implantation method 700 may include, in step 702, piercing tissue of the eye (e.g., the sclera, cornea), optionally using a needle or a cannula of an implantation system; and, in step 704, advancing the distal end of the cannula of the implantation system to a desired implantation location, such as directly into the mural tissue or into a space within the eye, the cannula carrying one or more implants or implant formulations (e.g., a dry implant formulation as disclosed herein) within the lumen of the cannula. The desired implantation location may include, for example, the posterior chamber, the anterior chamber, the subconjunctival space, the Tenon's capsule, the sub-Tenon's capsule space, or the vitreous body. In some variations, the implantation method may include, in step 706, ejecting or otherwise releasing the one or more implants or implant formulations (e.g., a dry implant formulation as disclosed herein) from the cannula into the target location. In some variations, ejection or release may include operating an actuator of the implantation system, which may result in moving (e.g., advancing) a push rod of the implantation system relative to the cannula, retracting the cannula relative to the push rod, or a combination of both. In some variations, the method may include creating an intramural tunnel or passageway separately from and prior to advancing the cannula to the target location. In some variations, the tunnel or passageway may be created using an instrument such as a needle or a femtosecond laser. In other variations, the passageway or tunnel may be created using an implant system before 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 mural tissue or within the tunnel or passageway. An actuator of the implant system may then be operated to eject or otherwise release the implant or dry implant formulation into the mural tissue, tunnel or passageway, or other naturally occurring space within the eye.

[0147] In some variations, the target location may be the subtenon space. Figure 7 An exemplary method of implantation into the subtenon's space is depicted. In this variation, a distal portion 804 of a cannula 802 of an implant system 800 can pierce the conjunctiva and the Tenon's capsule. The cannula 802 can be loaded with at least one implant or dry implant formulation 806, which can be positioned within the lumen of the cannula. The distal end 804 can be advanced into the subtenon's space. Once the distal end 804 is in the subtenon's space, an actuator on a handle of the implant system can be operated to eject or otherwise release the implant or dry implant formulation 806 within the cannula 802 into the subtenon's space. Figure 7 In the depicted variation, the handle of the implant system is a syringe 810 and the actuator is a plunger 812. It should be understood that although depicted using another variation of the implant system, Figure 7 The methods described may utilize any of the implant systems described herein such as, for example, those described with respect to Figures 3A to 3D The implant system 300 is described.

[0148] In some variations, a guide wire may be used during the implantation procedure. For example, the guide wire may contact a portion of the implant, and the implant may be advanced and / or positioned from the cannula using the guide wire. After the implant is delivered to the target tissue using the guide wire, the implant may be released from the guide wire and / or the guide wire may be withdrawn, leaving the implant in place.

[0149] As described above, advancing one or more implants or implant formulations (e.g., dry implant formulations as disclosed herein) may include advancing a portion of an implant 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 include advancing the cannula beneath one or more tissues (e.g., conjunctiva, Tenon's capsule). The implant or implant formulation (e.g., dry implant formulations as disclosed herein) may be disposed within the implant system. For example, the implant or implant formulation (e.g., dry implant formulations as disclosed herein) may be disposed within the cannula of the implant 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 allow for the complete positioning of a drug eluting implant within the wall, wherein at least a portion of the drug eluting implant is within the limbus of the eye. The methods described herein may also allow for the delivery of a drug from the drug eluting implant to one or more target tissues of the eye (e.g., the anterior chamber, the subconjunctival space, the subtenon's capsule space) after placement of the implant to alleviate symptoms of an eye condition. The one or more target tissues may be the one or more tissues in which the implant resides and / or may be one or more different tissues.The one or more target tissues may not be in contact with the implant.

[0150] The methods described herein are suitable for use with any of the drug eluting implants described herein, including implant formulations (eg, dry implant formulations as disclosed herein).

[0151] Visualization of intubation

[0152] After advancing the cannula in which the implant or implant formulation (e.g., a dry implant formulation as disclosed herein) is disposed, the cannula can be visualized in a specific portion of the eye or at a specific depth, thereby informing the location in the eye where the implant will reside once the cannula is retracted. Thus, the method may further include visualizing the distal tip of the cannula within a specific tissue, cavity, or structure of the eye (e.g., the anterior chamber) prior to releasing the implant from the implant system. For example, the cannula can be visualized within one or more tissues, cavities, or structures of the eye in which the implant will reside. Additionally or alternatively, the cannula can be visualized within one or more tissues, cavities, or structures of the eye adjacent to or near the desired implant location.

[0153] Visualizing the cannula through the posterior portion of the eye can help the user properly position the implant within the eye, as described above. Thus, the method can 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 the desired depth within the eye, the method can also include: retracting the cannula and / or advancing the pusher; and releasing the drug eluting implant in the target tissue (e.g., at least partially in the anterior chamber, posterior chamber, limbus, subconjunctival space, or vitreous body).

[0154] In some variations, a portion of the implant system (e.g., a cannula) and / or the drug eluting implant may be visualized during advancement and / or positioning using a magnifying glass, a slit lamp, a surgical microscope, or any combination thereof. Additionally or alternatively, the drug eluting implant may be implanted in a structure of the eye (e.g., the suprachoroidal space) using gonioscopy.

[0155] Dissemination of drugs to locations other than the implant site

[0156] Drug eluting implants, including implant formulations (e.g., dry implant formulations as disclosed herein), can deliver drugs to various positions, regardless of the position in which they reside in the eye. In any of the methods described herein, the drug eluting implant (or multiple implants) can deliver drugs to the position or tissue in which the drug eluting implant resides, and / or to a position or tissue different from the position or tissue in which the drug eluting implant resides. For example, the drug eluting implant can reside completely within the wall, within the posterior chamber, within the subconjunctival space, or within the vitreous body, but can deliver the drug to the anterior chamber of the eye (or vice versa) via diffusion through tissue. The drug eluting implant that resides completely in the subconjunctival space or the space under the capsule of the eye can deliver the drug to one or more of the following: 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 completely in the vitreous body can deliver the drug to one or more of the following: the limbus, sclera, cornea, anterior chamber, posterior chamber, or any other nearby tissue or structure of the eye. A drug eluting implant that resides completely in the ciliary sulcus can deliver the drug to one or more of the following: the limbus, sclera, cornea, anterior chamber, vitreous body, posterior chamber, or any other nearby tissue or structure of the eye. A drug eluting implant that resides partially in the limbus and partially in the sclera can deliver the drug to one or more of the following: the limbus, sclera, cornea, anterior chamber, or any other nearby tissue or structure of the eye. In some variations, the drug from the drug eluting implant can diffuse through one or more aqueous outflow channels. In some embodiments, a plurality of microspheres are implanted in the ciliary sulcus of the eye.

[0157] Eye diseases

[0158] As described herein, the methods of treating a condition of a subject's eye can be used to treat a variety of ocular disorders or conditions. These ocular disorders include, but are 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 can be used to treat macular edema, vascular occlusion, diabetic retinopathy, retinal degeneration and retinal dystrophy, iritis, uveitis, vitritis, cataracts, herpes zoster or simple infection, keratitis, keratoconus or other corneal degeneration, dry eye, scleritis, episcleritis, corneal ulcer, astigmatism, hyperopia, presbyopia, corneal ectasia, corneal dystrophy, corneal scarring, graft-versus-host disease, autoimmune eye diseases, Tergersen's keratitis, post-viral keratitis, herpes simplex, viral keratitis, uveitis, Stevens-Johnson disease, conjunctivitis, blepharitis, postoperative inflammation, postoperative infection prevention, postoperative pain, palpebral fissure maculitis, blepharitis, pterygium, spring and atopic keratoconjunctivitis, allergic conjunctivitis, chemical injury, thermal injury, chemical In some embodiments, the methods described herein can result in a reduction in the duration, severity, and / or occurrence of one or more symptoms of any of the foregoing conditions, and / or can result in the treatment of any of the foregoing conditions. Thus, the methods described herein can utilize drug-eluting implants that deliver a drug to treat any of these or other disorders or conditions. In some embodiments, the drug-eluting implant can deliver a glaucoma drug. In some variations, the methods described herein can utilize a drug-eluting implant that is partially located in a first portion of an eye to treat a disorder in the same portion of the eye or in another portion of the eye.

[0159] Multiple implants

[0160] The methods described herein may include delivering one or more implants or implant units of an implant formulation (e.g., a dry implant formulation as described herein) to the eye. For various reasons or purposes, multiple implants or implant units of an implant formulation (e.g., a dry implant formulation as disclosed herein) may be implanted. For example, a previously implanted implant or implant unit of an implant formulation (e.g., a dry implant formulation as disclosed herein) may have been exhausted or dissolved. Multiple doses of a drug or a plurality of different drugs may be implanted at the same location or different locations during the same sitting, or may be implanted at staggered times. Implants or implant units of an implant formulation (e.g., a dry implant formulation as disclosed herein) may be delivered simultaneously or sequentially and may reside in the eye simultaneously and / or sequentially (e.g., the implants or implant units of an implant formulation may all be implanted for the same time period, for different overlapping time periods, or for different non-overlapping time periods). In variations employing multiple implants, any number of implants (e.g., one, multiple, a subset of all implants, or an implant formulation of all implanted units) may contain the same drug, may contain different drugs with the same mechanism of action for one or more conditions of the eye, or may contain different drugs with different mechanisms of action for one or more conditions of the eye. An implant or an implant formulation of an implant unit (e.g., a dry implant formulation as disclosed herein) may contain a drug intended to treat or alleviate the symptoms of the same condition of the eye, or may contain a drug intended to treat or alleviate the symptoms of different conditions of the eye. In addition, an implant or an implant formulation of an implant unit (e.g., a dry implant formulation as disclosed herein) may be positioned in the same general location in the eye or in different areas of the eye. It should be understood that although the implant is described as containing a drug, this may include a combination of drugs. In other words, multiple implants or implant formulations of an implant unit (e.g., a dry implant formulation as disclosed herein) may be delivered sequentially during the same surgery or may be delivered simultaneously. In variations in which implants or implant formulations of implant units are delivered sequentially, the implants or implant formulations of implant units can be advanced together to a target implant location (e.g., ciliary sulcus, posterior chamber, anterior chamber vitreous, subtenon space, subconjunctival space) (e.g., when contained within a common implant system), or the implants or implant formulations of implant units can be advanced individually to a target implant location (e.g., positioned one at a time within a common implant system, positioned using different implant systems).

[0161] For example, a method may comprise: positioning one or more first implants (which may be a first subset of implants or a first implant formulation) comprising a first drug or drug combination intended to treat or alleviate symptoms of a first condition at a first location in the eye; and positioning one or more second implants (which may be a second subset of implants or a second implant formulation) comprising a second drug or drug combination intended to treat or alleviate symptoms of a second condition at a second location in the eye. 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 implant location and the second implant 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 drug combinations, the first condition and the second condition may be different conditions, the first implant location and the second implant location may be different locations, and / or the first drug or drug combination and the second drug or drug combination may utilize different mechanisms of action. Thus, in some variations, the first drug or drug combination and the second drug or drug combination can be different drugs or combinations utilizing different mechanisms of action, but the first location and the second location can be the same location, and the first condition and the second condition can be the same condition. In another example, the first drug or drug combination and the second drug or drug combination can be different drugs or different drug combinations utilizing different mechanisms of action, and the first location and the second location can be different locations, but the first condition and the second condition of the eye can be the same. It should be understood that when utilizing a method that includes the use of multiple drug eluting implants, any combination of drugs, mechanisms of action, locations, and conditions of the eye described herein may be used in combination. In any of the embodiments described herein, the drug or drug combination can 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).

[0162] For some subjects, it may be advantageous to deliver multiple implants or implant formulations (e.g., dry implant formulations as disclosed herein) that are configured to deliver different drugs, or to deliver drugs that utilize different mechanisms of action, as this may allow for more comprehensive treatment. For example, the method may include positioning one or more first implants (which may be a first subset of implants in an implant formulation, or a first implant formulation) containing a first drug with a first mechanism of action in the ciliary sulcus; and positioning one or more second implants (which may be a second subset of implants in an implant formulation, or a second implant formulation) containing a second drug with a second mechanism of action at least partially in the anterior chamber or the posterior chamber. In some variations, the first mechanism of action may be to inhibit the production of aqueous humor, and the second mechanism of action may be to increase the drainage of aqueous humor using one or more of the trabecular canalicular pathway and the uveoscleral pathway. In other variations, both the first mechanism of action and the second mechanism of action may be to inhibit the drainage of aqueous humor or to increase the drainage of aqueous humor using one or more of the trabecular canalicular pathway and the uveoscleral pathway. In some variations, the first mechanism of action and the second mechanism of action may be increased drainage of the aqueous humor, however, the first mechanism of action may be increased drainage via the trabecular canalicular pathway and the second mechanism of action may be increased drainage via the uveoscleral pathway. In some variations, the first implant may contain a drug for treating or alleviating one or more symptoms of glaucoma (e.g., by inhibiting the aqueous humor, increasing drainage of the aqueous humor using the trabecular canalicular pathway, increasing drainage of the aqueous humor using the uveoscleral pathway), or a condition of the retina, lens, cornea, uvea, vitreous, iris, ciliary body, sclera, or ocular surface, and the second implant may contain a drug for treating or alleviating one or more symptoms of glaucoma, or a condition of the retina, lens, cornea, uvea, vitreous, iris, ciliary body, sclera, or ocular surface. For example, one or more first implants (which may be a first subset of implants in a formulation of implants, or a first implant formulation) and one or more second implants (which may be a second subset of implants in a formulation of implants, or a second implant formulation) may each contain a drug for treating or alleviating one or more symptoms of glaucoma, and the drugs may be the same drug (or combination of drugs) or different drugs (or different combinations of drugs). In some variations, to reduce intraocular pressure, for example to treat glaucoma, the first mechanism of action may be blocking beta-2-adrenergic receptors (e.g., using timolol), and the second mechanism of action may be inhibiting carbonic anhydrase (e.g., using brinzolamide or dorzolamide). In other variations, to reduce intraocular pressure, for example to treat glaucoma, the first mechanism of action may be blocking beta-2-adrenergic receptors (e.g., using timolol), and the second mechanism of action may be administering a prostaglandin analog or prostamide analog (e.g., using latanoprost or bimatoprost).In other variations, to reduce intraocular pressure, for example, to treat glaucoma, the first mechanism of action may be blocking beta-2-adrenergic receptors (e.g., using timolol), and the second mechanism of action may be inhibiting rho kinase (e.g., using rosudil or nesudil). In other variations, to reduce intraocular pressure, for example, to treat glaucoma, the first mechanism of action may be administering a prostaglandin analog or prostamide analog (e.g., using latanoprost or bimatoprost), and the second mechanism of action may be inhibiting rho kinase (e.g., using rosudil or nesudil). In another example, one or more first implants (which may be a first subset of implants in a formulation of implants, or a first implant formulation) may contain a drug for treating or alleviating one or more symptoms of glaucoma, and one or more second implants (which may be a second subset of implants in a formulation of implants, or a second implant formulation) may contain a drug for treating or alleviating one or more symptoms of retinal disease. In some variations, one or more first implants (which can be a first subset of the implants in an implant formulation, or a first implant formulation) and one or more second implants (which can be a second subset of the implants in an implant formulation, or a second implant formulation) can each contain a drug for treating or alleviating one or more symptoms of AMD, and the drug can be the same drug (or drug combination) or a different drug (or drug combination). In another example, one or more first implants (which can be a first subset of the implants in an implant formulation, or a first implant formulation) can contain a drug for treating or alleviating one or more symptoms of glaucoma, and one or more second implants (which can be a second subset of the implants in an implant formulation, or a second implant formulation) can contain a drug for treating or alleviating one or more symptoms of AMD. In another example, one or more first implants (which may be a first subset of implants in a preparation of implants, or a first implant preparation) may contain a drug for treating or alleviating one or more symptoms of glaucoma, and one or more second implants (which may be a second subset of implants in a preparation of implants, or a second implant preparation) may contain a drug for treating or alleviating one or more symptoms of dry eye disease.

[0163] It should be understood that one or more first implants (which can be a first subset of implants, or a first implant formulation) can be advanced to a first position, and then one or more second implants (which can be a second subset of implants, or a second implant formulation) can be subsequently advanced to a second position. In some variations, a portion of a single subset of implants in an implant system can be advanced to a first position, and then one or more subsequent portions can be advanced to a second position (or a third position, a fourth position, etc.) from the same implant system. In some embodiments, a first implant or a first subset of implants can be advanced from an implant system to a first position in the eye, and the same implant system can be reloaded with additional implants or subsets to advance to one or more additional positions in the eye.

[0164] Exemplary embodiments

[0165] Embodiment I-1. A drug eluting implant for treating a condition of an eye of a subject, the drug eluting implant comprising bioerodible microspheres, wherein the drug eluting implant is configured to be implanted in the eye of the subject without a carrier.

[0166] Embodiment I-2. The drug eluting implant of embodiment I-1, wherein the bioerodible microspheres comprise a drug eluting matrix.

[0167] Embodiment I-3. The drug eluting implant of embodiment I-2, wherein the drug eluting matrix comprises a bioerodible polymer and a drug.

[0168] Embodiment I-4. A drug eluting implant according to 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).

[0169] 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.

[0170] Embodiment I-6. The drug eluting implant of any one of Embodiments I-1 to I-5, wherein the bioerodible microspheres have a diameter between about 1 μm and about 500 μm.

[0171] Embodiment I-7. The drug eluting implant of any one of Embodiments I-1 to I-6, wherein the bioerodible microspheres have a diameter between about 10 μm and about 100 μm.

[0172] Embodiment 1-8. The drug eluting implant of any one of Embodiments 1-1 to 1-7, wherein the condition of the eye is glaucoma and / or dry eye.

[0173] Embodiment 1-9. The drug eluting implant of any one of Embodiments 1-1 to 1-8, wherein the drug eluting implant is configured to be positioned in one or more of the ciliary sulcus, posterior chamber, anterior chamber, vitreous body, and subconjunctival space of the eye.

[0174] 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.

[0175] Embodiment I-11. The drug eluting implant of any one of Embodiments I-3 to I-10, wherein the drug is latanoprost, bimatoprost, travoprost, nerve growth factor, anti-VEGF antibody, or cyclosporine.

[0176] Embodiment 1-12. The drug eluting implant of any one of Embodiments 1-3 to 1-11, wherein the bioerodible microspheres contain between about 1 μg and about 500 μg of the drug.

[0177] Embodiment 1-13. The drug eluting implant of any one of Embodiments 1-3 to 1-12, wherein the bioerodible microspheres contain between about 5 μg and about 100 μg of the drug.

[0178] Embodiment 1-14. The drug eluting implant of any one of Embodiments 1-3 to 1-13, wherein the drug is delivered to the eye at a rate of between about 1 ng / day and about 3000 ng / day.

[0179] Embodiment 1-15. The drug eluting implant of any one of Embodiments 1-3 to 1-14, wherein the drug is delivered to the eye at a rate between about 5 ng / day and about 2000 ng / day.

[0180] Embodiment 1-16. A drug eluting implant according to any one of Embodiments 1-3 to 1-15, wherein the drug is delivered 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.

[0181] Embodiment 1-17. The drug eluting implant of any one of Embodiments 1-1 to 1-16, wherein the microspheres comprise an imaging agent.

[0182] Embodiment 1-18. The drug eluting implant of embodiment 1-17, wherein the imaging agent is one or more of a dye, a radiolabel, and a fluorescent marker.

[0183] Embodiment 1-19. The drug eluting implant of Embodiments 1-17 to 1-18, wherein the imaging agent is fluorescein.

[0184] Embodiment 1-20. A drug eluting implant according to any one of Embodiments 1-17 to 1-19, wherein the microspheres comprise a drug and an imaging agent, and wherein the microspheres are configured to deliver the drug and the imaging agent into the eye at the same rate.

[0185] Embodiment 1-21. A method for treating a condition of an eye in a subject, the method comprising:

[0186] 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

[0187] wherein a drug is delivered to said eye from said at least one drug eluting implant,

[0188] To alleviate the symptoms of the condition in the eye.

[0189] Embodiment 1-22. The method of embodiment 1-21, wherein the condition of the eye is glaucoma and / or dry eye.

[0190] Embodiment 1-23. The method of embodiment 1-21 or 1-22, wherein the at least one drug eluting implant is delivered from the at least one drug eluting implant to the ciliary sulcus, posterior chamber, anterior chamber, vitreous body, and subconjunctival space of the eye.

[0191] Embodiment 1-24. The method of any one of Embodiments 1-21 to 1-23, further comprising: advancing the at least one drug eluting implant in an implant system to an implantation site in the eye.

[0192] Embodiment 1-25. The method of embodiment 1-24, wherein the advancing step comprises advancing the at least one drug eluting implant using a push rod.

[0193] Embodiment 1-26. The method of embodiment 1-24 or 1-25, wherein the implant system comprises a needle or a cannula, and the method further comprises: piercing tissue of the eye with the needle or the cannula.

[0194] Embodiment 1-27. The method of any one of Embodiments 1-24 to 1-26, 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.

[0195] Embodiment 1-28. The method of embodiment 1-27, wherein more than one drug eluting implant is released from the implant system.

[0196] Embodiment 1-29. A method according to embodiment 1-28, wherein operating the actuator advances the push rod.

[0197] Embodiment 1-30. The method of any one of Embodiments 1-27 to 1-29, wherein the actuator comprises one or more of a button, a knob, a slider, a lever, and a wheel.

[0198] Embodiment 1-31. The method of any one of Embodiments 1-21 to 1-30, wherein the at least one drug eluting implant is advanced and / or positioned using one or more of a collar, a slit lamp, and a surgical microscope.

[0199] Embodiment 1-32. The method of any one of Embodiments 1-21 to 1-31, wherein the at least one drug eluting implant delivers a glaucoma medication and / or a dry eye medication.

[0200] Embodiment 1-33. The method of any one of Embodiments 1-21 to 1-32, wherein the at least one drug eluting implant delivers a prostaglandin or a prostaglandin analog.

[0201] Embodiment 1-34. The method of any one of Embodiments 1-21 to 1-33, wherein the at least one drug eluting implant delivers latanoprost, bimatoprost, travoprost, nerve growth factor, anti-VEGF antibody, or cyclosporine.

[0202] Embodiment 1-34. The method of any one of Embodiments 1-21 to 1-34, 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 in the eye.

[0203] Embodiment 1-36. The method of embodiment 1-35, 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.

[0204] Embodiment 1-37. The method of embodiment 1-36, wherein the first mechanism of action and the second mechanism of action are the same.

[0205] Embodiment 1-38. The method of embodiment 1-36, wherein the first mechanism of action is different from the second mechanism of action.

[0206] Embodiment 1-39. The method of any one of Embodiments 1-34 to 1-38, wherein the first drug eluting implant is implanted in a first site in the eye and the second drug eluting implant is implanted in a second site in the eye.

[0207] Embodiment 1-40. The method of any one of Embodiments 1-34 to 1-38, wherein the first drug eluting implant and the second drug eluting implant are implanted in the same site in the eye.

[0208] Embodiment 1-41. The method of any one of Embodiments 1-21 to 1-40, wherein the at least one drug eluting implant comprises a plurality of microspheres, and wherein the plurality of microspheres are implanted in the ciliary sulcus of the eye.

[0209] Embodiment II-1. A dry implant formulation for treating a condition of an eye of a subject, the dry implant formulation comprising a plurality of drug eluting particulate implants, wherein the dry implant formulation is configured to be implanted in the eye of the subject without a carrier.

[0210] Embodiment II-2. The dry implant formulation of embodiment II-1, wherein each microparticle implant of the plurality of microparticle implants comprises a drug eluting matrix.

[0211] Embodiment II-3. The dry implant formulation of Embodiment II-2, wherein the drug eluting matrix comprises a bioerodible polymer and a drug.

[0212] Embodiment II-4. A drug eluting implant according to any one of Embodiments II-1 to II-3, wherein the microparticle implant comprises poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA), poly-ε-caprolactone (PCA), or poly(glycolic acid) (PGA).

[0213] Embodiment II-5. The drug eluting implant of any one of Embodiments II-1 to II-4, wherein the microparticle implant comprises a mixture of two bioerodible polymers.

[0214] Embodiment II-6. The dry implant formulation of any one of Embodiments II-1 to II-5, wherein each microparticle implant of the plurality of microparticle implants has a diameter between about 1 μm and about 500 μm.

[0215] Embodiment II-7. The dry implant formulation of any one of Embodiments II-1 to II-6, wherein each microparticle implant of the plurality of microparticle implants has a maximum linear dimension of between about 10 μm and about 100 μm.

[0216] Embodiment II-8. The dry implant formulation of any one of Embodiments II-1 to II-7, wherein the condition of the eye is glaucoma and / or dry eye.

[0217] 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 ciliary sulcus, posterior chamber, anterior chamber, vitreous body, subtenon space, and subconjunctival space of the eye.

[0218] 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.

[0219] 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.

[0220] Embodiment II-12. The dry implant formulation of any one of Embodiments II-3 to II-11, wherein the plurality of microparticle implants comprises a total of between about 5 μg and about 15 mg of the drug.

[0221] Embodiment II-13. The dry implant formulation of any one of Embodiments II-3 to II-12, wherein the plurality of microparticle implants collectively comprise between about 10 μg and about 10 mg of the drug.

[0222] Embodiment II-14. The dry implant formulation of any one of Embodiments II-3 to II-13, wherein the plurality of microparticle implants are collectively configured to deliver the drug to the eye at a rate between about 1 ng / day and about 50 μg / day.

[0223] Embodiment II-15. The dry implant formulation of any one of Embodiments II-3 to II-14, wherein the plurality of microparticle implants are collectively configured to deliver the drug to the eye at a rate between about 5 ng / day and about 2000 ng / day.

[0224] 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, 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.

[0225] Embodiment II-17. The dry implant formulation of any one of Embodiments II-1 to II-16, wherein at least a subset of the plurality of microparticle implants comprises an imaging agent.

[0226] Embodiment II-18. The dry implant formulation of embodiment II-17, wherein the imaging agent is one or more of a dye, a radiolabel, and a fluorescent marker.

[0227] Embodiment II-19. The dry implant formulation of Embodiments II-17 to II-18, wherein the imaging agent is fluorescein.

[0228] Embodiment II-20. The dry implant formulation of any one of Embodiments II-17 to II-19, wherein each of the plurality of microparticle implants comprises a drug and an imaging agent, and wherein each of the plurality of microparticle implants is configured to deliver the drug and the imaging agent into the eye at the same rate.

[0229] Embodiment II-21. The dry implant formulation of any one of Embodiments II-1 to II-20, wherein the dry implant formulation comprises a first microparticle implant comprising a first drug and a second microparticle implant comprising a second, different drug.

[0230] Embodiment II-22. The dry implant formulation of Embodiment II-21, wherein the first drug is a beta-adrenergic blocking agent.

[0231] Embodiment II-23. The dry implant formulation of embodiment II-22, wherein the beta-adrenergic blocking agent is timolol.

[0232] Embodiment II-24. The dry implant formulation of embodiment II-23, wherein the timolol is timolol maleate or timolol hemihydrate.

[0233] 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.

[0234] Embodiment II-26. The dry implant formulation of embodiment II-25, wherein the carbonic anhydrase inhibitor is dorzolamide or brinzolamide.

[0235] Embodiment II-27. The dry implant formulation of embodiment II-26, wherein the dorzolamide is dorzolamide hydrochloride or dorzolamide base.

[0236] Embodiment II-28. The dry implant formulation of Embodiments II-22 to II-24, wherein the second drug is a prostaglandin analog or a prostamide analog.

[0237] 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.

[0238] Embodiment II-30. The dry implant formulation of embodiment II-28, wherein the second drug is the prostaglandin analog, and the prostaglandin analog is latanoprost.

[0239] Embodiment II-31. The dry implant formulation of Embodiments II-22 to II-24, wherein the second drug is a rho kinase inhibitor.

[0240] Embodiment II-32. The dry implant formulation of embodiment II-31, wherein the rho kinase inhibitor is rosudil or nesudil.

[0241] Embodiment II-33. The dry implant formulation of Embodiment II-21, wherein the first drug is a prostaglandin analog or a prostamide analog.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] Embodiment II-37. The dry implant formulation of embodiment II-36, wherein the rho kinase inhibitor is rosudil or nesudil.

[0246] Embodiment II-38. A dry implant formulation for treating glaucoma in an eye of a subject, the dry implant formulation 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 in the subtenon's space in the eye of the subject without a carrier.

[0247] Embodiment II-39. The dry implant formulation of any one of Embodiments II-1 to II-38, wherein each particulate implant of the plurality of particulate implants is a microsphere.

[0248] Embodiment II-40. The dry implant formulation of any one of Embodiments II-1 to II-39, wherein each microparticle implant of the plurality of microparticle implants comprises a bioerodible polymer and at least a majority of the microspheres of the plurality of microspheres have been heated to above the glass transition temperature of the bioerodible polymer.

[0249] Embodiment II-41. The dry implant formulation according to any one of Embodiments II-1 to II-40, further comprising a binder.

[0250] Embodiment II-42. The dry implant formulation of embodiment II-41, wherein the binder is selected from the group consisting of sugars, gelatin, collagen, polyethylene glycol (PEG), starch, cellulose, alginate, and chitosan.

[0251] 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.

[0252] 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.

[0253] Embodiment II-45. A system for treating a condition of an eye of a subject, the system comprising: a cannula comprising a lumen and a distal tip, the 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 lumen of the cannula without a carrier.

[0254] Embodiment II-46. The system of embodiment II-44, wherein the dry implant formulation is malleable and does not readily dissociate into individual implants.

[0255] Embodiment II-47. The system of Embodiment II-45 or II-46, wherein the distal tip of the cannula has a beveled edge.

[0256] Embodiment II-48. A system according to embodiment II-45 or II-46, wherein the cannula includes a proximal portion and a distal portion terminating at a distal tip, wherein the distal tip is tapered and has a smaller outer diameter than the proximal portion.

[0257] Embodiment II-49. The system of any one of Embodiments II-45 to II-48, wherein the cannula is transparent.

[0258] Embodiment II-50. The system of any one of Embodiments II-45 to II-49, further comprising: a push rod slidably positionable within the lumen, wherein a distal tip of the push rod contacts at least a portion of the dry implant formulation.

[0259] Embodiment II-51. The system of embodiment II-50, further comprising: a handle connected to the cannula, wherein the handle is sized and shaped to comfortably hold and manipulate the cannula.

[0260] Embodiment II-52. A system according to embodiment II-51, wherein the handle includes an actuator that is operatively connected to the push rod, the cannula, or both, wherein engaging the actuator moves the push rod, the cannula, or both.

[0261] Embodiment II-53. A system according to 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 the rotational movement of the wheel into linear motion of the push rod.

[0262] Embodiment II-54. A system according to embodiment II-53, wherein the drive assembly includes: a first pinion, which is coaxially or tangentially attached to the wheel; an idler gear, which is engaged with the first pinion; and a first slender member, which is connected to the push rod, wherein the first slender member is engaged with the idler gear to convert the rotational movement of the wheel into a first linear movement of the first slender member.

[0263] Embodiment II-55. A system according to embodiment II-54, wherein the first slender member is a first linear gear.

[0264] Embodiment II-56. A system according to embodiment II-53, wherein the actuator is operatively connected to the cannula and is operable to move the cannula relative to the handle and the push rod to retract the distal opening of the cannula toward the end of the push rod.

[0265] Embodiment II-57. A system according to 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 the rotational movement of the wheel into linear motion of the cannula.

[0266] Embodiment II-58. A system according to embodiment II-57, wherein the drive assembly includes: a second pinion, which is coaxially or tangentially attached to the wheel; and a second slender member, which is connected to the cannula and engages with the pinion to convert the rotational movement of the wheel into a second linear movement of the second slender member.

[0267] Embodiment II-59. A system according to embodiment II-58, wherein the second slender member is a second linear gear.

[0268] Embodiment II-60. A system according to embodiment II-53, wherein the actuator is operatively connected to the push rod and is capable of operating to: move the push rod relative to the handle and the cannula to advance the end of the push rod toward the distal opening of the cannula; and move the cannula relative to the handle and the push rod to retract the distal opening of the cannula toward the end of the push rod.

[0269] Embodiment II-61. A system according to 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 movement of the wheel into linear motion of the push rod and opposite linear motion of the cannula.

[0270] Embodiment II-62. A system according to embodiment II-61, wherein the drive assembly includes: a first pinion, the first pinion being coaxially or tangentially attached to the wheel; an idler gear, the idler gear being engaged with the first pinion; a first slender member, the first slender member being connected to the push rod, the first slender member being engaged with the idler gear to convert the rotational movement of the wheel into a first linear movement of the first slender member; a second pinion, the second pinion being coaxially or tangentially attached to the wheel; and a second slender member, the second slender member being connected to the cannula, the second slender member being engaged with the pinion to convert the rotational movement of the wheel into a second linear movement of the second slender member,

[0271] Wherein the first linear movement and the second linear movement are in opposite directions.

[0272] Embodiment II-63. A method of forming a system for treating a condition of an eye of a subject, the method comprising: inserting a dry implant formulation comprising a plurality of drug-eluting microparticle implants into a lumen of a cannula, wherein the cannula is configured for insertion into a target location in the eye, and wherein the dry implant formulation does not comprise a carrier; heating and / or compressing the dry implant formulation to enhance adhesion between the plurality of microparticle implants.

[0273] Embodiment II-64. A method according to embodiment II-63, the method comprising: heating the cannula, wherein each of the plurality of microparticle implants comprises a bioerodible polymer, and at least a majority of the plurality of microparticle implants are heated to or above the glass transition temperature of the bioerodible polymer, thereby enhancing the adhesion of at least a portion of the microparticle implants to each other.

[0274] Embodiment II-65. The method of embodiment II-64, comprising compressing the dry implant formulation while heating the majority of the plurality of microparticle implants to above the glass transition temperature of the bioerodible polymer.

[0275] Embodiment II-66. The method of any one of Embodiments II-63 to II-65, wherein the dry implant formulation comprises a binder.

[0276] Embodiment II-67. The method of embodiment II-66, wherein the binder is selected from the group consisting of: sugars, gelatin, collagen, polyethylene glycol (PEG), starch, cellulose, alginate, and chitosan.

[0277] Embodiment II-68. The method of embodiment II-67, wherein the binder is a sugar, and the sugar is glucose, sucrose, lactose, or fructose.

[0278] Embodiment II-69. The method of embodiment II-68, wherein the dry implant formulation is compressed to enhance adhesion between the plurality of microparticle implants and the binder.

[0279] Embodiment II-70. A method for treating a condition of an eye of a subject, the method comprising: implanting at least one drug eluting implant in the eye of the subject, wherein the at least one implant is implanted without a carrier; and wherein a drug is delivered from the at least one drug eluting implant to the eye to alleviate symptoms of the condition of the eye.

[0280] Embodiment II-71. The method of embodiment II-70, wherein the condition of the eye is glaucoma and / or dry eye.

[0281] 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 ciliary sulcus, posterior chamber, anterior chamber, vitreous body, subtenon space, and subconjunctival space of the eye.

[0282] Embodiment II-73. The method of any one of Embodiments II-70 to II-72, further comprising: advancing the at least one drug eluting implant in an implant system to an implantation site in the eye.

[0283] Embodiment II-74. The method of Embodiment II-73, wherein the advancing step comprises advancing the at least one drug eluting implant using a push rod.

[0284] Embodiment II-75. The method of embodiment II-73, wherein the implant system comprises a cannula, the at least one implant being housed in the cannula, and the method further comprises: piercing tissue of the eye using the cannula.

[0285] 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 the at least one drug eluting implant from the implant system.

[0286] Embodiment II-77. The method of any one of Embodiments II-74 to II-76, wherein more than one drug eluting implant is released from the implant system.

[0287] Embodiment II-78. A method according to any one of Embodiments II-74 to II-77, wherein operating the actuator advances the push rod.

[0288] 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.

[0289] Embodiment II-80. The method of any one of Embodiments II-70 to II-79, wherein the at least one drug eluting implant is advanced and / or positioned using one or more of a collar, a slit lamp, and a surgical microscope.

[0290] Embodiment II-81. The method of any one of Embodiments II-70 to II-80, wherein the at least one drug eluting implant delivers a glaucoma medication and / or a dry eye medication.

[0291] Embodiment II-82. The method of any one of Embodiments II-70 to II-81, wherein the at least one drug eluting implant delivers a prostaglandin or a prostaglandin analog.

[0292] Embodiment II-83. The method of any one of Embodiments II-70 to II-82, wherein the at least one drug eluting implant delivers a beta-adrenergic blocking agent; a carbonic anhydrase inhibitor, a prostaglandin analog, an immunosuppressant, a rho-kinase inhibitor, or a combination thereof.

[0293] Embodiment II-84. The method of any one of Embodiments II-70 to II-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 in the eye.

[0294] 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.

[0295] Embodiment II-86. The method of embodiment II-85, wherein the first mechanism of action and the second mechanism of action are the same.

[0296] Embodiment II-87. The method of Embodiment II-86, wherein the first mechanism of action is different from the second mechanism of action.

[0297] Embodiment II-88. The method of any one of Embodiments II-84 to II-87, wherein the first drug eluting implant is implanted in a first site in the eye and the second drug eluting implant is implanted in a second site in the eye.

[0298] 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 in the same site in the eye.

[0299] Embodiment II-90. The method of any one of Embodiments II-70 to II-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.

[0300] Embodiment II-91. A method for treating a condition of an eye of a subject, the method comprising: advancing a distal portion of a cannula of an implant system toward a target location in the eye, wherein the cannula comprises a lumen and a distal tip configured to pierce tissue, and wherein the cannula contains a dry implant formulation comprising a plurality of drug-eluting microparticle implants in the absence of a carrier; and actuating the implant system such that the dry implant formulation is released from the distal portion of the cannula into the target location.

[0301] Embodiment II-92. The method of embodiment II-91, wherein each microparticle implant of the plurality of microparticle implants comprises a drug selected from the group consisting of: a beta-adrenergic blocking agent; a carbonic anhydrase inhibitor, a prostaglandin analog, an immunosuppressant, a rho kinase inhibitor, or a combination thereof.

[0302] Embodiment II-93. A method according to embodiment II-91 or II-92, wherein the target location in the eye is the ciliary sulcus, the posterior chamber, the anterior chamber, the vitreous body, the subtenon space, or the subconjunctival space.

[0303] Embodiment II-94. The method of any one of Embodiments II-91 to II-93, wherein the dry implant formulation delivers the drug to the target site at a rate of between about 1 ng / day and about 50 μg / day after being released into the target site.

[0304] Embodiment II-95. The method of any one of Embodiments II-91 to II-93, wherein the dry implant formulation delivers the drug to the eye at a rate of between about 5 ng / day and about 2000 ng / day after being released into the target site.

[0305] 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 over a period of time after being released into the target location, 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.

[0306] 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 microparticle implants comprising a first drug and a second subset of microparticle implants comprising a second, different drug.

[0307] Embodiment II-98. The method of embodiment II-96, wherein the condition of the eye is glaucoma or increased intraocular pressure.

[0308] Embodiment II-99. The method of embodiment II-97 or II-98, wherein the first drug is a beta-adrenergic blocking agent.

[0309] Embodiment II-100. The method of embodiment II-99, wherein the beta-adrenergic blocking agent is timolol.

[0310] Embodiment II-101. The method of embodiment II-100, wherein the timolol is timolol maleate or timolol hemihydrate.

[0311] Embodiment II-102. The method of any one of Embodiments II-99 to II-101, wherein the second drug is a carbonic anhydrase inhibitor.

[0312] Embodiment II-103. The method of embodiment II-102, wherein the carbonic anhydrase inhibitor is dorzolamide or brinzolamide.

[0313] Embodiment II-104. The method of embodiment II-103, wherein the dorzolamide is dorzolamide hydrochloride or dorzolamide base.

[0314] 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.

[0315] 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.

[0316] Embodiment II-107. The method of embodiment II-105, wherein the second drug is the prostaglandin analog, and the prostaglandin analog is latanoprost.

[0317] Embodiment II-108. The method of any one of Embodiments II-99 to II-101, wherein the second drug is a rho kinase inhibitor.

[0318] Embodiment II-109. The method of embodiment II-108, wherein the rho kinase inhibitor is rosudil or nesudil.

[0319] Embodiment II-110. The method of embodiment II-97 or II-98, wherein the first drug is a prostaglandin analog or a prostamide analog.

[0320] 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.

[0321] Embodiment II-112. The method of embodiment II-111, wherein the first drug is the prostaglandin analog, and the prostaglandin analog is latanoprost.

[0322] Embodiment II-113. The method of any one of Embodiments II-110 to II-112, wherein the second drug is a rho kinase inhibitor.

[0323] Embodiment II-114. The method of embodiment II-113, wherein the rho kinase inhibitor is rosudil or nesudil.

[0324] Example

[0325] Example 1: Dry subconjunctival delivery of drug-eluting implants formulated with prostaglandins or cyclosporine

[0326] The implant system, loaded with carrier-free drug-eluting microspheres, each containing at least one prostaglandin or cyclosporine, is removed from its sterile packaging and placed on a sterile surface. The subject's eye and periocular area are treated with an antimicrobial agent. The eye is then draped with a sterile drape in the typical manner of ophthalmic surgery, and the surgical microscope and lid speculum are appropriately positioned and placed. The conjunctiva is grasped with conjunctival clamps.

[0327] The implant system needle is advanced into the subconjunctival space under direct microscopic visualization. An actuator (button, slider, lever, and / or wheel) on the device handle is activated. A pusher inside the needle moves distally toward the distal end of the needle and pushes a predetermined number of microspheres out of the needle into the subconjunctival space. This is visualized using a microscope. Visualization can also be performed using a slit lamp, a magnifying glass, 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.

[0328] Example 2: Dry delivery of a drug-eluting implant formulated with prostaglandins into the posterior chamber / ciliary sulcus

[0329] The implant 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 antimicrobial agent. The eye is then draped with a sterile drape in a manner typical of ophthalmic surgery, and the surgical microscope and eyelid speculum are appropriately positioned and placed.

[0330] Under direct microscopic visualization, the implant system needle is advanced through the cornea, near the limbus, into the anterior chamber. The end of the needle is advanced to the pupil and just past the pupillary ciliary region. The needle can be curved or straight. An actuator (button, slider, rod, or wheel) on the device handle is activated. The push rod inside the needle moves forward / distal to the end of the needle and removes a predetermined amount of microspheres from the needle into the posterior chamber. This is visualized using a microscope. Alternatively, a soft, non-invasive catheter is inserted into the posterior chamber before implanting a pre-dosed dose of microspheres. Visualization can also be performed using a slit lamp, a magnifying glass, 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.

[0331] Example 3: Dry subconjunctival delivery using a drug-eluting implant formulated with timolol and dorzolamide

[0332] An implant system comprising: a cannula loaded with carrier-free drug-eluting microspheres (e.g., a dry implant formulation) and a handle comprising a housing and an actuator and coupled 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 preloaded microspheres contains timolol (e.g., timolol maleate or timolol hemihydrate), and a second subset of preloaded microspheres contains dorzolamide (e.g., dorzolamide hydrochloride, dorzolamide base) or brinzolamide. The first and second subsets of microspheres can be combined in a dry implant formulation comprising two subsets of implants in a single implant unit. The subject's eye and periocular area are treated with an antimicrobial agent. The eye is then sterilized and draped in a manner typical of ophthalmic surgery, and a surgical microscope (or slit lamp) and a lid speculum are appropriately positioned and placed. The conjunctiva is grasped using conjunctival clamps.

[0333] The cannula of the implant system is advanced under direct microscope visualization, thereby penetrating the conjunctiva and entering the target position in the eye, which can be the subconjunctival space or the subtenon space. The actuator (button, slider, rod and / or wheel) on the handle is activated. The push rod inside the cannula moves distally toward the distal end of the cannula and releases the preloaded microspheres from the cannula into the target position. The microsphere release is visualized using a microscope or a slit lamp. Visualization can also be performed using a slit lamp, a magnifying glass or the naked eye. The cannula is then withdrawn from the conjunctiva. Antibiotic drops are applied to the eye and the eyelid speculum is removed.

Claims

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

2. The dry implant formulation of claim 1, wherein each of the plurality of microparticle 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. The drug eluting implant according to any one of claims 1 to 3, wherein the microparticle 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 according to any one of claims 1 to 4, wherein the microparticle implant comprises a mixture of two bioerodible polymers.

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

7. The dry implant formulation of any one of claims 1 to 6, wherein each particulate implant of the plurality of particulate implants has a maximum linear dimension of between about 10 μm and about 100 μm.

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

9. The dry implant formulation of any one of claims 1 to 8, wherein the dry implant formulation is configured to be positioned in one or more of the ciliary sulcus, posterior chamber, anterior chamber, vitreous body, subtenon's space, and subconjunctival space of the eye.

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 beta-adrenergic blocker, a carbonic anhydrase inhibitor, a nerve growth factor, an anti-VEGF antibody, or cyclosporine.

12. The dry implant formulation of any one of claims 3 to 11, wherein the plurality of microparticle implants contain a total of between about 5 μg and about 15 mg of the drug.

13. The dry implant formulation of any one of claims 3 to 12, wherein the plurality of microparticle implants collectively comprise between about 10 μg and about 10 mg of the drug.

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

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

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 the plurality of microparticle implants comprises an imaging agent.

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

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

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

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

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

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

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

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

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

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. The dry implant formulation of claim 28, wherein the second drug is the 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. The dry implant formulation of claim 31, wherein the rho kinase inhibitor is rosudil or nesudil.

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

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. 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. The dry implant formulation of claim 36, wherein the rho kinase inhibitor is rosudil or nesudil.

38. A dry implant formulation for treating glaucoma in an eye of a subject, the dry implant formulation 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 in the subtenon's space in the eye of the subject without a carrier.

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

40. The dry implant formulation of any one of claims 1 to 39, wherein each microparticle implant of the plurality of microparticle implants comprises a bioerodible polymer, and at least a majority of the microspheres of the plurality of microspheres have been heated to 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. The dry implant formulation of claim 41, wherein the binder is selected from the group consisting of sugars, gelatin, collagen, polyethylene glycol (PEG), starch, cellulose, alginate, and chitosan.

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

44. 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. A system for treating a condition of an eye of a subject, the system comprising: a cannula comprising a lumen 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 lumen of the cannula without a carrier.

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

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

48. The system of claim 45 or claim 46, wherein the cannula comprises a proximal portion and a distal portion terminating at a distal tip, wherein the distal tip is tapered and has 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. The system of any one of claims 45 to 49, further comprising: A pushrod is slidably positioned within the lumen, wherein a distal tip of the pushrod contacts at least a portion of the dry implant formulation.

51. The system of claim 50, further comprising: A handle is connected to the cannula, wherein the handle is sized and shaped to comfortably grasp and manipulate the cannula.

52. The system of claim 51 , wherein the handle comprises an actuator operatively coupled to the pushrod, the cannula, or both, wherein engaging the actuator moves the pushrod, the cannula, or both.

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 movement of the wheel into linear motion of the push rod.

54. The system of claim 53, wherein the drive assembly comprises: a first pinion coaxially or tangentially attached to the wheel; an idler gear engaged with the first pinion; and A first elongated member is connected to the push rod, wherein the first elongated member engages the idler gear to convert the rotational movement of the wheel into a first linear movement of the first elongated member.

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

56. The system of claim 53, wherein the actuator is operatively coupled to the cannula and operable to move the cannula relative to the handle and the push rod to retract the distal opening of the cannula toward the tip of the push rod.

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 movement of the wheel into linear motion of the cannula.

58. The system of claim 57, wherein the drive assembly comprises: a second pinion coaxially or tangentially attached to the wheel; and A second elongated member is connected to the cannula, the second elongated member engaging the pinion to convert the rotational movement of the wheel into a second linear movement of the second elongated member.

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

60. The system of claim 53, wherein the actuator is operatively coupled to the push rod and is operable to: moving the push rod relative to the handle and the cannula to advance the distal end of the push rod toward the distal opening of the cannula; and The cannula is moved relative to the handle and the push rod to retract the distal opening of the cannula toward the distal end of the push rod.

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 movement of the wheel into linear motion of the push rod and opposite linear motion of the cannula.

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

63. A method of forming a system for treating a condition of an eye of a subject, the method comprising: inserting a dry implant formulation comprising a plurality of drug eluting microparticle implants into a lumen of a cannula, wherein the cannula is configured for insertion into a target location in an eye, and wherein the dry implant formulation does not comprise a carrier; The dry implant formulation is heated and / or compressed to enhance adhesion between the plurality of microparticle implants.

64. The method of claim 63, comprising: The cannula is heated, wherein each of the plurality of particulate implants comprises a bioerodible polymer and at least a majority of the plurality of particulate implants are heated to or above a glass transition temperature of the bioerodible polymer, thereby enhancing adhesion of at least a portion of the particulate implants to each other.

65. The method of claim 64, comprising: The dry implant formulation is compressed while the majority of the plurality of microparticle implants are heated above the glass transition temperature of the bioerodible polymer.

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

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

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

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

70. A method for treating a condition of an eye of 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; and wherein a drug is delivered from the at least one drug eluting implant to the eye to alleviate symptoms of the condition in the eye.

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

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

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

74. The method of claim 73, wherein the advancing step comprises advancing the at least one drug eluting implant using a push rod.

75. The method of claim 73, wherein the implant system comprises a cannula, the at least one implant being housed within the cannula, and the method further comprising: The cannula is used to pierce tissue of the eye.

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

77. The method of any one of claims 74 to 76, wherein more than one drug eluting implant is released from the implant system.

78. A method according to any one of claims 74 to 77, wherein operating the actuator advances the push rod.

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. 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 collar, a slit lamp, and a surgical microscope.

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 medication.

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

84. The method of any one of claims 70 to 83, wherein the at least one drug eluting implant comprises a first drug eluting implant, and the method further comprises: A second drug eluting implant is implanted in the eye.

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

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

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

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

90. The method of any one of claims 70 to 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. A method for treating a condition of an eye of a subject, the method comprising: advancing a distal portion of a cannula of an implant system toward a target location in the eye, wherein the cannula comprises a lumen and a distal tip configured to penetrate tissue, and wherein the cannula contains a dry implant formulation comprising a plurality of drug-eluting microparticle implants in the absence of a carrier; The implant system is actuated to release the dry implant formulation from the distal portion of the cannula into the target location.

92. The method of claim 91, wherein each microparticle implant of the plurality of microparticle implants comprises a drug selected from the group consisting of: a beta-adrenergic blocking agent; a carbonic anhydrase inhibitor, a prostaglandin analog, an immunosuppressant, a rho kinase inhibitor, or a combination thereof.

93. The method of claim 91 or claim 92, wherein the target location in the eye is the ciliary sulcus, the posterior chamber, the anterior chamber, the vitreous body, the subtenon space, or the subconjunctival space.

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

95. 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 between about 5 ng / day and about 2000 ng / day after being released into the target site.

96. The method of any one of claims 91 to 95, wherein a dry implant formulation delivers the drug to the eye over a period of time after being released into the target location, 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.

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

98. The method of claim 96, wherein the condition of the eye is glaucoma or increased intraocular pressure.

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

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

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

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

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

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

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

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

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

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

109. The method of claim 108, wherein the rho kinase inhibitor is rosudil or nesudil.

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

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

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

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

114. The method of claim 113, wherein the rho kinase inhibitor is rosudil or nesudil.

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