Ophthalmic implant

Abstract

The present invention relates generally to compositions and methods for treating an animal or human patient in need of treatment of an ophthalmic disease or disorder involving oxidative stress and treatments employing an ophthalmic implant containing (2R, 2R ')-3, 3'-disulfanediylbis (2-acetamidopropanamide) (diNACA), wherein such ophthalmic diseases or conditions include, but are not limited to, cataract, cataract in a subject not suffering from diabetes, loss of corneal endothelial cells, age-related macular degeneration, presbyopia, retinitis pigmentosa (RP), Usher syndrome, Stargardt syndrome, glaucoma, diabetic retinopathy, and / or retinal disease.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63,358,946, filed on July 7, 2022, the entire contents of which are incorporated herein by reference.

[0003] Statement on Federally Sponsored Research

[0004] none.

[0005] Technical field of the invention

[0006] The present invention generally relates to identifying an animal or human patient in need of treatment for an ophthalmic disease or condition involving oxidative stress and treating with an ophthalmic implant containing (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropionamide) (diNACA), such ophthalmic diseases or conditions including, but not limited to, cataracts, cataracts in subjects without diabetes, corneal endothelial cell loss, age-related macular degeneration, presbyopia, retinitis pigmentosa (RP), Usher syndrome, Stargardt syndrome, glaucoma, diabetic retinopathy, and / or other retinal diseases.

[0007] Background of the Invention

[0008] Age-related macular degeneration (AMD) is a term used to describe the loss of vision or blurring of the center of the visual field. The difficulty in detecting the early stages of AMD is the lack of symptoms, which are very progressive and may affect one or both eyes. Although all vision may not be lost, the loss of vision in the center of the visual field makes it difficult to identify objects, drive, read or perform normal activities. Generally, AMD is a disease that affects individuals in later life and becomes worse due to smoking, high blood pressure, atherosclerosis, elevated cholesterol, obesity, fat intake and exposure to sunlight. AMD also has a genetic component, because sibling studies have shown an increased recurrence ratio, and to date, at least 5 different genes have been shown to have some connection with AMD. Unfortunately, AMD is a complex disease caused by various environmental, genetic and lifestyle factors.

[0009] Clinical signs of AMD include visual field distortion, which often manifests as metamorphopsia, a type of visual distortion in which a straight grid appears wavy and parts of the grid may appear blank. Other symptoms of AMD include slow recovery of visual function due to exposure to bright light (e.g., using a light stress test), a sharp decrease in visual acuity, blurred vision, difficulty distinguishing colors, and loss of contrast sensitivity. AMD shows an accumulation process of drusen deposits between the retinal pigment epithelium and the underlying choroid in the macula. These drusen are accumulations of extracellular proteins and lipids that are thought to damage the retina over time. However, the presence of drusen does not indicate disease progression, as most people over the age of 60 have drusen without any negative effects. The various stages of AMD are known and are generally divided into early AMD, intermediate AMD, late AMD, dry (or non-exudative) AMD, atrophic (or map-like) AMD, and / or wet (or exudative) AMD. Currently, there are drugs approved for the treatment of "wet" AMD, but there are no drugs for the treatment of "dry" AMD.

[0010] Diabetic retinopathy (DR) is the leading cause of blindness worldwide, and its pathogenesis remains to be fully elucidated. Several studies have shown a close relationship between oxidative stress and DR. Zhu et al. (2012) conducted a study to investigate the effects of antioxidants on DR and the expression of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1) in retinal vessels in diabetic rats. A diabetic rat model was established by intraperitoneal injection of streptozotocin (60 mg / kg) and confirmation of high serum glucose levels in the animals. The antioxidant N-acetylcysteine ​​was administered to diabetic rats to induce an antioxidant response, and the rats were sacrificed at 3 and 5 months. The ultrastructure of retinal vascular tissue was observed under a transmission electron microscope, and the pathology of retinal capillaries was examined using retinal vascular digestion preparations. Changes in the expression of VEGF and ICAM-1 were examined by immunofluorescence; and the content of reactive oxygen species in the retina was detected using the dichlorofluorescein assay. Compared with normal rats, diabetic rats showed significant retinopathy under both electron and light microscopy, accompanied by increased levels of reactive oxygen species in the retina; N-acetylcysteine ​​treatment alleviated the pathological changes and also reduced reactive oxygen species, most significantly at 5 months. The expression of VEGF and ICAM-1 was significantly upregulated in the retinal vessels of diabetic rats, and this upregulation was attenuated by N-acetylcysteine ​​treatment. The expression of both factors returned to basal levels after 5 months of N-acetylcysteine ​​treatment. Long-term N-acetylcysteine ​​treatment may play a protective role in diabetic retinopathy by downregulating the expression of VEGF and ICAM-1 and reducing the content of reactive oxygen species in the retinal vascular tissue of diabetic rats (Zhu et al. 2012).

[0011] Vitreoretinal eye surgery consists of a group of procedures performed deep within the eye with lasers or conventional surgical instruments. The goal of vitreoretinal surgery is to protect, restore, and enhance vision in individuals with one of a range of blinding conditions. In the United States, vitreoretinal surgery occurs at an incidence of approximately 225,000 per year. Although vitreoretinal surgery is effective, it is associated with a variety of undesirable complications. By far the most prevalent complication is cataract formation (opaqueness or clouding of the lens that focuses light onto the retina). After vitreoretinal surgery, 80% of patients develop noticeable cataracts within the first year (Belin and Parke, 2020).

[0012] Studies in which the vitreous gel was intentionally maintained or disrupted have highlighted the importance of the vitreous in protecting the lens from the effects of oxygen and from nuclear cataracts. Surgery to remove epiretinal membranes usually involves a vitrectomy, followed soon after by a nuclear cataract. However, patients who underwent a conventional procedure that did not disrupt the vitreous gel did not develop nuclear cataracts, even after 5 years of follow-up. These studies are important because they show that by simply maintaining the structure of the vitreous, nuclear cataracts can be prevented even in patients who have undergone surgery to repair retinal problems. Unfortunately, patients who underwent this modified procedure were more likely to have recurrence of epiretinal fibrous membranes, thereby offsetting the lens-protective properties of the modified surgery. Recent studies in animals have shown that liquefying the vitreous or producing enzyme-induced detachment of the vitreous from the retina increases the level of oxygen in the vitreous and causes higher levels of oxygen to reach the lens nucleus. These studies demonstrate that the gel state of the vitreous protects the lens from the effects of oxygen and from nuclear cataracts. The liquefaction of the vitreous, which occurs to varying degrees with age, can be considered a slow form of vitrectomy. Loss of the gel state of the vitreous is likely to increase the exposure of the lens to oxygen and place the patient at increased risk for nuclear cataracts (Beebe et al., 2010).

[0013] A safe and effective pharmacological therapy to prevent cataract formation caused by vitreoretinal surgery would be a medical breakthrough that would eliminate the need for subsequent cataract surgery. Accumulating experimental evidence suggests that oxidative stress is a factor in the development of cataracts (Lim et al., 2016). Therefore, agents that treat oxidative stress should have activity as anti-cataract agents.

[0014] “Glaucoma” describes several eye diseases caused by damage to the optic nerve that results in vision loss. Primary open-angle glaucoma (POAG) is a chronic, irreversible optic neuropathy that results in progressive death of retinal ganglion cells, clinically observed as asymptomatic visual field loss and decreased color and contrast sensitivity (Ster et al., 2014). POAG is the leading cause of irreversible blindness worldwide (1) yet our approach to its treatment has remained essentially unchanged for over 100 years: eye drops to lower intraocular pressure (IOP) as an initial approach, followed by surgery to enhance outflow if eye drops are insufficient. Elevated IOP is a major risk factor for glaucoma, as is a family history of glaucoma and hypertension, however, the etiology of glaucoma is still under investigation. Although elevated IOP is the major risk factor associated with glaucomatous neuropathy (perhaps even the most important single factor), it is by no means the only factor contributing to glaucomatous neuropathy. Extensive studies have revealed a variety of additional risk factors, such as mutations in specific nuclear genes, increased glutamate levels, alterations in nitric oxide (NO) metabolism, changes in the mitochondrial genome, vascular disturbances, and toxic effects and oxidative damage caused by reactive oxygen species (ROS) (Ster et al., 2014). The pathogenic role of ROS in glaucoma is supported by various experimental results, including (a) increased resistance to aqueous humor outflow by hydrogen peroxide through induction of trabecular meshwork (TM) degeneration; (b) TM has significant antioxidant activity, mainly related to superoxide dismutase-catalase and glutathione pathways that are altered in glaucoma patients; and (c) the severity of IOP elevation and visual field loss in glaucoma patients is comparable to the amount of oxidative DNA damage affecting TM (Izzotti et al., 2006).

[0015] A cataract is any opacity of the lens. Cataracts are often considered an inevitable consequence of aging. Age-related cataracts are responsible for almost half of blindness worldwide and half of visual impairment in the United States. In the United States alone, age-related cataract surgery is the most expensive ocular surgical procedure, with expenditures exceeding $3 billion per year. Lens opacities may result from protein aggregation, protein phase separation, or disruption or accumulation of the regular arrangement of fiber cells, all of which may result in increased light scattering. Nuclear opacities sometimes also involve increased pigmentation, resulting in reduced light transmission. Oxidative damage is the primary cause or consequence of cortical and nuclear cataracts, the most common types of age-related cataracts. Considerable evidence suggests that exposure to elevated levels of molecular oxygen accelerates age-related opacification of the lens nucleus, leading to nuclear cataracts. Therefore, factors in the eye that maintain a low oxygen partial pressure around the lens are important in protecting the lens from nuclear cataracts (Beebe et al., 2010).

[0016] The vitreous is a clear, gel-like substance that fills the ocular cavity behind the lens and helps stabilize the various retinal layers and retinal vasculature. The gel-like properties of the vitreous are due to a network of collagen fibers that extend throughout the gel. Because the vitreous gel has no circulation and does not mix, it effectively blocks the distribution of signaling molecules or nutrients that may be released from surrounding tissues.

[0017] Although vitreous gel is remarkably stable, over time, the gel has a tendency to gradually collapse, most likely as a result of degradation or alteration of the collagen fiber network. Patients with degenerated vitreous are at increased risk of developing traction forces on the underlying retina, which predisposes them to retinal detachment and disruption of the delicate layers that characterize a healthy retina. In addition to age-related vitreous liquefaction, other conditions may require removal of the vitreous gel, such as uncontrolled bleeding in unstable retinal vessels, which is a typical feature of patients with diabetic retinopathy. In such conditions, a vitrectomy procedure is used to remove the native gel as well as trapped blood components, followed by replacement with a balanced salt solution. Although vitrectomy is a major therapeutic advance in the treatment of retinal diseases, it carries a high risk of developing nuclear cataracts. Recent studies point to oxygen as a byproduct of cataract-inducing vitrectomy procedures. Most of the oxygen in the vitreous gel is thought to originate from the retinal vasculature. Due to its diffusion-restricted physical properties, there is an oxygen gradient in the natural eye, with the highest level closest to the retina and relatively low levels near the posterior surface farthest from the lens. When the contents of the vitreous humor are removed by vitrectomy and replaced with a saline solution, the physical barrier to oxygen diffusion is destroyed. Because the components of the vitreous replacement solution mix freely, small molecules released from the retinal vessels are distributed throughout the vitreous cavity, exposing the posterior lens to abnormally high levels of oxygen (Petrash, 2013).

[0018] Because vitrectomy is a common procedure that causes rapid and definitive opacification of the lens nucleus, patients undergoing vitrectomy provide a promising “model system” to test anti-cataract hypotheses. Successful protection of patients from developing nuclear cataracts after vitrectomy would lay the foundation for interventions to prevent these cataracts in subjects with advanced vitreous degeneration (Beebe et al., 2010).

[0019] Presbyopia is a condition in which the ability to focus on near objects is reduced. The effects of presbyopia are almost universal as people enter middle age. Although near vision can be simply regained by using reading glasses, there is a great need for correction methods that do not require corrective lenses for practical and professional reasons. The biological basis of presbyopia has been studied intensively over the years. In order to accommodate near vision, the lens must be "rounded up" from its ill-fitting shape. This shape change is made possible when the ciliary muscles contract and the tissues surrounding the lens come together in a sphincter-like movement. In response, the body of the lens assumes a more rounded shape, changing the radius of curvature primarily on the front surface. The accommodative response shortens the focal length of the lens so that near objects are clearly focused on the retina. The process of accommodating near vision therefore relies on changes in the shape of the lens in response to the contraction of the ciliary muscles (Petrash, 2013).

[0020] As the lens ages, the nucleus becomes harder, but the cortex remains soft. This stiffening of the nucleus is the primary cause of presbyopia (Beebe et al., 2010).

[0021] Flexibility is a key factor in the ability of the lens to change shape. Many researchers have shown that the human lens stiffens over time, leading to the hypothesis that presbyopia occurs when the lens becomes too stiff to change shape in response to ciliary muscle contraction. Studies conducted by various methods have demonstrated that lens stiffness increases significantly beginning in the third to fifth decades of life, which is roughly the age at which the loss of accommodative ability becomes apparent in the early stages of presbyopia. The molecular basis for increased lens stiffness is unclear. Fiber cells in the lens nucleus are held together by an array of intercellular adhesion molecules, gap junction complexes, and ball-and-socket cross-junctions along their extensive lateral membranes. As the lens ages and more of the lens mass is internalized into the nuclear region, the cells are likely to become riveted together with these intercellular junctions, possibly resulting in a decrease in the deformability of the tissue (Petrash, 2013).

[0022] If uncorrected or undercorrected, the onset of presbyopia in midlife results in potential loss of productivity in otherwise healthy adults. In 2011, there were an estimated 1,272 million cases of presbyopia worldwide. Among people aged <50 years, the total 244 million uncorrected or undercorrected cases were associated with potential productivity losses of US$ 11,023 million (0.016% of global GDP), or US$ 25,367 million (0.037% of global GDP), assuming that people aged <65 years were productive. The economic burden is even more significant in low-income countries, where up to 94% of cases may be uncorrected or undercorrected (Frick et al., 2015).

[0023] Retinitis pigmentosa (RP) is a group of diseases in which one of a large number of mutations causes rod photoreceptor cell death. After rod photoreceptor cell death, cone photoreceptors slowly degenerate in a distinctive pattern. The mechanism of rod photoreceptor cell death varies depending on the gene that is mutated, and the rate of rod degeneration is an important prognostic feature because cone photoreceptors do not begin to degenerate until almost all rod photoreceptors have been eliminated. Rod photoreceptor cell death causes night blindness, but visual disability and blindness are caused by cone degeneration, so it is critical to determine the mechanism by which this occurs. Rod death reduces oxygen consumption, resulting in high tissue levels of oxygen in the outer retina. Excess oxygen stimulates superoxide radical production through mismatches in the electron transport chain in the mitochondria and stimulation of NADPH oxidase activity in the cytoplasm. High levels of superoxide radicals overwhelm antioxidant defenses and generate more reactive species, including peroxynitrite, which is extremely damaging and difficult to detoxify. This results in progressive oxidative damage to cone photoreceptors, promoting cone photoreceptor cell death and loss of function, because drugs or gene transfer that reduce oxidative stress promote cone survival and maintenance of function. Compared with aqueous humor samples from control patients, aqueous humor samples from RP patients showed significantly elevated levels of carbonyl groups on proteins, indicative of oxidative damage, and a decreased ratio of reduced to oxidized glutathione, suggesting that major components of the antioxidant defense system are depleted by persistent oxidative stress. The first step in clinical trials will be to identify doses of therapeutic agents that reverse these disease biomarkers to help design longer trials with functional and anatomical endpoints (Campochiaro and Mir, 2018).

[0024] N-acetylcysteine ​​(NAC) is a free radical scavenger that is converted to cysteine, a substrate for the synthesis of glutathione, a key component of the endogenous antioxidant defense system (Dilger and Baker, 2007). NAC is approved for the treatment of acetaminophen overdose and is a life-saving treatment if administration is initiated relatively quickly after ingestion; this is quite remarkable because in untreated patients, the severity of oxidative damage to the liver is so severe that extensive hepatic necrosis and liver failure occur (Prescott et al., 1977; Smilkstein et al., 1988). rd10 mice given NAC in the drinking water showed a dose-dependent, statistically significant reduction in oxidative damage and improvements in cone survival and function compared to untreated rd10 mice (Lee et al., 2011). After several months of NAC treatment, cone function and survival showed some deterioration but remained significantly higher than in untreated mice, demonstrating a long-term effect. N-acetylcysteine ​​amide (NACA), a precursor to NAC, penetrates the blood-retinal barrier and enters cells better than NAC. rd10 mice treated with a 7-fold lower dose of N-acetylcysteine ​​amide (NACA) showed greater protection of cone function and survival compared to rd10 mice treated with NAC (Campochiaro and Mir, 2018).

[0025] Although the Argis II retinal prosthesis system was approved by the FDA in 2013 as an implantable device to treat adults with severe vision loss, it only produces light perception to help patients identify the location or movement of objects and people; it is not designed to improve the disease.

[0026] Currently, there is one FDA-approved gene therapy for RP, LUXTURNA, an adeno-associated viral vector-based gene therapy indicated for the treatment of patients with confirmed biallelic RPE65 mutation-related retinal dystrophy (LUXTURNA Prescribing Information, 2017). Other than LUXTURNA for patients with RPE65 mutations (biallelic RPE65 mutation-related retinal dystrophy affects approximately 1,000 to 2,000 patients in the United States (FDA, 2017)), there are no other FDA-approved therapies to halt disease progression or restore vision caused by retinitis pigmentosa. Current treatments are limited to slowing the degenerative process through sun protection and vitamin A supplementation, treating complications (cataracts and macular edema), and helping patients cope with the social and psychological impacts of blindness.

[0027] U.S. Patent Application No. 15 / 523,665 teaches the use of NACA for the treatment of retinitis pigmentosa. NACA has been shown to improve visual parameters in a mouse model of RP to a greater extent than NAC.

[0028] Therefore, there remains a need for new compositions and methods for treating ophthalmic diseases and conditions associated with oxidative stress, including but not limited to age-related macular degeneration, cataracts, corneal endothelial cell protection, glaucoma, diabetic retinopathy, presbyopia, retinitis pigmentosa, and other retinal diseases. SUMMARY OF THE INVENTION

[0030] As embodied and broadly described herein, one aspect of the present disclosure relates to a biodegradable intraocular implant comprising: (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropionamide) (diNACA) in a pharmaceutically acceptable polymer. In one aspect, the implant further comprises an antioxidant selected from N-acetylcysteine, N-acetylcysteine ​​amide, lipoic acid, lipoic acid choline ester, salts thereof, and mixtures thereof. In another aspect, the implant has a diameter of about 0.1-0.5 mm and a length of about 4-10 mm. In another aspect, the implant has a diameter of about 0.2-0.4 mm and a length of about 5-8 mm. In another aspect, the implant has a diameter of about 0.3 mm and a length of about 6-7 mm. In another aspect, the implant has a diameter of about 0.4 mm and a length of about 7 mm. In another aspect, the implant has a diameter of 0.05 mm or about 0.05 mm and a length of between 5 and 8 mm or about 5 to 8 mm. In another aspect, the biodegradable polymer is a poly(lactide-co-glycolide) copolymer. In another aspect, the amount of diNACA in the implant is at least 21-65 weight percent (wt%), 1-20 wt%, 5-15 wt%, 7-12 wt%, or about 10 wt%. In another aspect, the diNACA is present with an adjuvant. In another aspect, the implant comprises a plurality of openings or holes in the polymer. In another aspect, the intraocular implant comprises: diNACA in a biodegradable polymer in the form of a first intraocular implant; and an adjuvant associated with the biodegradable polymer in the form of a second intraocular implant; wherein the diNACA is present in the first intraocular implant in an amount of at least about 10 wt%. In another aspect, the implant is adapted for placement within the vitreous of an eye of an individual, the diNACA being present in an amount effective to treat an ocular condition of the eye; and an adjuvant associated with a biodegradable polymer component in the form of an intraocular implant is constructed for placement within the vitreous of an eye of an individual, the adjuvant being present in an amount effective to reduce the occurrence of at least one undesirable reaction that would otherwise be present when the diNACA is administered alone; wherein the diNACA is present in the intraocular implant in an amount of at least about 10 weight percent. In another aspect, the molecular weight of the polymer in the diNACA implant is reduced, such as by hydrolysis, becoming a hydrogel, and then dissolving, as evidenced by mass loss of the implant over time. The molecular weight loss process controls the release of the drug from the implant.

[0031] As embodied and broadly described herein, one aspect of the present disclosure relates to a biodegradable intraocular implant system containing an antioxidant suitable for treating an ophthalmic disease or condition involving oxidative stress in an animal or a human. In one aspect, the antioxidant comprises (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropionamide) (diNACA) or a combination of (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropionamide) (diNACA) and an adjuvant in a matrix of a polymer or in alternating layers. In another aspect, the antioxidant comprises (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropionamide) (diNACA), or diNACA and the adjuvant are contained in the same implant or in different implants. In another aspect, the amount of diNACA in the implant is at least 21-65 weight percent (wt%), 1-20 wt%, 5-15 wt%, 7-12 wt%, or about 10 wt%. On the other hand, the molecular weight of the polymer in the diNACA implant is reduced, for example by hydrolysis, and becomes a hydrogel, which then dissolves, as evidenced by the mass loss of the implant over time. The molecular weight loss process controls the release of the drug from the implant.

[0032] As embodied and broadly described herein, one aspect of the present disclosure relates to a method for treating ophthalmic oxidative stress in an animal or human subject, the method comprising: identifying an animal or human patient in need of treatment for ophthalmic oxidative stress in the eye; and administering a therapeutically effective amount of N-acetylcysteine ​​amide (NACA) or (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropionamide) (diNACA) to the animal or human patient as an intravitreal implant (diNACA implant). In one aspect, the ophthalmic oxidative stress in the eye is selected from at least one of cataracts, cataracts in a subject without diabetes, corneal endothelial cell loss, age-related macular degeneration, presbyopia, retinitis pigmentosa (RP), Usher syndrome, Stargardt syndrome, glaucoma, diabetic retinopathy, or a retinal disease. In another aspect, the diNACA is provided in or with a pharmaceutically acceptable carrier. In another aspect, diNACA is in a dosage form for a delivery route selected from the group consisting of intravitreal, intrastromal, intracameral, subtenon, retinal, subretinal, retrobulbar, peribulbar, suprachoroidal, subchoroidal, conjunctival, subconjunctival, suprascleral, posterior juxtascleral, anterior juxtascleral, pericorneal, topical, and lacrimal. In another aspect, diNACA is administered at a daily dose of about 0.25, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 25, 30, 40, 45, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140 to 150 mg / Kg. In another aspect, diNACA is administered in a single dose of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 25, 30, 40, 45, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 175, 200, 250, 300, 400, 500, 600, 700, 750, 800 to 900 micrograms. In another aspect, diNACA is administered once every 1, 2, 3, 4, 5 or 6 months. In another aspect, diNACA is administered with a second active agent selected from at least one of ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, NAC, NACA, propyl gallate, alpha-tocopherol, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, or phosphoric acid.In another aspect, the amount of diNACA in the implant is at least 21-65 weight percent (wt%), 1-20 wt%, 5-15 wt%, 7-12 wt%, or about 10 wt%. In another aspect, the dosage for administration is about 1, 10, 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1000, 2500, 5000, 7500, or 10000 micrograms per dose. In another aspect, the dosage for administration is 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1000, 2500, 5000, 7500, or 10000 mg per dose. In another aspect, the diNACA implant is manually inserted into the eye. In another aspect, the diNACA implant is injected into the eye. In another aspect, the diNACA implant breaks down and dissolves or biodegrades in the eye. In another aspect, the molecular weight of the polymer in the diNACA implant is reduced, such as by hydrolysis, becomes a hydrogel, and then dissolves, as evidenced by mass loss of the implant over time. The molecular weight loss process controls the release of the drug from the implant. In another aspect, diNACA is administered prophylactically to prevent an ophthalmic disease or condition involving oxidative stress.

[0033] As embodied and broadly described herein, one aspect of the present disclosure relates to a non-biodegradable, non-bioerodible or non-bioabsorbable intraocular implant comprising: (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropionamide) (diNACA) in a pharmaceutically acceptable polymer. In one aspect, the antioxidant is selected from N-acetylcysteine, N-acetylcysteine ​​amide, (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropionamide) (diNACA), lipoic acid, lipoic acid choline ester, salts thereof, and mixtures thereof. In another aspect, the implant has a diameter of about 0.1-0.5 mm and a length of about 4-10 mm. In another aspect, the implant has a diameter of about 0.2-0.4 mm and a length of about 5-8 mm. In another aspect, the implant has a diameter of about 0.3 mm and a length of about 6-7 mm. In another aspect, the implant has a diameter of about 0.4 mm and a length of about 7 mm. In another aspect, the implant has a diameter of at or about 0.05 mm and a length of between at or about 5 and 8 mm. In another aspect, the biodegradable polymer is polyurethane polyurea, poly(vinyl ester), poly(methyl methacrylate), poly(vinyl chloride), polyamide, nylon, poly(ethylene terephthalate), rubber, silicone, polyisoprene, polyisobutylene, polybutadiene, polyethylene, polytetrafluoroethylene, poly(vinylidene chloride), polyacrylonitrile, polyvinyl pyrrolidone, chlorinated polyethylene, polychlorotrifluoroethylene, poly(ethylene chlorotrifluoroethylene), polytetrafluoroethylene, poly(ethylene tetrafluoroethylene), poly(4,4-isopropylidene diphenylene carbonate), poly Urethane, polyperfluoroalkoxy, poly(vinylidene fluoride), vinylidene chloride-acrylonitrile copolymer, vinyl chloride-diethyl fumarate copolymer, silicone, silicone rubber, polydimethylsiloxane, ethylene-propylene rubber, silicone-carbonate copolymer, vinylidene chloride-vinyl chloride copolymer, vinyl chloride-acrylonitrile copolymer, vinylidene chloride-acrylonitrile copolymer, poly(olefin), poly(vinyl-olefin), poly(styrene), poly(halogenated-olefin), poly(vinyl) ester, alkyl acrylate, polyoxide, polyester, polyamide and polycarbonate, or a mixture thereof. On the other hand, the amount of diNACA in the implant is at least 21-65 weight percent (wt%), 1-20 wt%, 5-15 wt%, 7-12 wt% or about 10 wt%. On the other hand, the molecular weight of the polymer in the diNACA implant is reduced, for example, by hydrolysis, the molecular weight is reduced, it becomes a hydrogel, and then dissolves, as demonstrated by the mass loss of the implant over time. The molecular weight loss process controls the release of the drug from the implant. On the other hand, the implant also contains an adjuvant. In another aspect, the implant comprises a plurality of openings or pores in the polymer or coating.In another aspect, the diNACA implant is suitable for administration to the eye at a location selected from the group consisting of intravitreal, intrastromal, intracameral, subfascial, retinal, subretinal, retrobulbar, peribulbar, suprachoroidal, subchoroidal, conjunctival, subconjunctival, suprascleral, posterior juxtascleral, anterior juxtascleral, pericorna!e, topical, and lacrimal.

[0034] As embodied and broadly described herein, one aspect of the present disclosure relates to a method for treating a disease or condition of ophthalmic oxidative stress in an eye of an animal or human subject, comprising: obtaining an intravitreal implant (diNACA implant) comprising a therapeutically effective amount of N-acetylcysteine ​​amide (NACA) or (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropionamide) (diNACA); and delivering the diNACA implant to a predetermined area in, at, or around the eye, the diNACA implant delivering a therapeutically effective amount of diNACA to the predetermined area of ​​the eye. In one aspect, the disease or condition is selected from at least one of cataracts, cataracts in a subject without diabetes, corneal endothelial cell loss, age-related macular degeneration, presbyopia, retinitis pigmentosa (RP), Usher syndrome, Stargardt syndrome, glaucoma, diabetic retinopathy, or a retinal disease. On the other hand, diNACA implants are administered to a predetermined area of ​​the eye, the predetermined area being selected from the group consisting of intravitreal, intrastromal, intracameral, subfascial, retinal, subretinal, posterior to the eyeball, periorbital, suprachoroidal, subchoroidal, conjunctival, subconjunctival, suprascleral, posterior near sclera, anterior near sclera, corneal periphery, local, and lacrimal duct. On the other hand, diNACA is administered at a daily dose of about 0.25 to 150 mg / Kg. On the other hand, diNACA is administered at a single dose of about 1 to 900 micrograms. On the other hand, diNACA is administered once every 1, 2, 3, 4, 5, or 6 months. In another aspect, diNACA is administered with a second active agent selected from at least one of ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, NAC, NACA, propyl gallate, alpha-tocopherol, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, or phosphoric acid. In another aspect, the amount of diNACA in the implant is at least 21-65 weight percent (wt %), 1-20 wt %, 5-15 wt %, 7-12 wt %, or about 10 wt %. In another aspect, the dosage for administration is about 1, 10, 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1000, 2500, 5000, 7500, or 10000 micrograms per dose. In another aspect, the dosage for administration is 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1000, 2500, 5000, 7500, or 10000 mg per dose. In another aspect, the diNACA implant is manually inserted into the eye.In another aspect, the diNACA implant breaks down and dissolves or biodegrades in a predetermined region of the eye. In another aspect, the molecular weight of the polymer in the diNACA implant is reduced, such as by hydrolysis, and becomes a hydrogel, which then dissolves, as evidenced by the mass loss of the implant over time. The molecular weight loss process controls the release of the drug from the implant. In another aspect, diNACA is administered prophylactically to prevent an ophthalmic disease or condition in or around a predetermined region of the eye. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] For a more complete understanding of the features and advantages of the present invention, reference is now made to the detailed description of the invention and to the accompanying drawings, in which:

[0037] Figure 1A , 1B Displays individual NACA ( Figure 1A ) and diNACA ( Figure 1B ) pretreatment on the transparency of rat lens (the opacities are marked with *).

[0038] 2A to 2L show the effects of NACA and diNACA on GO-induced cataracts in isolated rat lenses.

[0039] Figure 3 The effects of NACA and diNACA in inhibiting H2O2-induced cataract in isolated porcine lenses were shown.

[0040] FIG. 4 shows that diNACA inhibits cataract formation (clouding) induced by oxidizing agents in isolated rat lenses and isolated porcine lenses based on comparison with negative controls (no oxidizing agent, transparent).

[0041] FIG. 5 shows that the diNACA (NPI-002) intravitreal implant delivers diNACA, NACA, and NAC to the rabbit vitreous humor.

[0042] FIG6 shows the in vitro release profile of diNACA (NPI-002) from intravitreal implants.

[0043] Figure 7 A method flow for manufacturing an implant is shown.

[0044] Figure 8 shows the dimensions of the implant.

[0045] Fig.9A is a graph showing NAC concentrations in aqueous humor and vitreous humor at 3 months after surgery for Group 1 (Control), Group 2 (NPI-002, one implant), and Group 3 (NPI-002, two implants). Data represent mean ± SEM, with n=5-6.

[0046] Fig. 9Bis a graph showing NAC concentrations in the lens, retina, and RPE / choroid at 3 months after surgery for Group 1 (control), Group 2 (NPI-002, one implant), and Group 3 (NPI-002, two implants). Data represent mean ± SEM, with n=6.

[0047] Fig. 10A is a graph showing NACA concentrations in aqueous humor and vitreous humor at 3 months after surgery for Group 1 (control), Group 2 (NPI-002, one implant), and Group 3 (NPI-002, two implants). Data represent mean ± SEM, with n=5-6.

[0048] Fig. 10B is a graph showing NACA concentrations in the lens, retina, and RPE / choroid at 3 months after surgery for Group 1 (control), Group 2 (NPI-002, one implant), and Group 3 (NPI-002, two implants). Data represent mean ± SEM, with n=6.

[0049] Fig.11A is a graph showing di-NACA concentrations in aqueous humor and vitreous humor at 3 months after surgery for Group 1 (Control), Group 2 (NPI-002, one implant), and Group 3 (NPI-002, two implants). Data represent mean ± SEM, with n=5-6.

[0050] Fig. 11B is a graph showing di-NACA concentrations in the lens, retina, and RPE / choroid at 3 months after surgery for Group 1 (control), Group 2 (NPI-002, one implant), and Group 3 (NPI-002, two implants). Data represent mean ± SEM, with n=6.

[0051] Fig. 12A is a graph showing GSH concentrations in aqueous humor and vitreous humor at 3 months after surgery for Group 1 (Control), Group 2 (NPI-002, one implant), and Group 3 (NPI-002, two implants). Data represent mean ± SEM, with n = 5-6.

[0052] Fig. 12B is a graph showing GSH concentrations in the lens, retina, and RPE / choroid at 3 months after surgery for Group 1 (control), Group 2 (NPI-002, one implant), and Group 3 (NPI-002, two implants). Data represent mean ± SEM, with n=6. DETAILED DESCRIPTION OF THE INVENTION

[0054] Although the formation and use of various embodiments of the present invention are discussed in detail below, it should be understood that the present invention provides many applicable inventive concepts that can be embodied in multiple specific contexts. The specific embodiments discussed herein are only examples of specific ways to form and use the present invention, and do not limit the scope of the present invention.

[0055] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art. In the event of a conflict, this document (including definitions) shall prevail. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods and examples disclosed herein are illustrative only and not restrictive.

[0056] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments that "comprise," "consist of," and "consist essentially of," the embodiments or elements presented herein, whether explicitly stated or not.

[0057] The conjunction "or" includes any and all combinations of one or more of the listed elements associated by the conjunction. For example, the phrase "a device including A or B" may refer to a device including A but B is not present, a device including B but A is not present, or a device including both A and B. The phrase "at least one of A, B, ..., and N" or "at least one of A, B, ..., N or a combination thereof" is defined in the broadest sense, meaning one or more elements selected from the group including A, B, ..., and N, that is, any combination of one or more of the elements A, B, ..., or N, including any one element alone or in combination with one or more other elements, which other elements may also include additional elements not listed in combination.

[0058] The modifier "about" used in conjunction with a quantity is inclusive of the stated value and has a meaning dictated by the context (e.g., it includes at least the degree of error associated with the measurement of a particular quantity). The modifier "about" should also be considered to disclose a range defined by the absolute values ​​of the two endpoints. For example, the expression "about 2 to about 4" also discloses a range of "2 to 4". The term "about" may refer to plus or minus 10% of the indicated number. For example, "about 10%" may indicate a range of 9% to 11%, and "about 1" may mean 0.9-1.1. Other meanings of "about" may be apparent from the context, such as rounding, so, for example, "about 1" may also mean 0.5 to 1.4.

[0059] As used herein, weight percent is abbreviated as "wt %".

[0060] As used herein, "active oxygen species" or "reactive oxygen species" is understood to be an anion having the form of "O2" or an anion having the formula O2 that produces superoxide, an anion having the form of "O2" or an anion having the formula - " superoxide anion, or compounds containing an O-O single bond, such as hydrogen peroxide and lipid peroxides. Such superoxides and peroxides are highly reactive and can cause damage to cellular components including proteins, nucleic acids and lipids.

[0061] As used herein, the term "agent" refers to a therapeutically active compound or a potentially therapeutically active compound, such as an antioxidant. The agent may be a previously known or unknown compound. As used herein, an agent is generally a non-cell-based compound, however, an agent may include a biotherapeutic agent, such as a peptide or nucleic acid therapeutic agent, such as siRNA, shRNA, cytokine, antibody, etc.

[0062] As used herein, the term "improvement" or "treatment" is understood to mean to alleviate or reduce at least one sign, symptom, indication or effect of a particular disease or condition. For example, improvement or treatment of age-related macular degeneration, glaucoma and / or diabetic retinopathy can be to reduce, delay or eliminate one or more signs or symptoms of age-related macular degeneration, glaucoma and / or diabetic retinopathy, including but not limited to decreased night vision, decreased overall visual acuity, reduced visual field, decreased cone density in one or more quadrants of the retina, thinning of the retina (particularly the outer nuclear layer), decreased a-wave or b-wave amplitude on a dark or bright electroretinogram (ERG); or any other clinically acceptable indicator of disease state or progression. Improvement and treatment may require administration of more than one dose of an agent alone or in combination with other therapeutic agents and interventions. Improvement or treatment does not require a cure for a disease or condition.

[0063] As used herein, the term "antioxidant" refers to a molecule that is used to slow down or prevent the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidant. Such a reaction can be promoted by superoxide anions or peroxides, or produce superoxide anions or peroxides. Oxidation reactions can produce free radicals, which trigger chain reactions that damage cells. Antioxidants terminate these chain reactions by removing free radical intermediates and inhibit other oxidation reactions by self-oxidation. Therefore, antioxidants are generally reducing agents, such as thiols, ascorbic acid or polyphenols. Antioxidants include, but are not limited to, alpha-tocopherol, ascorbic acid, Mn(III)tetrakis(4-benzoic acid)porphyrin, alpha-lipoic acid and n-acetylcysteine.

[0064] As used herein, the term "adjuvant" refers to an agent that can reduce at least one side effect of an antioxidant drug. Adjuvants include compounds that can reduce or prevent a condition associated with at least one side effect of an antioxidant drug in the absence of the antioxidant drug.

[0065] As used herein, the term "co-administration" refers to administering one or more agents to a subject such that the agents are simultaneously present in the subject and active in the subject. Co-administration does not require the preparation of a mixture of the agents or the simultaneous administration of the agents.

[0066] As used herein, the term "effective amount" or "effective dose" refers to the amount of a medicament producing an expected pharmacological, therapeutic or preventive result. The pharmacologically effective amount results in an improvement in one or more signs or symptoms of a disease or condition or the progress of a disease or condition, or causes the disappearance of a disease or condition. For example, a therapeutically effective amount preferably refers to a time period defined, such as 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 5 years or longer, compared to untreated control subjects, to reduce vision loss, overall visual acuity loss, visual field loss by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more of the amount of the therapeutic agent. More than one dosage may be required to provide an effective dose.

[0067] As used herein, the terms "effective" and "effectiveness" include both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of a treatment to produce a desired biological effect in a patient. Physiological safety refers to the level of toxicity caused by the administration of treatment, or adverse physiological effects (commonly referred to as side effects) at other cell, organ and / or organism levels. On the other hand, the term "ineffective" means that at least in an unstratified population, the treatment does not provide enough pharmacological effects to become useful in treatment, even in the absence of harmful effects (such as treatment in a subgroup that can be identified by one or more expression profiles may be ineffective). "Less effective" means that treatment results in a significantly lower level of pharmacological effectiveness in treatment and / or a higher level of adverse physiological effects in treatment, such as greater hepatotoxicity.

[0068] Thus, with respect to the administration of a drug, a drug that is "effective against" a disease or condition means that its administration in a clinically appropriate manner results in a beneficial effect on at least a statistically significant portion of patients, such as amelioration of symptoms, cure, reduction in disease signs or symptoms, prolongation of life, improvement in quality of life, or other effect generally recognized as positive by medical practitioners familiar with treating a particular type of disease or condition.

[0069] As used herein, the phrase "oxidative stress-related ocular disorders" includes, but is not limited to, age-related macular degeneration, macular degeneration including age-related macular degeneration, glaucoma and / or diabetic retinopathy, Lebers optic neuropathy, and optic neuritis.

[0070] As used herein, the term "peroxidase" or "peroxide metabolizing enzyme" refers to a large class of enzymes that generally catalyze reactions of the form:

[0071] ROOR1 + electron donor (2e-) + 2H+ → ROH + R1OH.

[0072] For many of these enzymes, the best substrate is hydrogen peroxide, where each R is H, but others are more active towards organic hydroperoxides, such as lipid peroxides. Peroxidases may contain a heme cofactor, or a redox-active cysteine ​​or selenocysteine ​​residue in their active site.

[0073] As used herein, the term phrase "pharmaceutically acceptable carrier" is recognized in the art and includes pharmaceutically acceptable materials, compositions or vehicles suitable for administering the compounds of the invention to mammals. Carriers include liquid or solid fillers, diluents, excipients, solvents or encapsulating materials that participate in carrying or transporting the subject agent from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. For example, a pharmaceutically acceptable carrier for administration to cells is generally a carrier that is acceptable for delivery by injection and does not include agents such as detergents or other compounds that may damage the cells to be delivered. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffered saline; and other nontoxic compatible substances used in pharmaceutical formulations, particularly phosphate-buffered saline solutions, which are preferred for intraocular delivery.

[0074] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0075] Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0076] Preparations of the present invention include preparations suitable for oral, nasal, topical, transdermal, buccal, sublingual, intramuscular, intraperitoneal, intraocular, intravitreal, posterior scleral, anterior scleral, posterior eyeball, subretinal and / or other parenteral administration routes. The specific route of administration will depend in particular on the specific cells to be targeted. The preparation can be conveniently present in unit dosage form and can be prepared by any method known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally the amount of the compound that produces the therapeutic effect.

[0077] As used herein, "plurality" is understood to mean more than one. For example, plurality means at least two, three, four, five or more.

[0078] As used herein, the term "polypeptide" or "peptide" is understood to be two or more independently selected natural or non-natural amino acids linked by covalent bonds (e.g., peptide bonds). A peptide may include 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more natural or non-natural amino acids linked by peptide bonds. The polypeptides described herein include full-length proteins (e.g., fully processed proteins) as well as shorter amino acid sequences (e.g., fragments of naturally occurring proteins or synthetic polypeptide fragments).

[0079] As used herein, "prevention" is understood to limit, reduce the incidence or degree of disease, or inhibit the development of at least one sign or symptom of a disease or disorder, particularly in a subject susceptible to developing the disease or disorder. For example, a subject having a mutation in a gene, such as an opsin gene, is likely to develop age-related macular degeneration, glaucoma, and / or diabetic retinopathy. The age of onset of one or more symptoms of a disease can sometimes be determined by a specific mutation. Prevention can include delaying the onset of one or more signs or symptoms of age-related macular degeneration, glaucoma, and / or diabetic retinopathy, and need not be preventing the appearance of at least one sign or symptom of the disease during the subject's lifetime. Prevention may require administration of more than one dose of an agent or therapeutic agent.

[0080] As used herein, the term "small molecule" refers to a compound, typically an organic compound, having a molecular weight of no more than about 1500 Da, 1000 Da, 750 Da or 500 Da. In one embodiment, small molecules do not include polypeptides or nucleic acids containing only natural amino acids and / or nucleotides.

[0081] As used herein, the term "subject" refers to a living organism, particularly a human. In certain embodiments, the living organism is an animal, in certain preferred embodiments, the subject is a mammal, in certain embodiments, the subject is a domesticated mammal or primate, including a non-human primate. Examples of subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, goats, and sheep. Human subjects may also be referred to as subjects or patients.

[0082] As used herein, a subject "suspected of having" a particular disease, condition, or syndrome has a sufficient number of risk factors or exhibits a sufficient number of signs or symptoms of the disease, condition, or syndrome, or a combination thereof, such that a qualified individual would diagnose or suspect the subject of having the disease, condition, or syndrome. Methods for identifying subjects who have or are suspected of having a condition such as age-related macular degeneration, glaucoma, and / or diabetic retinopathy are within the capabilities of those skilled in the art. Subjects who have and are suspected of having a particular disease, condition, or syndrome are not necessarily two distinct populations.

[0083] As used herein, the term "superoxide dismutase" refers to an enzyme that dismutates superoxide into oxygen and hydrogen peroxide. Examples include, but are not limited to, SOD1, SOD2, and SOD3. Sod1 and SOD3 are two isoforms of Cu-Zn-containing superoxide dismutase present in mammals. Cu-Zn-SOD or SOD1 is present in the intracellular space, while extracellular SOD (ECSOD or SOD3) is primarily present in the extracellular matrix of most tissues.

[0084] As used herein, the phrase "therapeutically effective amount" refers to an amount of an agent that, following single or multiple dose administration to a cell or subject, is effective in prolonging the survivability of a patient having such a disorder, reducing one or more signs or symptoms of the disorder, preventing or delaying, etc., over what would be expected in the absence of such treatment.

[0085] The pharmaceutical agent or other therapeutic intervention may be administered to a subject alone or in combination with one or more additional therapeutic agents or interventions as a pharmaceutical composition or therapeutic treatment mixed with conventional excipients such as pharmaceutically acceptable carriers.

[0086] The medicament can be conveniently administered in unit dosage form and can be prepared by any method known in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1985). Formulations for parenteral administration can contain conventional excipients, such as sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes, etc. In particular, biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers or polyoxyethylene-polyoxypropylene copolymers can be useful excipients for controlling the release of certain medicaments.

[0087] The present invention relates to the use of implants with diNACA for treating age-related macular degeneration, glaucoma and / or diabetic retinopathy. In one embodiment, the present invention includes a method for treating age-related macular degeneration in a person, the method comprising administering a therapeutically effective amount of diNACA to a person. In some embodiments, diNACA is provided in a pharmaceutically acceptable carrier or provided together with a pharmaceutically acceptable carrier. In other embodiments, a diNACA implant is administered intraocularly or periorbitally, such as intraocularly, subretinaally, intravitreally, posteriorly near the sclera, anteriorly near the sclera, posteriorly behind the eyeball, intramuscularly or locally. The implant of the present invention can be injected into one or more unrestricted positions, such as a predetermined position, which may include, for example, intravitreal, intrastromal, intracameral, subfascial, retinal, subretinal, posteriorly behind the eyeball, periorbital, suprachoroidal, subchoroidal, conjunctival, subconjunctival, supra-scleral, posteriorly near the sclera, anteriorly near the sclera, pericorneal, local and lacrimal duct.

[0088] Administration of therapeutic agents such as antioxidants by use of one or more intraocular implants can improve the treatment of eye diseases or conditions involving oxidative stress. The implant comprises a pharmaceutically acceptable polymer composition and is formulated to release one or more pharmaceutically active agents over an extended period of time. In certain embodiments involving delivery of a medicament, the dosage regimen can be configured to provide a drug to the anterior or posterior segment of the eye. For example, in order to deliver an ocular drug to the posterior region of the eye, the implant may be introduced as an intravitreal implant, inserted into the vitreous cavity.

[0089] In certain embodiments involving delivery of more than one medicament, the dosage regimen can be configured to provide two or more drugs to the posterior segment of the eye under different dosage regimens. For example, the dosage of the antioxidant in the implant can be discontinuous during treatment, while the non-discontinuous dosage of the adjuvant can be given with the implant in the same total time period. The implant containing the antioxidant and the implant containing the adjuvant can be different implants, or the same implant containing a way of distinguishing the way of giving the antioxidant and the adjuvant, such a way includes different coatings or shells, which may not contain one or two drugs, or one or two drugs are covalently linked to the biodegradable polymer of the implant through a biodegradable bond, thereby allowing the delivery of one or more drugs to be adjusted during treatment. The implant can effectively provide a therapeutically effective dose of one or more medicaments directly to the area of ​​the eye to treat one or more eye diseases or disorders involving oxidative stress. Therefore, in the case of a single administration, the therapeutic agent will be available at the site where they are needed, and can be maintained for an extended period of time, rather than subjecting the patient to repeated injections, or in the case of self-administered drops, only limited burst exposure to ineffective treatment of one or more active agents.

[0090] As used herein, the term "adjuvant" refers to agents that do not deleteriously interact with the antioxidants of the formulation, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants, flavorings and / or aromatic substances, etc.

[0091] According to one such intraocular implant disclosed herein, a therapeutic component and a drug release maintenance component associated with the therapeutic component. According to the present invention, the therapeutic component comprises, is essentially composed of, or is composed of the antioxidant diNACA. The drug release maintenance component is associated with the therapeutic component to maintain the release of a therapeutically effective amount of antioxidant into the eye in which the implant is placed. After the implant is placed in the eye, the time period in which the therapeutic amount of antioxidant is released into the eye is greater than about two months.

[0092] For the purposes of this specification, we use the following terms as defined in this section, unless the context of the words indicates a different meaning.

[0093] As used herein, "intraocular implant" refers to a device or component or drug that is constructed, sized or otherwise configured to be placed in the "eye", including the subconjunctival space. Intraocular implants are generally biocompatible with the physiological conditions of the eye and do not cause adverse side effects. Intraocular implants can be placed in the eye without disrupting the vision of the eye.

[0094] As used herein, "therapeutic component" refers to a portion of an intraocular implant that contains one or more therapeutic agents or substances for treating an ocular medical condition. The therapeutic component can be a discrete area of ​​the intraocular implant, or it can be uniformly distributed throughout the implant. The therapeutic agent of the therapeutic component is generally ophthalmologically acceptable and is provided in a form that does not cause adverse reactions when the implant is placed in the eye.

[0095] As used herein, "drug release sustaining component" refers to a portion of an intraocular implant that is effective to provide sustained or extended release of the therapeutic agent of the implant. The drug release sustaining component can be a biodegradable polymer matrix, or it can be a coating covering the core region of the implant containing the therapeutic component.

[0096] As used herein, "associated with" means mixed with, dispersed within, coupled to, covered with, or surrounded by. With respect to intraocular implants comprising a therapeutic component associated with a biodegradable polymer matrix, "associated with" specifically excludes a biodegradable polymer coating that may be provided on or around the matrix.

[0097] As used herein, an "ocular region" or "ocular site" generally refers to any area of ​​the eyeball, including the anterior and posterior segments of the eye, and generally includes, but is not limited to, any functional (e.g., used for vision) or structural tissue present in the eyeball, or a tissue or cell layer that partially or completely lines the inside or outside of the eyeball. Specific examples of ocular regions within the ocular region include the anterior chamber, the posterior chamber, the vitreous cavity, the choroid, the suprachoroidal space, the conjunctiva, the subconjunctival space, the suprascleral space, the intracorneal space, the supracorneal space, the sclera, the pars plana, the surgically induced avascular zone, the macula, and the retina.

[0098] As used herein, an "ophthalmic or ocular disease" or "ophthalmic or ocular condition" is a disease, ailment, or condition that affects or involves the eye or one of the parts or regions of the eye. Broadly speaking, the eye includes the eyeball or globe, the tissues and fluids that make up the eye, the muscles around the eye (such as the oblique and rectus muscles), and portions of the optic nerve in or near the eye.

[0099] Anterior ocular disorders are diseases, ailments, or conditions that affect or involve the anterior (i.e., front part of the eye) ocular region or area, such as the periocular muscles, eyelids, or ocular tissue or fluid, which is located in front of the posterior wall of the lens capsule or ciliary muscle. Thus, anterior ocular disorders primarily affect or involve the conjunctiva, cornea, anterior chamber, iris, posterior chamber (behind the retina but in front of the posterior wall of the lens capsule), lens or lens capsule, and the blood vessels and nerves that vascularize or innervate the anterior ocular region or area.

[0100] Anterior ocular conditions may include diseases, ailments, or conditions such as, for example, aphakia; pseudophakia; astigmatism; blepharospasm; cataracts; conjunctival disease; conjunctivitis; corneal disease; corneal ulcers; dry eye syndrome; eyelid disease; lacrimal apparatus disease; tear duct obstruction; myopia; presbyopia; pupillary disorders; refractive disorders, and strabismus. Glaucoma may also be considered an anterior ocular condition, as the clinical goal of glaucoma treatment may be to reduce the high pressure of aqueous fluid in the anterior chamber of the eye (i.e., reduce intraocular pressure).

[0101] Posterior ocular disorders are diseases, ailments, or conditions that primarily affect or involve the posterior ocular region or area, such as the choroid or sclera (located posteriorly through the plane of the posterior wall of the lens capsule), the vitreous body, the vitreous cavity, the retina, the optic nerve (i.e., the optic disc), and the blood vessels and nerves that vascularize or innervate the posterior ocular region or area.

[0102] Thus, posterior ocular conditions may include diseases, ailments, or conditions such as, for example, acute macular neuroretinopathy; Behet's disease; choroidal neovascularization; diabetic uveitis; histoplasmosis; infections, such as those caused by fungi or viruses; macular degeneration, such as acute macular degeneration, non-exudative age-related macular degeneration, and exudative age-related macular degeneration; edema, such as macular edema, cystoid macular edema, and diabetic macular edema; multifocal choroiditis; ocular trauma affecting a posterior ocular region or location; ocular tumors; retinal disorders, such as central retinal vein occlusion, diabetic retinopathy (including proliferative diabetic retinopathy), proliferative vitreoretinopathy (PVR), retinal artery occlusive disease, retinal detachment, uveitic retinal disease; sympathetic ophthalmia; Vogt-Koyanagi-Harada (Vogt Koyanagi-Harada) (VKH) syndrome; uveal effusion; posterior ocular conditions caused by or affected by ocular laser therapy; posterior ocular conditions caused by or affected by photodynamic therapy, photocoagulation, radiation retinopathy, epiretinal membrane disorders, branch retinal vein occlusion, anterior ischemic optic neuropathy, non-retinopathy diabetic retinal dysfunction, retinitis pigmentosa, and glaucoma. Glaucoma can be considered a posterior ocular condition because the goal of treatment is to prevent or reduce the occurrence of vision loss due to damage or loss of retinal cells or optic nerve cells (i.e., neuroprotection).

[0103] As used herein, the term "biodegradable" refers to a material that will break down into soluble substances or will degrade under physiological conditions into smaller units or chemicals that are themselves non-toxic to the subject (biocompatible) and can be metabolized, eliminated or excreted by the subject. As used herein, the terms biodegradable, bioabsorbable and bioerodible are equivalent and are used interchangeably herein.

[0104] As used herein, the term "non-biodegradable" refers to a material that will not break down into soluble substances or will not degrade under physiological conditions into smaller units or chemicals that are themselves non-toxic (biocompatible) to a subject and can be metabolized, eliminated or excreted by a subject. As used herein, the terms non-biodegradable, non-bioerodible and non-bioabsorbable are equivalent and are used interchangeably herein.

[0105] As used herein, the term "biodegradable polymer" refers to one or more polymers that degrade in vivo, and wherein erosion and / or breakdown of the one or more polymers over time occurs simultaneously with or subsequent to the release of the therapeutic agent. Specifically, hydrogels such as methylcellulose that release drugs by polymer swelling are specifically excluded from the term "biodegradable polymer." A biodegradable polymer can be a homopolymer, a copolymer, or a polymer comprising more than two different polymer units.

[0106] As used herein, the terms "treat," "treating," or "treatment" refer to reducing or eliminating or preventing an ocular condition, ocular damage or injury, or promoting healing of damaged or injured ocular tissue.

[0107] As used herein, the term "therapeutically effective amount" refers to the level or amount of an agent required to treat an ocular condition or reduce or prevent ocular damage or injury without causing significant negative or adverse side effects to the eye or area of ​​the eye.

[0108] As used herein, "susceptible" or "prone to" or "predisposed to" a particular disease or condition, etc., refers to an individual who is more likely to develop the disease or condition than the general population based on genetic, environmental, health and / or other risk factors. The increased likelihood of developing a disease can be an increase of about 10%, 20%, 50%, 100%, 150%, 200% or more.

[0109] As used herein, the term "lactide" refers to lactide and lactic acid monomers.

[0110] As used herein, the term "glycolide" refers to glycolide and glycolic acid monomers.

[0111] The present invention provides novel drug delivery formulations or preparations, and methods of using such formulations or preparations, for extended or sustained release of a drug into the eye, e.g., to achieve a sustained desired therapeutic effect. The drug delivery formulation or preparation is in the form of an implant or implant element that can be placed in the eye.

[0112] The intraocular implant according to the disclosure herein comprises an antioxidant drug. The antioxidant drug may be present in or on the same implant or a different implant. The antioxidant drug may reduce oxidative stress in the eye within an acceptable range.

[0113] Such intraocular implants may include a therapeutic component and a drug release-maintaining component associated with the therapeutic component. According to the present invention, the therapeutic component includes, consists essentially of, or consists of an antioxidant drug. The drug release-maintaining component is associated with the therapeutic component to maintain the release of a therapeutically effective amount of the steroid into the eye in which the implant is placed. After the implant is placed in the eye, it is preferred that the time period during which the therapeutically effective amount of the antioxidant is released into the eye is greater than about one month or two months or more.

[0114] In one embodiment, the intraocular implant comprises an antioxidant drug and a biodegradable polymer matrix. The antioxidant drug is associated with a biodegradable polymer matrix, and the biodegradable polymer matrix releases the drug such as by dissolution, rupture or degradation, and its rate effectively maintains the time of therapeutically effective amount of antioxidant drug released from the implant greater than or longer than about one month or two months or more months from the time when the implant is placed in the eye part or the area of ​​the eye. The intraocular implant is biodegradable or bioerodible, and provides sustained release of antioxidant drugs in the eye for an extended period of time, such as more than a few days, a few weeks, two months, or about three months or longer, up to about six months or longer.

[0115] The biodegradable polymer component of the implant can be a mixture of biodegradable polymers, wherein at least one biodegradable polymer is a polylactide or poly(lactide-co-glycolide) polymer having a molecular weight of less than 40 kilodaltons (kD). Additionally or alternatively, the implant can include a first biodegradable polymer having a terminal free acid group and a different second biodegradable polymer having a terminal free acid group. Additionally or alternatively, the implant can include a first biodegradable polymer having a terminal ester and a different second biodegradable polymer having a terminal ester group. Furthermore, the aforementioned implant can include a mixture of different biodegradable polymers, each biodegradable polymer having an intrinsic viscosity ranging from about 0.16 deciliters per gram (dL / g) to about 0.24 dL / g. Examples of suitable biodegradable polymers include polymers synthesized from lactide monomers, glycolide monomers, and mixtures thereof. Other examples of suitable biodegradable polymers include polymers synthesized from lactic acid monomers, glycolic acid monomers, and mixtures thereof.

[0116] In another embodiment, the intraocular implant comprises a therapeutic component comprising an antioxidant drug and a polymer outer layer covering the therapeutic component. The polymer outer layer may include one or more orifices or openings or holes that effectively allow liquid to enter the implant and allow steroids to flow out of the implant. The therapeutic component is provided in the core or inner portion of the implant, and the polymer outer layer covers or coats the core. The polymer outer layer may include one or more biodegradable parts. The implant can provide extended release of steroids for more than or longer than about two months, more than about one year, or even more than about five years or about ten years.

[0117] In one embodiment, the polymer outer layer of the implant may comprise two or more layers or coatings of biodegradable materials, wherein each such layer has a different composition or degradation rate than the layer immediately adjacent thereto. For example, the polymer outer layer of the implant may comprise concentric rings or nested coatings comprising a first layer, wherein the first layer may comprise, for example, a biodegradable polymer and no antioxidant drug, a biodegradable polymer comprising a therapeutically effective amount of an antioxidant drug, a biodegradable polymer comprising an amount of an adjuvant effective to reduce at least one side effect of the antioxidant drug, a biodegradable polymer comprising a therapeutically effective amount of an antioxidant drug and an amount of an adjuvant effective to reduce at least one side effect of a steroid, and a biodegradable polymer without any additional drug.

[0118] The second layer may also comprise, for example, a biodegradable polymer in the absence of an antioxidant drug, a biodegradable polymer comprising a therapeutically effective amount of an antioxidant drug, a biodegradable polymer comprising an amount of an adjuvant capable of reducing at least one side effect of the antioxidant drug, a biodegradable polymer comprising a therapeutically effective amount of a steroid and an amount of an adjuvant capable of reducing at least one side effect of the steroid, and a biodegradable polymer without any additional drug, with the additional proviso that the first layer and the second layer are positioned adjacent to each other in the biodegradable implant, the first layer and the second layer are not identical, and the first layer is designed to be substantially eroded prior to the second layer.

[0119] Additional layers may be present; preferably, each such layer will be different from the layers immediately surrounding it.

[0120] It is well known that long-term ophthalmic treatment with medications must be closely monitored due to potential toxicity and long-term side effects. For example, adverse reactions listed for conventional ophthalmic dexamethasone preparations include: glaucoma (with optic nerve damage, visual acuity and visual field defects, and ocular hypertension), posterior subcapsular cataract formation, and secondary ocular infections caused by pathogens including herpes simplex. Other adverse side effects of conventional topical treatment with steroids may include hypertension, hyperglycemia, increased susceptibility to infection, and peptic ulcers.

[0121] Age-related macular degeneration ("AMD") comprises a large group of inherited vision disorders that cause progressive loss of the retina's photoreceptor cells, leading to severe visual impairment and often incurable blindness. The most common form of AMD is rod-cone dystrophy, in which the first symptom is night blindness, followed by progressive loss of peripheral vision in daylight, and ultimately blindness decades later. As a common pathology, rod cells die early, while light-insensitive, morphologically altered cone cells persist longer.

[0122] Diabetic retinopathy (DR), sometimes called diabetic eye disease, is a condition in which diabetes causes damage to the retina and is the leading cause of blindness. Typically, DR affects up to 80% of people with diabetes. Importantly, the longer a person has diabetes, the higher their chances of developing diabetic retinopathy. In the United States, diabetic retinopathy accounts for 12% of all new cases of blindness and is the leading cause of blindness in people aged 20 to 64.

[0123] Glaucoma describes several eye diseases caused by damage to the optic nerve leading to vision loss. Typical symptoms of glaucoma include, for example, eye pain, blurred vision, mid-pupil dilation, eye redness, and nausea. Increased intraocular pressure is a major risk factor for glaucoma, as is a family history of glaucoma and hypertension, however, the etiology of glaucoma is still under investigation.

[0124] (2R,2R')-3,3'-Disulfanediylbis(2-acetamidopropionamide) (diNACA), also referred to herein as NPI-002, has the following chemical structure:

[0125]

[0126] (2R,2R')-3,3'-Disulfanediylbis(2-acetamidopropionamide) (diNACA), a dimer form of N-acetyl-L-cysteinamide, can be used to treat ophthalmic diseases and conditions involving oxidative stress, including but not limited to age-related macular degeneration, cataracts, corneal endothelial cell loss or protection, glaucoma, diabetic retinopathy, presbyopia, and retinitis pigmentosa.

[0127] Glutathione (GSH) is a tripeptide, cL-glutamyl-L-cysteinyl-glycine, present in all mammalian tissues. It has several important functions, including detoxification of electrophiles, scavenging ROS, maintaining the thiol status of proteins, and regeneration of the reduced forms of vitamins C and E. GSH is the major non-protein thiol in mammalian cells; therefore it is essential for maintaining intracellular redox balance and the necessary thiol status of proteins. In addition, it is essential for the function of some antioxidant enzymes, such as glutathione peroxidase.

[0128] The level of intracellular GSH is determined by the balance between production and loss. Production is caused by de novo synthesis and regeneration of GSH from GSSG by GSSG reductase. Generally, there is enough capacity to maintain all intracellular GSH in a reduced state in the GSSG reductase system, so it is almost impossible to gain by improving this pathway. The main source of intracellular GSH loss is transport out of the cell. The intracellular GSH level ranges from 1-8 mM, while the extracellular level is only a few μM; this large concentration gradient basically prevents the transport of GSH into the cell, and once it is transported out of the cell, it is rapidly degraded by γ-glutamyl transpeptidase. Inhibition of GSH transporters can theoretically increase intracellular GSH levels, but there are potential problems because transporters are not specific to GSH, and their inhibition may lead to imbalances in other amino acids and peptides. Therefore, the intracellular GSH level is mainly regulated by changes in synthesis.

[0129] In the cytosol of almost all cells, GSH is synthesized by two ATP-requiring enzymatic steps: L-glutamate + L-cysteine ​​+ ATP [→] γ-glutamyl-L-cysteine ​​+ ADP + Pi and γ-glutamyl-L-cysteine ​​+ L-glycine + ATP [→] GSH + ADP + Pi. The first reaction is rate-limiting and is catalyzed by glutamate cysteine ​​ligase (GCL, EC6.3.2.2). GCL consists of a 73Kd heavy catalytic subunit (GCLC) and a 30Kd modifying subunit (GCLM), which are encoded by different genes. GCCL is non-allosterically competitively inhibited by GSH (Ki = 2.3 mM) and regulated by the availability of L-cysteine. The apparent Km of GLC for glutamate is 1.8 mM, and the intracellular glutamate concentration is approximately 10-fold higher, making glutamate not limiting, but the Km for cysteine ​​is 0.1-0.3 mM, which is close to its intracellular concentration. The second reaction is catalyzed by GSH synthase (GS, EC 6.3.2.3), which is 118 Kd and consists of two identical subunits. Although GS is not thought to be important in the regulation of GSH synthesis under normal conditions, it may play a role in stress situations, as GSH levels and GS activity decrease in response to surgical trauma, while GCL activity is unchanged. In addition, increasing the expression of both GCLC and GS results in higher levels of GSH compared to increased GCLC expression alone. In order to maximize the effect of increasing the synthase, elevated levels of cysteine ​​must be provided. In cultured neurons, 90% of cysteine ​​uptake occurs through the sodium-dependent excitatory amino acid transporter (EAAT) system. There are five EAATs, and neuronal uptake of cysteine ​​occurs primarily through EAAT3, which is more commonly known as excitatory amino acid carrier-1 (EAAC1). Under normal conditions, most EAAC1 is located in the ER and only translocates to the plasma membrane when activated. This translocation is negatively regulated by glutamate transporter-related protein 3-18 (GTRAP3-18), and inhibition of GTRAP3-18 increases GSH levels in neurons. Thus, internalization of cysteine ​​provides a roadblock to GSH synthesis, but fortunately it can be circumvented by N-acetylcysteine ​​(NAC), which readily enters cells even in the absence of activated EAAC1. Systemically administered NAC is able to enter the CNS, increase GSH levels, and provide benefits in neurodegenerative disorders in which oxidative stress is an important part of the pathogenesis.

[0130] All cellular compartments must be protected from oxidative damage, including the cytoplasm, mitochondria, and nucleus. The inventors have previously performed gene transfer of enzymes that detoxify reactive oxygen species, but this approach requires expression of two enzymes in the cytoplasm and two enzymes in the mitochondria. In contrast, since GSH can diffuse throughout the cell, the present invention provides protection for all cellular compartments by expressing only two enzymes in the cytosol.

[0131] NAC is used to treat acetaminophen overdose, with 140 mg / kg as a loading dose, followed by 70 mg / kg every 4 hours, for a total of 17 doses, starting 4 hours after the loading dose. In clinical studies, NAC has been orally administered 400 to 1000 mg once a day, and 200 to 600 mg three times a day. However, after oral administration of 600 mg, NAC is rapidly absorbed and then rapidly cleared. It has been reported that the plasma half-life of NAC is 2.5 hours and no NAC can be detected 10-12 hours after administration. During absorption, NAC is rapidly metabolized to cysteine, which is a direct precursor of glutathione. Based on this evidence, including NACA being a precursor and / or carrier of NAC, it is expected that the effect of NACA in vivo is similar to that of NAC. However, the inventors have demonstrated that NACA and diNACA are very different from NAC in the treatment of age-related macular degeneration, glaucoma and / or diabetic retinopathy.

[0132] According to one embodiment, the present invention provides a method for preventing, ameliorating or treating a disease or condition associated with oxidative stress in a subject, the method comprising administering a therapeutically effective amount of NACA to increase the amount of glutathione expressed in a tissue of the subject.

[0133] Intraocular implants have been developed that can release drug loads over varying periods of time. These implants, when inserted into an eye, such as but not limited to the vitreous or subconjunctival space of the eye, provide therapeutic levels of steroids and / or adjuvants for extended periods of time (e.g., about 2 months or longer). The disclosed implants are effective in treating ocular conditions, such as posterior ocular conditions.

[0134] In one embodiment of the present invention, the intraocular implant comprises a biodegradable polymer matrix. The biodegradable polymer matrix is ​​a drug release maintenance component. The biodegradable polymer matrix effectively forms a biodegradable intraocular implant. The biodegradable intraocular implant may include a steroid and / or adjuvant associated with the biodegradable polymer matrix. Such association may be "passive", such as coextrusion of (multiple) active agents with a biodegradable polymer, or "active", connected or coupled to the polymer by covalent chemical bonds, chelation, strong hydrogen bonds, ionic interactions, etc. The matrix is ​​degraded at a rate that effectively maintains the sustained release of a therapeutically effective amount of steroids, with a time greater than about two months from the time the implant is placed in an ocular region or ocular part such as the vitreous body of the eye.

[0135] It should be understood that the actual preferred amount of active compound for a given therapy will vary depending on, for example, the specific compound used, the specific composition formulated, the mode of administration and the characteristics of the subject, such as the species, sex, weight, general health and age of the subject. The optimal administration rate for a given dosing regimen can be readily determined by those skilled in the art using conventional dosage determination tests performed according to the aforementioned guidelines.

[0136] Ranges provided herein are understood to be shorthand for all of the values ​​within the range.

[0137] As used herein, embodiments of the present invention are defined to include pharmaceutically acceptable derivatives thereof. "Pharmaceutically acceptable derivatives" refers to any pharmaceutically salt, ester, salt of an ester, or other derivative of a compound of the present invention, which can provide (directly or indirectly) a compound of the present invention after administration to a recipient. Particularly advantageous derivatives are those that increase the bioavailability of such a compound when the compound of the present invention is administered to a mammal (e.g., by making the orally administered compound more easily absorbed into the blood to increase serum stability or reduce the clearance rate of the compound) or enhance the delivery of the parent compound to a biological compartment (e.g., brain or lymphatic system) relative to the parent substance. Derivatives include derivatives in which groups that enhance water solubility or active transport through the intestinal membrane are added to the structure of the formula described herein.

[0138] Embodiments of the present invention can be improved by adding appropriate functionality to enhance selective biological properties. Such improvements are known in the art and include increasing the biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), improving oral availability, increasing solubility to achieve improvements in administration by injection, changing metabolism and changing excretion rate. The pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. The example of suitable acid salts includes acetate, adipate, benzoate, benzenesulfonate, butyrate, citrate, digluconate, dodecyl sulfate, formate, fumarate, glycolate, hemisulfate, enanthate, caproate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate (palmoate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, toluenesulfonate and undecanoate (undeconaoate). Salts derived from appropriate bases include alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium, and N-(alkyl)4+ salts. The present invention also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water-soluble or oil-soluble or dispersible products can be obtained by such quaternization reactions.

[0139] Embodiments of the present invention can be administered, for example, by injection, intraocular, intravitreal, retrobulbar, posterior scleral, anterior scleral, subretinal, intravenous, intraarterial, subdermal, intramuscular or subcutaneous; or orally, buccal, nasal, transmucosal, via a catheter directly to the diseased organ, topically or in an ophthalmic preparation, with a dosage range of about 0.001, 0.01, 0.1, 0.5, 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90 to about 100 mg / kg body weight, or as required by a specific drug, more preferably 0.5-10 mg / kg body weight. It should be understood that when the compound is delivered directly to the eye, considerations such as body weight have less impact on the dosage.

[0140] The frequency of administration will depend on the medicament administered, the progression of the disease or condition of the subject, and other considerations known to those skilled in the art. For example, the pharmacokinetic and pharmacodynamic considerations for compositions delivered to the eye or even to a compartment within the eye are different, such as very low clearance in the subretinal space. Therefore, administration can be performed infrequently, such as once a month, once every three months, once every six months, once a year, once every five years, or less. If systemic administration of an antioxidant is to be combined with administration of an expression construct to the subretinal space, it is expected that the frequency of administration of the antioxidant will be higher than that of the expression construct, such as once a day or more, once a week or more.

[0141] The dosage can be determined in conjunction with one or more signs or symptoms of the disease being monitored, such as visual acuity, visual field, night vision, etc. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. A typical preparation will contain about 1% to about 95% of the active compound (weight / weight). Alternatively, such a preparation contains about 20% to about 80% of the active compound. A dosage lower or higher than the above dosage may be required. The specific dosage and treatment regimen for any particular patient will depend on various factors, including the activity of the specific compound used, age, body weight, overall health, sex, diet, administration time, excretion rate, drug combination, severity and course of the disease, disorder or symptom, and the patient's disposal of the disease, disorder or symptom and the judgment of the treating physician.

[0142] The pharmaceutical composition may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. The suspension may be prepared using suitable dispersants or wetting agents (such as, for example, TWEEN®) according to techniques known in the art. ® 80) and suspensions. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspension media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives can be used to prepare injections, as can natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethyl cellulose or similar dispersants, which are commonly used to formulate pharmaceutically acceptable dosage forms, such as emulsions and / or suspensions. Other commonly used surfactants, such as TWEEN ® or SPAN ®And / or other similar emulsifiers or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

[0143] In one or more embodiments, diNACA is administered at a daily dose of about 0.5 to 150 mg / Kg. In other embodiments, diNACA is administered twice or three times a day. On the other hand, diNACA is administered with a second active agent selected from ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; and metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0144] In some embodiments, the dose of diNACA for administration is 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1000, 2500, 5000, 7500 or 10000 mg per implant. On the other hand, the dose for administration is 0.1-0.25, 0.1-0.4, 0.35-0.5, 0.5-1, 1-2, 1-3, 1-4, 1-5, 1-2.5, 2.5-3.5, 4-6, 5-8, 6-9, 7-10 grams per implant. On the other hand, diNACA implants are given prophylactically to prevent eye diseases.

[0145] In another embodiment, the present invention includes a method for treating age-related macular degeneration, glaucoma and / or diabetic retinopathy, the method comprising: identifying a person in need of treatment for age-related macular degeneration; and administering to the person a therapeutically effective amount of diNACA sufficient to treat age-related macular degeneration, glaucoma and / or diabetic retinopathy. It should be understood that, as with the other embodiments defined above, diNACA is administered at a daily dose of about 0.5 to 150 mg / Kg. In another aspect, diNACA is administered twice or three times a day. In another aspect, NACA is administered together with a second active agent disclosed above.

[0146] In another aspect, additional doses of diNACA for administration are 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1000, 2000, 2500, 3000, 4000, 5000, 6000, 7000, 7500, 8000, 9000, or 10000 mg per dose. In another aspect, the dose for administration is 0.1-0.25, 0.1-0.4, 0.35-0.5, 0.5-1, 1-2, 1-3, 1-4, 1-5, 1-2.5, 2.5-3.5, 4-6, 5-8, 6-9, 7-10 grams per dose. In another aspect, NACA is delivered orally via a mini-tablet, capsule, tablet, effervescent, dual release, mixed release, sachet, powder or liquid. In another aspect, diNACA is administered prophylactically to prevent age-related macular degeneration, glaucoma and / or diabetic retinopathy.

[0147] The diNACA preparations described herein can also be delivered to the eye via local eye, intravitreal injection, posterior scleral injection, anterior scleral injection, and periocular injection routes. In one embodiment of the invention, the amount of an active agent or a poorly water-soluble agent or biological product will be about 0.001% to 30% by weight of the active agent in a solution for intravitreal administration. In other embodiments, the amount of the active agent can be 0.05% to 20% by weight and in some cases 0.1% to 18% by weight. Any active agent that is expected to be poorly water-soluble or slightly soluble can be included in the composition of the present invention. In other cases, highly water-soluble active agents or inactive agents can also be included in the composition of the present invention.

[0148] For example, a thick or viscous vehicle that achieves extended release of the active agent can deliver the present invention. For example, in the compositions and methods of the present invention, diNACA can be provided in any poly(ethylene glycol) (PEG) having a molecular weight greater than 500, 1000, 15000 or 2000. The PEG used in the compositions and methods of the present invention can also include PEG 3000, PEG 4000, PEG 6000, PEG 8000, PEG 20000, or higher molecular weight PEGs can be used in the compositions and methods of the present invention.

[0149] The diNACA formulations of the present invention provide many advantages over conventional formulations because PEG can successfully dissolve poorly soluble compounds, achieving effective ophthalmologically acceptable intravitreal, posterior juxta-scleral (PJ), anterior juxta-scleral (AJ) and / or periocular preparations for topical ocular delivery. The bioavailability of the drug can be adjusted by controlling the molecular weight or mixed molecular weight of the PEG used in the formulation. In addition, a 27-gauge or 30-gauge needle can be used to inject the formulation. The toxicity of the active agent can also be reduced or appropriately adjusted by extending its release. Another advantage of the present invention is that the stability of the biologic in the PEG-based solid dosage form described herein is improved.

[0150] The formulation of the present invention may also include lipids to regulate the delivery of the drug and extend the duration. Some examples of lipids include triglycerides, diglycerides, monoglycerides, propylene glycol esters, PEF esters of fatty acids and mixtures thereof. Preferred lipids include glyceryl monolaurate; glyceryl dilaurate; glyceryl monomyristate; glyceryl dimyristate; glyceryl monopalmitate; glyceryl dipalmitate; glyceryl monostearate; glyceryl distearate; glyceryl monooleate; glyceryl dioleate; glyceryl monolinoleate; glyceryl dilinoleate; glyceryl monoarachidate; glyceryl diarachidate; glyceryl monobehenate; glyceryl dibehenate; diethylene glycol monostearate; propylene glycol monostearate; glyceryl monostearate; glyceryl monolinoleate; glyceryl monooleate; glyceryl monopalmitate; and mixtures thereof. A preferred example of lipid is glyceryl palmitostearate. The concentration of lipid is generally less than 31 weight percent (wt%), but is typically less than 14 wt%, and in some cases less than 8 wt%.

[0151] For any particular human or animal, the specific dosage level of the active agent will depend on a variety of factors, including the activity of the active compound employed, age, weight, general health, time of administration, route of administration and the severity of the pathological condition being treated.

[0152] The present invention relates generally to devices and methods for treating a patient's eye, and more particularly to intraocular implants that provide extended release of a therapeutic agent to the eye in which the implant is placed. After the active agent is eluted and depleted from the implant, the therapeutic effect is no longer produced.

[0153] To remedy this, a sustained-release drug delivery system can be used. In 2000, Jaffe et al. reported the use of compressed fluocinolone acetonide pellets coated with silicone and poly(vinyl alcohol) as a sustained-release fluocinolone acetonide delivery device (Jaffe et al., 2000). Jaffe et al. (2000) obtained release rates of 1.9 ± 0.254 / day (6 months) and 2.2 ± 0.6 μg / day (45 days) for a 2-mg device and a 15-mg device, respectively. The release durations for the 2-mg and 15-mg devices were estimated to be 2.7 years and 18.6 years, respectively. U.S. Patents Nos. 6,217,895 and 6,548,078 disclose sustained-release implants for delivering corticosteroids such as fluocinolone acetonide to the eye. However, fluocinolone acetonide intravitreal implants made by Control Delivery Systems (assignee of US Pat. Nos. 6,217,895 and 6,548,078) were only partially successful and resulted in the development of cataracts and increased intraocular pressure.

[0154] Additional biocompatible implants for placement in the eye have been disclosed in a number of patents such as U.S. Pat. Nos. 4,521,210, 4,853,224, 4,997,652, 5,164,188, 5,443,505, 5,501,856, 5,766,242, 5,824,072, 5,869,079, 6,074,661, 6,331,313, 6,369,116, 6,699,493, and 6,726,918.

[0155] Other intravitreal treatment methods are described in U.S. Application Nos. 10 / 966,764, filed October 14, 2004, 11 / 039,192, filed January 19, 2005, and 60 / 587,092, filed July 12, 2004.

[0156] It would be advantageous to provide an eye-implantable drug delivery system, such as an intraocular implant, and methods of using such a system, which is capable of releasing a therapeutic agent at a sustained or controlled rate over an extended period of time, and in an amount with few or no negative side effects.

[0157] Biodegradable polymers may include multiple hydroxyl groups, and the medicament may be connected to the hydroxyl groups via a biodegradable bond. Biodegradable or biodegradable bonds are defined as the type of specific chemical moieties or groups that can be used within a chemical substance, which covalently reversibly couple or crosslink therapeutic agents and / or adjuvants to the biodegradable polymers contained in the implant. Therefore, in certain embodiments of the present invention, such bonds may be contained, and the embodiments provide a controlled release function of steroids and / or adjuvants. In certain embodiments of the present invention, an implant system comprising one or more implants is constructed so that therapeutic agents and adjuvants are released at different rates or at different times after (multiple) implants are implanted. Biodegradable linkages or bonds may be distinguished by their structure and function, and non-limiting examples of different categories or types are provided here.

[0158] One such category includes disulfide bonds, which are well known for covalent coupling. Such bonds are stable under oxidative conditions, but can be cleaved under reducing conditions. For drug delivery, they may be more useful in vivo for a shorter period of time because they are relatively easy to cleave. Simple ester bonds are another preferred type that can be easily formed between acids and alcohols. Another preferred type is any imidate formed from alkyl imidates. Maleimide bonds are also included, as are sulfhydryls or amines for introducing biocleavable bonds.

[0159] Another category in the present invention includes acid-cleavable biocleavable bonds. Preferred biocleavable bonds are used for such release of active agents and other moieties. One such type is an acid-sensitive (or acid-labile) hydrazone bond, as described by Greenfield et al. (1990) and references therein.

[0160] Other types of acid-labile bonds include polyorthoester or diorthoester bonds; examples of such bonds are disclosed in J. Heller et al. (1985), Heller et al. (1993) and Ahmad et al. (1979) and references therein. Also useful may be the acid-labile phosphonamide bonds disclosed by Rahil et al. (1981) and Jeong et al. (2003).

[0161] Implants can be placed in the eye region to treat a variety of eye conditions, including conditions affecting the anterior or posterior regions of the eye. For example, implants can be used to treat a number of eye conditions, including but not limited to maculopathy and retinal degeneration, uveitis, retinitis, choroiditis, vascular and exudative diseases, proliferative disorders, infectious disorders, genetic disorders, tumors, trauma and surgery, retinal tears or perforations, etc. In particular, it is particularly advantageous to treat retinal conditions by insertion, injection or other intravitreal or subconjunctival delivery of such implants.

[0162] A kit according to the invention may comprise one or more implants of the invention and instructions for use of the implants. For example, the instructions may explain how to administer the implants to a patient, and the types of conditions that can be treated with the implants.

[0163] The kit may also include a syringe device for delivering the implant to the eye. The kit, implant and syringe are all sterile.

[0164] Each and every feature described herein and each and every combination of two or more such features are included within the scope of the present invention, provided that the features included in such combinations are not mutually contradictory. In addition, any feature or combination of features may be specifically excluded from any embodiment of the present invention.

[0165] Additional aspects and advantages of the present invention are set forth in the following description and claims, particularly when considered in conjunction with the accompanying drawings and examples.

[0166] The antioxidant of the implant is preferably about 10 to 90% of the implant weight. More preferably, the antioxidant is about 50 to about 80% of the implant weight, or 10% to 49% of the implant, or 20% to 60% of the implant. In a preferred embodiment, the antioxidant accounts for about 30% of the implant weight. In a preferred embodiment, the antioxidant accounts for about 35% of the implant weight. In a preferred embodiment, the antioxidant accounts for about 40% of the implant weight. In a preferred embodiment, the antioxidant accounts for about 45% of the implant weight. In a preferred embodiment, the antioxidant accounts for about 50% of the implant weight. In another embodiment, the antioxidant accounts for about 70% of the implant weight.

[0167] Suitable polymeric materials or compositions for implants include those materials that are compatible with the eye, i.e., biocompatible, so as not to interfere substantially with the function or physiology of the eye. Such materials are preferably at least partially and more preferably substantially completely biodegradable, bioabsorbable or bioerodible.

[0168] Examples of useful polymeric materials include, but are not limited to, materials derived from and / or including organic esters and organic ethers that, when degraded, produce physiologically acceptable degradation products, including monomers. Examples of useful organic ester polymeric materials include, but are not limited to, polylactide, polyglycolide, polycaprolactone, poly(lactide-co-glycolide), poly(lactide-co-caprolactone), poly(lactic acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid), polyhydroxybutyrate, and the like. Similarly, it is found that polymeric materials derived from and / or including anhydrides, amides, orthoesters, etc., can also be used by themselves or in combination with other monomers. The polymeric material can be a ring-opening polymer or an addition polymer or a condensation polymer, advantageously a condensation polymer. The polymeric material can be cross-linked or non-cross-linked, for example, no more than slightly cross-linked, such as less than about 5% or less than about 1% of a cross-linked polymeric material. In most cases, in addition to carbon and hydrogen, the polymer will include at least one of oxygen and nitrogen, advantageously oxygen. Oxygen may be present in the form of oxy groups, such as hydroxyl or ether, carbonyl groups, such as non-oxycarbonyl groups, such as carboxylate, etc. Nitrogen may be present in the form of amides, cyano groups and amino groups. The polymers described in Heller (1987) may be used in the implants of the present invention, which describes encapsulation for controlled drug delivery.

[0169] Also of interest are polymers of hydroxyaliphatic carboxylic acids, whether homopolymers or copolymers, and polysaccharides. Polyesters of interest include polymers of D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, D-lactide, L-lactide, racemic lactide, glycolide, polycaprolactone, and combinations thereof. Herein, the term lactide refers to lactide and lactic acid. Herein, the term glycolide refers to glycolide and glycolic acid. Typically, by using L-lactate or D-lactate, a slowly biodegradable and / or bioabsorbable polymer or polymeric material is obtained, while the lactate racemate is used to significantly enhance biodegradation and / or bioabsorption.

[0170] Useful polysaccharides are, but are not limited to, calcium alginate and functionalized celluloses, particularly carboxymethylcellulose esters, characterized by water insolubility, for example, having a molecular weight of about 5 kD to 500 kD.

[0171] Other polymers of interest include, but are not limited to, poly(vinyl alcohol), polyesters, polyethers, and combinations thereof, which are biocompatible and may be biodegradable and / or bioabsorbable and / or bioerodible.

[0172] Some preferred properties of the polymers or polymeric materials used in the present invention may include biocompatibility, compatibility with therapeutic components, ease of use of the polymer in preparing the drug delivery formulations or preparations of the present invention, a half-life in a physiological environment of at least about 5 hours, preferably greater than about one day, no significant increase in vitreous viscosity, and water insolubility.

[0173] The biodegradable polymeric material included to form the matrix is ​​desirably susceptible to enzymatic instability or hydrolytic instability. The water-soluble polymer can be cross-linked with a hydrolytically or biodegradable unstable cross-link to provide a useful water-insoluble polymer. Depending on the choice of monomer, whether a homopolymer or a copolymer is used, whether a mixture of polymers is used, and whether the polymer includes terminal acid groups, the degree of stability can vary widely.

[0174] Equally important for controlling the biodegradation of polymers and therefore controlling the extended release profile of implants is the relative average molecular weight of the polymer composition used in the implant. The same or different polymer compositions of different molecular weights may be included in the implant to regulate the agent release profile. In some implants, the relative average molecular weight range of the polymer will be about 10 to about 70 kD, typically about 10 to about 55 kD, more typically about 10 to about 45 kD, most typically less than about 40 kD.

[0175] In some implants, copolymers made from glycolide and lactide monomers are used, where the rate of biodegradation is controlled by the ratio of glycolide monomer to lactide monomer incorporated into the polymer chain. The most rapidly degrading copolymers have approximately equal amounts of glycolide and lactide incorporated. Homopolymers or copolymers with unequal ratios will take longer to absorb. The ratio of glycolide to lactide incorporated will also affect the brittleness of the implant, where a more flexible implant is desired for larger geometries. The percentage of lactide monomer incorporated into a poly(lactide-co-glycolide) (PLG) copolymer can be 0-100%, preferably about 15-85%, and more preferably about 35-65%. In some implants, a 50 / 50 PLG copolymer is used.

[0176] The biodegradable polymer matrix of intraocular implant can comprise a mixture of two or more biodegradable polymers. For example, implant can comprise a mixture of a first biodegradable polymer and a second different biodegradable polymer. One or more biodegradable polymers can have terminal acid groups. One or more biodegradable polymers can have ester end groups. In some implants, matrix comprises a first biodegradable polymer with terminal acid groups and a second different biodegradable polymer with terminal acid groups. The first biodegradable polymer can be poly (DL-lactide-co-glycolide). The second biodegradable polymer can be poly (DL-lactide).

[0177] The release of drugs from bioabsorbable polymers is the result of several mechanisms or combinations of mechanisms. Some of these mechanisms include desorption, dissolution, diffusion and erosion of porous channels through hydrated polymers from the implant surface. Erosion can be overall or surface or a combination of the two. As discussed herein, the matrix of intraocular implants can release drugs at a rate of more than three months with the steroids that effectively maintain the therapeutic effective amount after implantation in the eye. In some implants, the drug of the therapeutic amount is released more than four months after implantation. For example, the implant may include an antioxidant, and the matrix of the implant is degraded at a rate of about three months with the antioxidant that effectively maintains the therapeutic effective amount after being placed in the eye. As another example, the implant may include an antioxidant, and the matrix releases drugs at a rate of more than three months, such as about three months to about six months, with the antioxidant that effectively maintains the therapeutic effective amount.

[0178] The rate at which the drug is released from the implant of the present invention may be related to the physical structure of the implant. In a simple but very useful embodiment, the biodegradable polymer of the present invention may comprise a substantially uniform matrix mixed with (multiple) active agents. After drying and formulating the matrix into an intraocular implant, the active agent may be substantially uniformly distributed in the matrix. In such an embodiment, the release characteristics of the medicament are primarily determined by the nature of the solvent and the degradation rate of the matrix.

[0179] In another embodiment, the implant may comprise layers or shells of biodegradable polymers that differ in formulation, to which therapeutic agents and / or adjuvants may be associated and released. The concentration of the polymer, therapeutic agent and / or adjuvant may differ between layers, or the biodegradable polymer may be formulated to deliver such agents at different rates, according to different release profiles, or in different time periods than other layers, or in different time periods than the core portion of the implant. Each layer may differ in formulation from at least one other layer due to, but not limited to, differences in drug concentrations within different layers, absence or presence of therapeutic agents and / or adjuvants within different layers; differences in the manner in which the drug(s) are associated with the polymer matrix in different layers, or differences in the chemistry and density of the biodegradable material.

[0180] Therefore, the release of the medicament from the implant of the present invention can be related to the amount of drug present in the implant and the properties of the polymer of the implant, such as the polymer molecular weight and the ratio of glycolide and lactide added to the polymer. In one embodiment of the implant of the present invention, one or more drugs, such as antioxidants and / or adjuvants, are released at a first rate in a first time period substantially independent of the polymer properties, and the one or more drugs are released at a second rate in a second time period after the first time period according to the polymer properties of the implant. For example, the implant comprises a steroid and a polymer component, the polymer component releases the antioxidant from the implant for a period of about thirty days mainly due to the dissolution of the steroid, and after thirty days, the steroid is released from the implant mainly due to the polymer properties.

[0181] An example of a biodegradable intraocular implant comprises an antioxidant (and / or adjuvant) associated with a biodegradable polymer matrix, the matrix comprising a mixture of different biodegradable polymers. At least one of the biodegradable polymers is a polylactide having a molecular weight of less than 40 kD. Such a mixture can effectively maintain the release of at least one (multiple) agents in a therapeutically effective amount for a period of more than about two months from the time the implant is placed in the eye. In certain embodiments, the polylactide has a molecular weight of less than 20 kD. In other embodiments, the polylactide has a molecular weight of about 10 kD. The polylactide can be poly(D,L-lactide), and the polylactide can include a polymer having terminal free acid groups. In a specific embodiment, the matrix of the implant comprises a mixture of poly(lactide-co-glycolide) and polylactide. Poly(lactide-co-glycolide) and polylactide can each have terminal free acid groups.

[0182] Another example of a biodegradable intraocular implant comprises an antioxidant (and / or adjuvant) associated with a biodegradable polymer matrix, the matrix comprising a mixture of different biodegradable polymers, each biodegradable polymer having an intrinsic viscosity of about 0.15 dL / g to about 0.25 dL / g. For example, one of the biodegradable polymers may have an intrinsic viscosity of about 0.15 dL / g. Alternatively, the mixture may comprise two different biodegradable polymers, and each of the biodegradable polymers may have an intrinsic viscosity of about 0.25 dL / g.

[0183] Other implants may comprise a biodegradable polymer matrix of biodegradable polymers, at least one of which has an intrinsic viscosity of about 0.25 dL / g to about 0.35 dL / g. Additional implants may comprise a mixture of biodegradable polymers, each of which has an intrinsic viscosity of about 0.50 dL / g to about 0.70 dL / g.

[0184] The release of antioxidants (and / or adjuvants) from intraocular implants comprising a biodegradable polymer matrix may include an initial burst of agent release followed by a gradual increase in the amount of agent released, or the release may include an initial delay in steroid release followed by an increase in release. When the implant is substantially completely degraded, the percentage of released agent is about one hundred. Compared to existing implants, in one embodiment, the implant disclosed herein is not completely released until about two months after being placed in the eye, or releases about 100% of at least one agent (antioxidant and / or adjuvant). Therefore, compared to existing implants, the implant exhibits a cumulative release curve that may have a gentler slope or a lower release rate over a longer period of time.

[0185] Implants can provide a therapeutically effective amount of antioxidants over an extended period of time, or a series of such periods, without the need for such large dosages. Therefore, implants of the present invention can contain 1, 2, 3, 4 or 5 micrograms of antioxidants, which are gradually released over time without causing significant eye toxicity or other adverse side effects. In one embodiment, antioxidants can be alternated in different shells of implants so that they are only delivered in a specific period of time, with significantly less (or no) antioxidants delivered in the middle period of time. In this way, it is possible to avoid or reduce the side effects of continued exposure of eyes to antioxidants and possible continual delivery. In another embodiment, an intravitreal implant comprises an antioxidant and an intravitreal implant in the form of a biodegradable polymer associated with the antioxidant, and the intravitreal implant releases the antioxidant with a reduced toxicity-related amount, and the reduced toxicity is relative to the toxicity associated with the antioxidant given with a liquid composition.

[0186] In some cases, it can be expected that a relatively constant rate of releasing antioxidants from an implant is provided during the life of the implant. For example, it can be expected that a steroid is released in an amount of about 0.01 μg to about 2 μg per day over the life of the implant. However, the release rate can become increased or decreased according to the formulation of a biodegradable polymer matrix. In addition, the release curve of steroids may include one or more linear portions and / or one or more nonlinear portions. Preferably, once the implant begins to degrade or erode, the release rate is greater than zero.

[0187] It may be desirable to include delivery of an adjuvant in conjunction with intravitreal or subconjunctival delivery of an antioxidant to reduce or eliminate at least one side effect compared to delivery of the steroid in an otherwise identical manner without the adjuvant. The adjuvant and antioxidant may be included in the same implant, or co-administered in separate implants during the same treatment period.

[0188] Implant can be integral, i.e. have one or more activating agents that are evenly distributed in the polymer matrix, or be encapsulated, wherein the activating agent is encapsulated by the polymer matrix. Due to being easy to manufacture, integral implant is normally a preferred core / shell reservoir type encapsulation form. However, in some cases where the therapeutic level of medicine falls in a narrow window, it may be useful to be provided by encapsulated or reservoir type implant better control. In addition, the therapeutic component comprising an antioxidant can be distributed in the matrix with a non-uniform pattern. For example, implant can include an antioxidant and / or a part of an auxiliary agent with respect to the second portion of the implant having a higher concentration.

[0189] In another embodiment of the present invention, the intraocular implant comprises a therapeutic component and a drug release maintenance component, wherein the therapeutic component comprises an antioxidant, and the drug release maintenance component comprises one or more coatings covering the core region of the implant. The therapeutic component and / or adjuvant are provided in the core region. The polymer outer layer can be relatively impermeable to the therapeutic component and the eye fluid. Alternatively, the polymer outer layer is initially impermeable to the therapeutic component and the eye fluid, but then becomes permeable to the therapeutic component or the eye fluid as the outer layer degrades. Therefore, the polymer outer layer can comprise a polymer, such as polytetrafluoroethylene, polyfluorinated ethylene propylene, polylactide, polyglycolide, silicone or a mixture thereof.

[0190] The aforementioned implants may be understood as reservoirs comprising one or more therapeutic agents such as antioxidants and / or adjuvants.

[0191] In some implants, the release of the agent maintenance component comprises a polymer outer layer covering the therapeutic component and / or auxiliary agent, and the outer layer comprises a plurality of openings or holes, through which the therapeutic component can reach the external environment of the implant, such as the eye region of the eye, from the drug delivery system. The hole enables liquid to enter the inside of the implant and dissolve the medicament contained therein. The release of the therapeutic agent and / or auxiliary agent from the implant may be affected by the solubility of the drug in the liquid, the size of (multiple) holes and the number of holes. In some implants, the number of hole sizes and holes can effectively provide the desired release characteristics of substantially all implants. Therefore, additional excipients may not be needed to achieve the desired result. However, in other implants, excipients may be provided to further enhance the release characteristics of the implant.

[0192] Various biocompatible substantially impermeable polymer compositions can be used to prepare the outer layer of implants. Some relevant factors to be considered when selecting polymer compositions include: compatibility of polymer with the biological environment of implant, compatibility of drug with polymer, ease of manufacture, half-life in physiological environment of at least a few days, viscosity of vitreous body not significantly enhanced, no cytotoxicity, and desired release rate of drug. According to the relative importance of these characteristics, the composition can be changed. Several such polymers and their preparation methods are well known in the art. See, for example, No. 4,304,765, 4,668,506, 4,959,217, 4,144,317 and No. 5,824,074 U.S. Patents, Encyclopedia of Polymer Science and Technology, Vol. 3, Interscience Publishers, Inc. publishes, New York, latest edition, and Scott, JR and Roff, WJ's Handbook of Common Polymers, published by CRC Press, Cleveland, Ohio, latest edition.

[0193] The polymer of interest may be non-biodegradable, non-bioerodible or non-bioabsorbable. The polymer of interest may be a homopolymer, a copolymer, a linear, branched or cross-linked derivative. Some exemplary polymers include: polyurethane or polyurea, cross-linked poly (vinyl acetate), etc., ethylene-vinyl ester copolymers with 4 to 80% ester content, such as ethylene-vinyl acetate (EVA) copolymers, ethylene-vinyl hexanoate copolymers, ethylene-vinyl propionate copolymers, ethylene-vinyl butyrate copolymers, ethylene-vinyl valerate copolymers, ethylene-trimethylacetate copolymers, ethylene-diethylacetate copolymers, ethylene-3-methylbutyrate copolymers, ethylene-3-3-dimethylbutyrate copolymers and ethylene-vinyl benzoate copolymers, or mixtures thereof.

[0194] Additional examples include polymers such as poly(methyl methacrylate), polybutyl methacrylate, plasticized poly(vinyl chloride), plasticized polyamide, plasticized nylon, plasticized soft nylon, plasticized poly(ethylene terephthalate), natural rubber, silicone, polyisoprene, polyisobutylene, polybutadiene, polyethylene, polytetrafluoroethylene, poly(vinylidene chloride), polyacrylonitrile, cross-linked polyvinyl pyrrolidone, chlorinated polyethylene, poly(chlorotrifluoroethylene), poly(ethylene chlorotrifluoroethylene), polytetrafluoroethylene, poly(ethylene tetrafluoroethylene), poly(4,4-isopropylidene diphenylene carbonate), polyurethane, polyperfluoroalkoxy, poly(vinylidene fluoride), vinylidene chloride-acrylonitrile copolymer, vinyl chloride-diethyl fumarate copolymer, silicone, silicone rubber (medical grade, such as SILASTIC ® Medical grade ETR elastomer Q7-4750 or Dow Corning ® MDX 4-4210 medical grade elastomer); and a cross-linked copolymer of polydimethylsilane silicone polymer.

[0195] Some other examples of polymers include: polydimethylsiloxane, ethylene-propylene rubber, silicone-carbonate copolymers, vinylidene chloride-vinyl chloride copolymers, vinyl chloride-acrylonitrile copolymers, vinylidene chloride-acrylonitrile copolymers, poly(olefins), poly(vinyl-olefins), poly(styrenes), poly(halo-olefins), polyethylenes such as poly(vinyl acetate), cross-linked polyvinyl alcohol, cross-linked poly(vinyl butyrate), ethylene ethyl acrylate copolymers, poly(ethylhexyl acrylate), poly(vinyl chloride), poly(vinyl acetal), plasticized ethylene vinyl acetate copolymers, polyvinyl alcohol, poly(vinyl acetate), ethylene vinyl chloride copolymers, polyvinyl esters, polyvinyl butyrate, polyvinyl formals, polyacrylates, polymethacrylates, poly(oxides), polyesters, polyamides and polycarbonates, or mixtures thereof.

[0196] In some aspects, implants with an outer coating (with or without pores) can be biodegradable, wherein the outer coating degrades after the drug has been released for a desired duration. The biodegradable polymer composition can comprise any of the biodegradable polymers defined above or a combination thereof. In some implants, the polymer is polytetrafluoroethylene (commercially known as TEFLON ® ), ethyl vinyl alcohol or ethylene vinyl acetate, all of which are not biodegradable, bioerodible or bioabsorbable.

[0197] The implant containing antioxidants generally exhibits a desired release time, wherein the orifice is configured to have a total area less than 1% of the total surface area of ​​the implant. A substantially cylindrical implant has a first end, a second end, and a main body portion between the first end and the second end. Generally, the implant disclosed herein is sealed at the first section and the second end. One or more holes are formed in the main body portion of the implant. The hole generally has a diameter of at least about 250 μm and less than about 500 μm. For example, the hole can have a diameter of about 250 μm, 325 μm, 375 μm, or 500 μm. Smaller holes can be provided in other implants. Generally, two or three holes are provided in the implant outer layer. For an implant having a length of about 7 mm to about 10 mm, the holes can be spaced apart by a distance of about 1 mm to about 2 mm.

[0198] The implant may be capable of releasing the antioxidant at a concentration of less than 2 μg / day. Some implants may be capable of releasing the antioxidant at a concentration of about 0.5 μg / day. The implant may be capable of providing a therapeutically effective amount of the antioxidant to the ocular region of the eye for more than one year, such as more than five years, or even about 10 years.

[0199] The implant may include a coating formed around a core containing a therapeutic agent.The core may contain the therapeutic agent (or therapeutic component and adjuvant) associated with a biodegradable polymer matrix, or the core may be formed by filling a preformed coating such as a tube.

[0200] Antioxidants and / or adjuvants can be deposited in the preformed coating in the form of dry powder, granules, fine particles or compressed solids. One or more medicaments can also be present in solution. In addition, the core can include a mixture of a biodegradable polymer matrix and one or more medicaments, such as the above-mentioned matrix containing implants. The polymer used in the matrix together with the therapeutic agent and / or adjuvant is biocompatible with body tissues and body fluids, and can be biodegradable or substantially insoluble in body fluids. Any of the above-mentioned biocompatible polymer compositions can be used to prepare the matrix. The amount of polymer in the core can be about 0% by weight to 80% by weight. These polymers are commercially available, and methods for preparing polymer matrices are well known in the art. See, for example, U.S. Pat. No. 5,882,682.

[0201] The biocompatible, substantially impermeable outer layer can be obtained by coating the core with the above-mentioned polymer composition. The coating can be applied using an organic solvent, and then the solvent can be vacuum removed from the coating to leave a dry coating. At an appropriate temperature, the polymer is dissolved or suspended in an organic solvent at a concentration of about 10 to about 80 weight percent, for example, 60°C to 90°C for poly(lactic acid) or polylactide polymers. The resulting mixture can be cut, molded, injection molded, extruded, or poured or sprayed onto a preformed core to any shape or size for implantation. Spraying can be completed in a rotating disk coater or a fluidized bed coater until the desired coating thickness is reached.

[0202] Alternatively, the core can be dip coated or melt coated. This type of coating is particularly useful with waxes and oils. In another embodiment, the core can be compression coated, wherein a suitable polymer composition can be pressed onto a preformed core. On the other hand, before applying the impermeable coating, an adhesive coating such as shellac or poly (vinyl acetate phthalate) (PVAP) is applied to the core to improve the adhesion of the impermeable coating to the core. These techniques are well known in the art. See, for example, JR Scott and WJ Roff's Handbook of Common Polymers, Chapter 64, (1971) CRC Press, Cleveland, Ohio.

[0203] When the outer layer is injection molded or extruded to form the desired shape, the cavity formed by the outer layer can then be filled with the therapeutic agent and / or adjuvant composition. The ends are then sealed with end caps. At least one orifice is drilled in the device. Optionally, the orifice is drilled or preformed in the wall, or the orifice is sealed with a breakable piece that is broken or cut open during use.

[0204] Alternatively, the non-core device can be loaded with a therapeutic agent by, for example, immersing the device in a solution comprising the therapeutic agent for a sufficient time to absorb the therapeutic agent. The device can be equipped with a hollow fiber, and the therapeutic agent and / or adjuvant can be directly loaded into the fiber, and the device is subsequently sealed. In the case where the activity of the therapeutic agent and / or adjuvant is not impaired, the device filled with the therapeutic agent can then be dried or partially dried for storage until use. The method can be used for specific applications, wherein the activity of the selected therapeutic agent is sensitive to exposure to solvents, heat or conventional solvent evaporation, molding, extrusion or other aspects of the above-mentioned other methods.

[0205] The holes can be formed by drilling holes of appropriate size through the wall of the device using mechanical or laser-based methods. In some implants, a digital laser marking system is used to drill the holes. The system allows an array of holes to be drilled on both sides of the dosage form simultaneously and at a rate suitable for dosage form production. The method utilizes a digital laser marking system (e.g., DigiMark™ variable marking system, available from Directed Energy, Inc.) to produce an unlimited number of holes through the surface or coating of the dosage form at a rate practically suitable for dosage form production.

[0206] The steps involved in the laser drilling method are as follows: focusing a digital laser marking system on a laser table; moving the dosage form onto the laser table of the digital laser marking system, pulsing the digital laser marking system to excite the laser tubes required to drill the desired holes along a linear array on the dosage form, moving the dosage form forward on the laser table, and pulsing the digital laser marking system again as needed to produce additional linear arrays of holes; and then removing the dosage form from the laser table.

[0207] Orifices and apparatus for forming orifices are disclosed in U.S. Pat. Nos. 3,845,770, 3,916,899, 4,063,064, and 4,008,864. Orifices formed by leaching are disclosed in U.S. Pat. Nos. 4,200,098 and 4,285,987. Laser drilling machines equipped with optical wavelength detection systems for orienting devices are described in U.S. Pat. Nos. 4,063,064 and 4,088,864.

[0208] For administration with a needle, the size of the intraocular implant can be about 5 μm to about 10 mm, or about 10 μm to about 1 mm, or about 0.4 mm to about 7 mm, or about 0.3 mm to about 7 mm or 8 mm, and for administration by surgical implantation, the size is greater than 1 mm, or greater than 2 mm, such as 3 mm or up to 10 mm. For implants injected with needles, the implant can have any appropriate length, as long as the diameter of the implant allows the implant to move through the needle. For example, implants with a length of about 6 mm to about 7 mm have been injected into the eye. The implant administered by the needle should have a diameter less than the inner diameter of the needle. In some implants, the diameter is less than about 500 μm. People's vitreous cavity can accommodate relatively large implants of different geometries with a length of, for example, 1 to 10 mm. The implant can be a cylindrical pellet (e.g., rod) with a size of about 0.2 mm to 0.75 mm in diameter. Alternatively, the implant may be a cylindrical pellet having a length of about 4 mm to about 6 mm or about 7 mm to about 10 mm and a diameter of about 0.4 mm to about 0.75 mm to about 1.5 mm.

[0209] The implant may also be at least slightly flexible to facilitate insertion of the implant into the eye, such as the vitreous body, and to accommodate the implant. The total weight of the implant is generally about 100, 150, 150, 250, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1000, 2000, 2500, 3000, 4000 to 5000 μg, more preferably about 500, 600, 700, 750, 800, 900, 1000 μg. For example, the implant may be about 500 μg, or about 1000 μg. For non-human individuals, the size and total weight of the implant may be larger or smaller, depending on the type of individual. For example, humans have a vitreous body volume of about 3.8 mL, compared to about 30 mL of a horse and about 60-100 mL of an elephant. An implant sized for use in humans may be scaled up or down accordingly for use in other animals, such as by a factor of about 8 for an implant for use in a horse, or by a factor of about 26 for an implant for use in an elephant.

[0210] Implants can be prepared where the core can be one material and the surface can have one or more layers of the same or different composition, where the layers can be cross-linked, or have different molecular weights, different densities or porosities, etc. For example, where rapid release of an initial bolus of drug is desired, the core can be polylactide coated with poly(lactide-co-glycolide) copolymer to enhance the rate of initial degradation. Alternatively, the core can be poly(vinyl alcohol) coated with polylactide so that as the polylactide exterior degrades, the core will dissolve and quickly wash out of the eye.

[0211] Implants, particularly those with antioxidants and / or adjuvants associated with a biodegradable polymer matrix, can be of any geometric shape, including fibers, sheets, films, microspheres and microparticles, spheres, discs, plates, and the like. The upper limit of the size of the implant will be determined by factors such as the tolerance of the implant, the size restrictions during insertion, and ease of handling. In the case of using sheets or films, the sheets or films will be at least about 0.5 mm x 0.5 mm, typically in the range of about 3-10 mm x 5-10 mm, with a thickness of about 0.1-1.0 mm for ease of handling. In the case of using fibers, the fiber diameter will generally be in the range of about 0.05 to 3 mm, and the fiber length will generally be in the range of about 0.5-10 mm. The diameter of the sphere can be in the range of about 0.5 μm to 4 mm, and particles of other shapes have similar volumes.

[0212] In certain embodiments of the present invention, the use of microparticle implants may be particularly advantageous. Methods for preparing such microparticles involve combining, associating or mixing a therapeutic agent and / or adjuvant with one or more biodegradable polymers. The mixture may then be extruded or compressed to form a single composition. The single composition may then be processed to form microparticles suitable for intravitreal or subconjunctival placement.

[0213] Alternatively, the method of preparing the microparticles of the present invention may also include using an oil-in-water emulsion method to form the microparticles. Such methods are particularly useful for forming microparticles, nanoparticles, etc. Therefore, embodiments of the present invention are directed to inserts comprising microparticles prepared using an oil-in-water emulsion method.

[0214] Multiple microparticles or nanoparticles can be placed in an ocular region, such as, but not limited to, intravitreal, intrastromal, intracameral, subfascial, retinal, subretinal, retrobulbar, peribulbar, suprachoroidal, subchoroidal, conjunctival, subconjunctival, suprascleral, posterior juxtascleral, anterior juxtascleral, pericorneal, topically, and / or lacrimal ductal, to treat various ocular conditions. For example, the microparticles can be administered intravitreally in a manner effective to deliver the therapeutic component and / or adjuvant to the posterior segment tissue, thereby reducing damage to the posterior segment tissue while reducing at least one side effect compared to administration of a steroid alone in an otherwise identical manner. Alternatively, subconjunctival administration of the microparticles of the present invention is very effective in delivering the therapeutic component to the retina and other posterior segment tissues for the treatment of neurodegenerative conditions such as age-related macular degeneration (AMD), such as "wet" or "dry" AMD, macular edema, etc.

[0215] The use of microparticles (or microspheres) and the like provides an excellent way to intermittently deliver antioxidants with the implants of the present invention. For example, in one embodiment, different batches (containing microparticles of the same or different sizes) are prepared, each with different properties, such as different erosion rates; different drug contents (for example, some may contain antioxidants and adjuvants, while others may contain only adjuvants; some may be formed of a bioabsorbable polymer with a fast dissolution rate, while others may be formed of different biopolymers with a slower dissolution rate). By engineering the microparticles so that the dose of the antioxidant during treatment is "pulsed", for example, from an initial substantially optimal therapeutically effective dose to a subsequent period of substantially optimal therapeutically effective dose lacking the antioxidant, and optionally to another treatment period in which a substantially optimal therapeutically effective dose of the antioxidant is administered again, at least one of the harmful side effects of long-term use of antioxidants can be reduced. For example, some microparticles can be loaded with adjuvants alone or in combination with antioxidants to provide a substantially constant (or at least slowly decaying) dose of adjuvant to the ocular tissue during treatment, while the dose of the antioxidant can vary.

[0216] Thus, combinations of different microparticles provide a powerful means to tailor the administration of antioxidants and adjuvants individually in discretely administered intravitreal or subconjunctival injections or insertions.Methods for preparing microparticles are provided in US Application No. 11 / 303,462 and US Application No. 10 / 837,260.

[0217] The size and form of the implant can also be used to control the release rate, treatment time, and drug concentration at the implant site. Larger implants will deliver proportionally larger doses, but may have slower release rates depending on the surface-to-mass ratio. The specific size and geometry of the implant are selected to fit the site of implantation.

[0218] The ratio of antioxidant and / or adjuvant, polymer and any other modifier can be determined empirically by preparing implants with several different ratios. Release rate can be measured using USP approved dissolution or release test methods (USP23; NF 18 (1995) pp. 1790-1798). For example, using infinite osmotic pressure, a weighed sample of the implant is added to a solution containing a measured volume of 0.9% NaCl aqueous solution, wherein the solution volume will make the drug concentration after release less than 5% of saturation. The mixture is maintained at 37 ° C and slowly stirred to maintain the implant suspension. The appearance of dissolved drug as a function of time can be tracked by various methods known in the art such as spectrophotometry, HPLC, mass spectrometry, etc. until the absorbance becomes constant or until greater than 90% of the drug is released.

[0219] Intraocular implants disclosed herein include antioxidants, and the intraocular implants may also include one or more additional ophthalmologically acceptable therapeutic agents.

[0220] The implant was injected into the vitreous of each patient's eye through the pars plana using an applicator with a 22-gauge needle. The patients were monitored following implant administration.

[0221] Example 1: diNACA inhibition of cataract in the rat lens method.

[0222] Lenses were extracted from 3-week-old male or female Wistar rats using existing animal ethics approval for tissue collection. Rats were euthanized using CO2, eyes were removed and lenses were dissected from the eyeballs and incubated for 6 h in phenol red-free Dulbecco's modified Eagle's medium (low glucose; DMEM; Savion et al., 2019) or Media 199 containing glutamine and 1% penicillin, streptomycin, and neomycin mixture under normoxic conditions with 5% CO2. At the end of the 6-h incubation, lenses were imaged under dark-field and bright-field microscopy, and only clear and transparent lenses were used for further experiments.

[0223] Control group: The lenses were incubated for an additional 18 hours, at which time dark-field and bright-field images were taken. The lenses were placed in fresh medium and then incubated for an additional 24 hours in DMEM or M199 containing 1% PSN. Images were then taken to assess lens transparency.

[0224] 10 mM diNACA pre-treatment group: After the initial 6-hour incubation, transparent lenses were incubated in 10 mM diNACA (NPI-002) for 18 hours. Images were taken, and then the lenses were placed in fresh medium containing 1 μg / mL glucose oxidase (GO). The lenses were then incubated for an additional 24 hours, after which images were taken to assess lens transparency.

[0225] 10 mM NACA pre-treatment group: After the initial 6-hour incubation, transparent lenses were incubated in 10 mM NACA (NPI-001) for 18 hours. Images were taken, and then the lenses were placed in fresh medium containing 1 μg / mL GO. The lenses were then incubated for an additional 24 hours, after which images were taken to assess lens transparency.

[0226] Results. Addition of 1 μg / mL of glucose oxidase (GO) after 24 hours produced cataracts by 48 hours (some grid lines were barely visible from bright field images (Figure 1)). NPI-002 (diNACA) alone maintained slightly better lens transparency in the absence of an oxidant compared to NPI-001 (NACA) alone. At 6 hours, clear, transparent lenses were assigned to either untreated or 10 mM DiNACA treated for 24 hours. NACA treated lenses developed imperceptible thin edge opacities at the limbus ( Figure 1A - opacities are marked with *). However, the underlying grid is clearly visible, and surprisingly, the diNACA-treated lens remains absolutely clear and transparent ( Figure 1B ).

[0227] Example 2: NACA or diNACA pretreatment of the lens reduces lens opacity in the GO-cataract model

[0228] Methods: Isolated rat lenses were pretreated with NACA or diNACA and subsequently pretreated with GO.

[0229] Results: Pretreatment with 10 mM NACA (NPI-001) followed by GO-cataract induction resulted in reduced opacity compared with cataract induction alone (n = 8; Figures 2A to 2L, compare Figures F to I and F' to I'). The opacity in the NACA group appeared reduced compared with the GO group (Figures 2A to 2L, compare Figures 2F to 2I), and the underlying grid was more clearly visible in the NACA group compared with the GO group (Figures 2A to 2L, compare Figures 2F' to 2I'). These differences in observations suggest that pretreatment with 10 mM NACA may help reduce GO-induced lens opacity. Pretreatment with 10 mM diNACA followed by GO-cataract induction also reduced lens opacity (n = 7; Figures 2A to 2L, compare Figures 2F and 2L), and improved grid visibility compared with GO-cataract induction alone (Figures 2A to 2L, compare Figures F' and L').

[0230] Conclusions: Exposure to diNACA was better tolerated by the rat lens than to NACA, as mild annular opacities developed after exposure to NACA, whereas diNACA did not.

[0231] Example 3: diNACA inhibition of cataract in isolated porcine lenses.

[0232] Methods: Lenses were obtained from fresh eyes of pigs. These lenses were first incubated in 4-5 mL TC-199 medium and 1% porcine serum for two hours in a 12-well plate. At the end of incubation, the lenses were imaged under dark field microscopy, and only clear and transparent lenses were used for further experiments. Lenses were pre-incubated with NAC, NACA, and diNACA for 24 hours. After pretreatment, the lenses were transferred to medium containing hydrogen peroxide (H2O2) and GO to maintain constant H2O2 levels during incubation, similar to published methods (Wang et al., 1997). At the end of the 6-hour incubation, the lenses were imaged under dark field microscopy ( Figure 3 ).

[0233] Results and Conclusion: Pretreatment with NAC, NACA, and diNACA dose-dependently prevented H2O2-induced cataracts, suggesting that these compounds may have anti-cataract potential. Surprisingly, diNACA had a better protective effect on the lens compared with NAC and NACA.

[0234] Example 4: Summary of the anti-cataract effect of diNACA in the in vitro lens model.

[0235] The anticataract effects of NPI-002 in isolated rat and porcine lenses were similar (Figure 4). In studies performed by two independent groups, NPI-002 prevented oxidative-induced cataracts caused by two different oxidative agents (GO in rats and H2O2 in pigs) in both species.

[0236] Example 5: Safety and pharmacokinetic study of a single dose of NPI-002 intravitreal (IVT) implant in rabbits for 3 weeks.

[0237] A study was conducted to evaluate intravitreal injection of di-NACA and NACA solutions as suspensions or implants in rabbits. The objectives were to assess safety and whether the implants could deliver diNACA, NACA, and NAC to ocular tissues. Sterile intravitreal implants containing diNACA were prepared (Formulation 1896-08, rapid release implant; Figure 7 Female New Zealand white rabbits were given two NPI-002 IVT implants per eye (total dose of NPI-002, 0.8 mg / eye). One group of animals received an IVT placebo implant without any test article. Figure 8 shows the dimensions of the implants.

[0238] Prior to placement for study, each rabbit underwent an ophthalmological examination, including slit-lamp biomicroscopy and indirect ophthalmoscopy. Ocular findings were scored according to the modified McDonald-Shadduck score.

[0239] Clinical ophthalmological examinations were performed at baseline and on post-dose days 8 and 23. General health observations were performed daily. Body weights were recorded at baseline and before endpoint.

[0240] Subject allocation is as shown in Table 1. Sterile NPI-002 or placebo IVT implants were preloaded into 22G bevel needles with wire plungers (1 implant / needle) and injected into the VH. NPI-002 suspensions and NPI-001 solutions were prepared in sterile phosphate buffered saline and injected into the VH.

[0241] Animals were euthanized on days 8, 15, or 23, and ocular tissues were collected and submitted for bioanalysis of diNACA, NACA, and NAC. IVT di-NACA delivery was associated with mild ocular conditions on the day of dosing. Observations of conjunctival swelling, discharge, and minor bleeding were determined to be related to the injection procedure and resolved in most eyes by the second day after dosing. Mild to moderate conjunctival hyperemia, swelling, and discharge observed by clinical ophthalmologic examination on day 8 resolved by day 23, indicating that these findings were related to the IVT injection procedure using a 22-gauge needle.

[0242] Di-NACA delivered as a suspension or implant, placebo implant, and NACA as a solution via IVT injection were associated with minor ocular events on the day of dosing. Observations of conjunctival bulging, discharge, and minor bleeding were determined to be related to the injection procedure and resolved in most eyes by the second day after dosing.

[0243] Table 1: Group allocation

[0244]

[0245] OU: both eyes; IVT: intravitreal injection; NA: not applicable; AH: aqueous humor; VH: vitreous humor; RPE: retinal pigment epithelium

[0246] # Group 1: N=5 at each time point; Groups 2 and 4: N=1 at each time point; Group 3: N=1 on day 7 (±1), and N=2 on days 14 (±1) and 21 (±2).

[0247] Mild to moderate conjunctival hyperemia, swelling, and discharge observed by clinical ophthalmologic examination on day 8 resolved by day 23, suggesting that these findings were related to the IVT injection procedure using a large 22G needle. In addition, choroidal / retinal inflammation was also observed in three eyes that received di-NACA implants due to implant impaction on the retina, and this was also related to the procedure. Vitreous cells and flares detected on days 8 and 23 were likely test article-related particles, as these particles were largely cleared or present only in small amounts in the vitreous humor on day 23 compared with day 8. Some of these reflective particles were attached to the posterior lens capsule.

[0248] No adverse effects of test article administration on systemic, non-ocular health, or body weight were observed.

[0249] After 1 week, intravitreal delivery of NPI-002 implants resulted in significant levels of diNACA, NACA, and NAC in the vitreous humor ( FIG. 5 ).

[0250] In conclusion, delivery of NACA solution and di-NACA as a suspension or implant or placebo implant was generally well tolerated when given via intravitreal (IVT) injection.

[0251] Intravitreal delivery of NPI-002 implants resulted in significant levels of diNACA, NACA, and NAC in the rabbit vitreous humor after 1 week, demonstrating that diNACA is the major metabolite and prodrug of the pharmacologically active substances NACA and NAC.

[0252] Example 6: Single-dose 3-month toxicology study of NPI-002 intravitreal (IVT) implants in rabbits.

[0253] A study was conducted to evaluate the safety of the diNACA (NPI-002) IVT implant. Four groups of six rabbits (New Zealand White rabbits) were included in the study: (1) an untreated control group; (2) a drug-treated group injected with one rapid-release NPI-002 implant in each eye; (3) a drug-treated group injected with one rapid-release and one slow-release NPI-002 implant in each eye (Figure 6); and (4) a placebo group injected with one placebo implant in the left eye and two placebo implants in the right eye. Clinical ophthalmologic examinations were performed at baseline and 1 day, 1 week, 1 month, and 3 months after implant delivery. In addition, fundus imaging, spectral domain optical coherence tomography (SD-OCT), and electroretinography were performed at baseline and 3 months. Blood samples were collected. For groups 1-3, the left eyes were dissected, fixed, and processed for histology and immunohistochemistry to assess safety / toxicity. The right eyes were dissected and used for bioanalysis. For Group 4, left and right eyes were dissected, fixed, and processed for histology and immunohistochemistry.

[0254] Overall, complications from implant injection were negligible. The overall health and weight of all 24 rabbits were satisfactory throughout the duration of the study. The most frequently encountered welfare incidents were related to minor wounds caused by momentary aggression between rabbits. All rabbits reached the designated endpoint of the study at 3 months. Blood samples were taken for future analysis. Of the 48 eyes, 30 eyes were taken for postmortem histopathology examination, while 18 eyes were dissected for future pharmacokinetic analysis. No adverse effects of the NPI-002 implant on overall health were observed. Weight gain was normal. Clinical ophthalmological examinations showed no evidence of acute or chronic deleterious effects of the NPI-002 implant on the anterior or posterior compartments of the eye. Rebound tonometry showed no evidence that the NPI-002 implant caused changes in intraocular pressure. Electroretinography showed no evidence that the NPI-002 implant adversely affected the electrical function of the retina. Fundus imaging or SD-OCT scanning showed no evidence that the NPI-002 implant caused deleterious effects on retinal morphology. Overall, no differences were observed between the untreated control cohort, the placebo-injected cohort, and the NPI-002-injected cohort for each parameter evaluated. No differences were observed between animals that received one or two NPI-002 implants.

[0255] This study demonstrated the safety of one or two NPI-002 implants in the vitreous cavity of rabbits. No drug-related toxicity was recorded at the clinical, retinal imaging, electroretinogram, or histological levels. These findings provide a warranted continuation of a human Phase 1 / 2 clinical trial to investigate the safety and efficacy of one or two intravitreal NPI-002 implants per eye in attenuating vitrectomy-induced cataracts.

[0256] Example 7: Repeated-dose topical ocular administration of NPI-002 in rabbits.

[0257] A study was conducted to evaluate the effect of topical ocular administration of diNACA or NACA in rabbits. An ophthalmic formulation containing 1% diNACA or 1% NACA was developed for repeated topical ocular instillations in Dutch rabbits. Three animals per group were given each test article four times a day via bilateral topical administration at approximately 8:00 AM, 11:00 AM, 2:00 PM, and 4:00 PM on Days 1-6, and once on Day 7 at approximately 8:00 AM. Ocular tolerance was assessed at baseline and before the first daily dose by scoring conjunctival edema, secretions, and hyperemia (Draize score). Ocular tissue was obtained at necropsy (Day 7). A qualified LC-MS analytical method was developed and used to quantify NACA levels in aqueous humor (AH). No serious adverse outcomes were observed after topical ocular administration.

[0258] Mild secretions were observed at low frequency in all groups, and mild congestion was observed in the vehicle group. No indication of conjunctival edema was seen in any administration group. Because the vehicle treatment showed similar or higher frequency of mild eye irritation indicated by secretions or congestion, the eye irritation seen in the test agent administration group may not be attributed to the test agent itself, but to the vehicle. After administering 1% diNACA or 1% NACA, the NACA level reached in the aqueous humor was observed (Table 2). The presence of diNACA in AH proves that diNACA penetrates the eye after topical ocular administration. The presence of NACA in AH proves that diNACA is used as a prodrug for delivering NACA to AH. It is unclear whether diNACA is cleaved into NACA on the surface of the eye or after penetrating into AH.

[0259] Table 2: NACA levels achieved in aqueous humor following topical administration of 1% diNACA or 1% NACA in rabbits

[0260]

[0261] BLQ: below the limit of quantitation.

[0262] Example 8: Fabrication of implants.

[0263] NPI-002 IVT implant manufacturing method flow is presented in Figure 7 middle.

[0264] A description of the IVT implant manufacturing process is as follows. A Fisher Pharma Mini twin screw extruder was used with the feed throat cooler set to 17 °C and the temperatures of both zones 1 and 2 set to 127 °C. With the extruder speed set to 5 rpm, the NPI-002 and 8515 9E-PLG blend was added to the extruder feed hopper. Note: Blending of NPI-002 and 8515 9E-PLG was previously performed using a Turbula blender (blending for 5 minutes at a speed setting of 46). Once all of the NPI-002 and 8515 9E-PLG blend was added to the extruder, the screw rpm was increased to 15 and the NPI-002 / 8515 9E-PLG material was recirculated in the extruder for another 10 to 12 minutes. The screw was then set to 5-10 rpm to allow the extrudate to pass through the extruder die. As the extrudate exited the die, it was conveyed by a conveyor through a Beta Lasermike to control the extrudate diameter to approximately 0.38 to 0.41 mm and collected as a bulk rod. The bulk rod was then cut into IVT implant lengths.

[0265] The amount of NPI-002 and impurities in the implant was determined using the drug content method. The NPI-002 implant was incubated in acetonitrile to dissolve the PLG. A diluent was then added to extract the NPI-002. The extracted NPI-002 was analyzed relative to a reference standard of NPI-002 using a reversed-phase gradient HPLC method with UV detection at 214 nm. The HPLC conditions are shown in Table 3.

[0266] Table 3: HPLC conditions

[0267]

[0268] Example 11: Clinical Study of NPI-002 Intravitreal Implant in Post-Vitrectomy Subjects.

[0269] Because vitrectomy is a common procedure that causes rapid and definitive opacification of the lens nucleus, patients undergoing vitrectomy provide a promising “model” system to test this hypothesis. Successful protection of patients after vitrectomy from developing nuclear cataracts will lay the foundation for interventions to prevent these cataracts in subjects with advanced vitreous degeneration (Beebe et al., 2010).

[0270] Prophetic Example: NPI-002 intravitreal implant for delaying cataract progression.

[0271] Study description.

[0272] Brief Overview: This study will examine the safety and efficacy of the NPI-002 intravitreal implant following vitrectomy.

[0273]

[0274] Study Design:

[0275] Type of study: Intervention (clinical trial) Estimated number of participants: 30 participants distribute: random Intervention Model: Parallel allocation hide: Both parties (participants, outcome assessors) Main purpose: prevention Official Title: Safety and efficacy of the NPI-002 intravitreal implant for delaying cataract progression in patients undergoing vitrectomy

[0276] Groups and Interventions:

[0277]

[0278] Outcome measures

[0279] Main outcome measures:

[0280] 1. Lens densitometry [Time frame: 6 months]

[0281] Change from baseline

[0282] Eligible age for the study: 18 years and above Eligible gender for the study: all Accepting healthy volunteers: no

[0283] standard

[0284] Inclusion criteria:

[0285] 1. Suitable for vitrectomy

[0286] 2. Studying the natural lens in the eye during vitrectomy

[0287] 3. Preoperative evaluation for the presence of some cataracts

[0288] Exclusion criteria:

[0289] 1. Previous intraocular surgery in the study eye.

[0290] 2. Obvious zonular weakness or loss / incompleteness.

[0291] 3. Unstable dosage of medications used for other conditions.

[0292] 4. Anticipated need for oral corticosteroids during study participation.

[0293] 5. Evidence or history of uveitis or ocular ischemia (ischemic retinopathy).

[0294] 6. Evidence or history of proliferative diabetic retinopathy.

[0295] 7. Previous panretinal photocoagulation surgery.

[0296] 8. Moderate or severe uncontrolled glaucoma.

[0297] 9. Current smoker.

[0298] 10. Use supplemental oxygen.

[0299] 11. Current lung disease causing decreased oxygen saturation.

[0300] 12. Sensitive to thiol compounds.

[0301] 13. Participate in another clinical trial.

[0302] Example 12: Rabbit Study of diNACA Intravitreal Implant

[0303] This example shows the measurement of NAC, NACA, di-NACA and GSH in plasma samples collected at baseline and 3 months after implant delivery. In addition, the measurement of NAC, NACA, di-NACA and GSH in aqueous humor, vitreous humor, lens, retina and RPE / choroid at 3 months after implant delivery was also determined.

[0304] Table 4: Treatment groups

[0305]

[0306] n = 6 rabbits per group, both eyes treated

[0307] Blood Collection. No blood was drawn from animals in Group 1 (Control). Blood was collected from each animal in Groups 2, 3, and 4 at the time of implant delivery and at the study endpoint (3 months after implant delivery). Blood was placed in pre-chilled tubes containing K2EDTA as an anticoagulant, mixed by inversion several times, and kept on wet ice until centrifugation. Blood samples were centrifuged at approximately 3000 x g for 5 minutes at a temperature of 4°C. The resulting plasma (at least 100 μL) was separated within approximately 30 minutes after centrifugation, collected into pre-labeled polypropylene tubes, snap-frozen on dry ice, and stored in a freezer set to maintain -60°C to -80°C. Prior to snap freezing, the plasma was acidified with formic acid to stabilize NPI-002 (0.5% plasma volume).

[0308] Tissue Collection: Tissues were obtained for pharmacokinetic evaluation.

[0309] The right eye was obtained from each rabbit in Group 1 (control), Group 2 (NPI-002, one implant), and Group 3 (NPI-002, two implants). Both eyes from Group 4 (placebo) were used for histological evaluation and were not available for pharmacokinetic analysis.

[0310] The following tissues were dissected: aqueous humor (AH); vitreous humor (VH); lens; retina; and choroid / retinal pigment epithelium (RPE).

[0311] Samples from each eye were separated and not combined. Samples were collected into separate, pre-labeled, pre-weighed polypropylene tubes. The weight of each sample was recorded. AH and VH (but not other ocular tissues) were acidified with formic acid to stabilize NPI-002 (0.2% body fluid volume). Samples were quickly frozen in liquid nitrogen and placed on dry ice until stored in a refrigerator set to maintain -60 to -80°C. All samples were transported frozen on dry ice to Agilex, a laboratory designated by the sponsor, for analysis. A total of 18 AH, 18 VH, 18 lens, 18 retina, and 18 choroid / RPE samples were collected and submitted for analysis.

[0312] Analyte concentrations in plasma: NAC plasma levels in the placebo group were 43.6 ng / mL at baseline and 38.2 ng / mL at 3 months after implant delivery. NAC plasma levels in both implant groups were approximately 65 ng / mL at baseline. No increase in plasma NAC was detected in either group at 3 months after implant delivery. In fact, NAC levels were slightly lower in both groups. NACA was essentially undetectable in all groups at baseline and 3 months after implant delivery. Di-NACA levels were extremely low in all groups at baseline and 3 months after implant delivery.

[0313] The GSH plasma level in the placebo group was 9782 ng / ml at baseline and 18270 ng / ml at 3 months after implant delivery. The GSH plasma levels in the single implant group and double implant group were 10427 ng / mL and 6513 ng / mL at baseline and 9747 ng / mL and 10377 ng / mL at 3 months after implant delivery, respectively.

[0314] These data demonstrate that intravitreal implants containing di-NACA do not increase plasma levels of NAC, NACA, di-NACA, or GSH when analyzed 3 months after surgery. Although statistically significant differences between baseline and 3-month data were found in some parameters, such results are unlikely to represent true cause-effect relationships.

[0315] Table 5: Metabolite concentrations in plasma.

[0316]

[0317] All concentrations are expressed as ng / mL. † P<0.05 (baseline vs. 3 months)

[0318] Metabolite concentrations in liquid and solid matrices.

[0319] NAC: Fig.9A As shown, NAC was undetectable in the aqueous humor of all three groups. In the vitreous humor, NAC was undetectable in the control group but was present at low levels (generally below the assay limit of quantitation) in samples from both treatment groups.

[0320] like Fig. 9B As shown, NAC was undetectable in lens samples from all three groups. In the retina, NAC was essentially undetectable in the untreated and single (rapid release) implant groups, but was substantially elevated in the dual implant group, although there was considerable variability between samples. In the RPE / choroid, NAC was undetectable in the untreated group and in all but one sample from the single (rapid release) implant group, but was substantially elevated in the dual implant group, although not to the magnitude measured in the corresponding retinal samples. Again, there was considerable variability between animals.

[0321] NACA: Fig. 10A As shown, NACA was present at very low levels in the aqueous humor of the control group. In both treatment groups, NACA concentrations increased, but remained very low. In the vitreous humor, NACA was present at very low levels in the control group (approximately 3 ng / mL), but was significantly higher in both treatment groups (approximately 15,000-20,000 ng / mL).

[0322] like Fig. 10B As shown, NACA was undetectable in lens samples from all three groups. In the retina, NACA was undetectable in the untreated group and only modestly elevated in the single (rapid release) implant group. The discrepancy between the elevated vitreous levels and the low retinal levels in the single implant group was surprising. In the dual implant group, NACA was substantially elevated on average; however, there was a great deal of variability between samples, with one of the six samples showing an extremely high level (30-fold higher than the second highest sample, which itself was 25-fold higher than the remaining four samples). In the RPE / choroid, the results showed the same pattern as the retina: NACA was undetectable in the untreated group and only modestly elevated in the single implant group, but was substantially elevated in the dual implant group, although not to the magnitude measured in the corresponding retinal samples. Again, there was a great deal of variability between animals in the dual implant group, with the same two animals showing high and very high levels of NACA.

[0323] di-NACA: Fig.11AAs shown, di-NACA was undetectable in the aqueous humor of the control group, while in both treatment groups, di-NACA concentrations were extremely low (approximately 1-2 ng / mL). In the vitreous humor, di-NACA was essentially undetectable in the control group (approximately 0.2 ng / mL), but was significantly higher in both treatment groups (approximately 9000-13000 ng / mL).

[0324] like Fig. 9B As shown, di-NACA was undetectable in lens samples from all three groups. In the retina, di-NACA was undetectable in the untreated group and essentially undetectable in the single implant group, but reasonably elevated in the double implant group (125 ng / g tissue weight). The difference between the high levels in the vitreous and the low levels in the retina in both treatment groups was surprising. In the RPE / choroid, the results showed the same pattern as the retina: di-NACA was undetectable in the untreated group, almost undetectable in the single implant group, and moderately elevated in the double implant group (78 ng / g tissue weight).

[0325] GSH: Fig. 12A As shown, GSH was present in high concentrations in the aqueous humor of the control group (approximately 14000 ng / mL). This level of GSH is equivalent to a molar concentration of 45 μM, which is roughly similar to the 25 μM value reported in the literature (Richer and Rose, 1998). GSH concentrations were higher in both the single implant group and the double implant group (approximately 37000-47000 ng / mL). In the vitreous humor, GSH was present in a concentration of approximately 17000 ng / mL in the control group. GSH concentrations were slightly higher in both the single implant group and the double implant group (approximately 19000-25000 ng / mL).

[0326] like Fig. 12B As shown, GSH was present at very high concentrations (approximately 20,000 ng / g tissue weight) in all three tissues (lens, retina, RPE / choroid) in all three groups. There was no pattern of GSH elevation in either the single or double implant groups in any tissue.

[0327] Summary: NAC, NACA, and di-NACA levels in the aqueous humor were low in all groups. This is not particularly surprising given the rapid turnover of the aqueous humor. However, it is interesting that GSH levels in the aqueous humor were higher in both treatment groups. In the lens, NAC, NACA, and di-NACA were undetectable in all groups.

[0328] In the vitreous, the data showed that implants containing NPI-002 (di-NACA) significantly elevated vitreous NACA and di-NACA levels when analyzed 3 months after surgery. Interestingly, while levels of both compounds were higher in the dual implant group, the difference between the single and dual implant groups was not particularly significant. The elevated levels of di-NACA and NACA in the vitreous humor of the treatment groups did not translate into statistically significantly higher GSH levels.

[0329] In the RPE / choroid, the results for NAC, NACA, and di-NACA essentially mirrored those for the retina, but at slightly lower levels.

[0330] It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method, kit, reagent or composition of the invention, and vice versa. In addition, the compositions of the invention can be used to implement the methods of the invention.

[0331] It should be understood that the specific embodiments described herein are shown by way of example and not as limitations of the present invention. The main features of the present invention may be used in various embodiments without departing from the scope of the present invention. Those skilled in the art will recognize or simply use routine experiments to determine many equivalents of the specific processes described herein. Such equivalents are considered to be within the scope of the present invention and are covered by the claims.

[0332] All publications and patent applications mentioned in the specification are indicative of the technical level of those skilled in the art to which the invention pertains. All publications and patent applications are incorporated herein by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0333] When used in conjunction with the term "comprising" in the claims and / or specification, the use of the words "a" or "an" can mean "one", but it is also consistent with the meaning of "one or more", "at least one", and "one or more than one". The term "or" used in the claims is used to mean "and / or" unless it is clearly indicated that only alternatives are referred to, or the alternatives are mutually exclusive, although the disclosure supports a definition that only refers to alternatives and "and / or". Throughout this application, the term "about" is used to indicate that a value includes error for the equipment, the inherent variation of the method being used to determine the value, or the variation that exists between the subjects of study.

[0334] As used in this specification and claim(s), the words "comprising" (and any forms of comprising, such as "comprise" and "comprises"), "having" (and any forms of having, such as "have" and "has"), "including" (and any forms of including, such as "includes" and "include"), "containing" (and any forms of containing, such as "contains" and "contain") are inclusive or open-ended, and do not exclude additional, unrecited elements or method steps. In any of the embodiments of the compositions and methods provided herein, "comprising" may be replaced with "consisting essentially of" or "consisting of". As used herein, the phrase "consisting essentially of" requires the specified (multiple) integers or steps as well as integers or steps that do not materially affect the characteristics or functions of the claimed invention. As used herein, the term "consiting" as published indicates only the presence of the recited integer (e.g., feature, element, characteristic, property, method / process step, or limitation) or group of integers (e.g., feature(s), element(s), characteristic(s), property(s), method / process step, or limitation(s). As outlined above, each composition of the present invention may comprise diNACA, may consist essentially of diNACA, or may consist of diNACA.

[0335] As used herein, the term "or a combination thereof" refers to all permutations and combinations of the items listed before the term. For example, "A, B, C, or a combination thereof" is intended to include at least one of A, B, C, AB, AC, BC, or ABC, and if the order is important in a particular context, also includes BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, explicitly included are combinations containing repetitions of one or more items or conditions, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, etc. The skilled person will understand that there is generally no limit to the number of items or conditions in any combination, unless otherwise apparent from the context.

[0336] As used herein, approximate words such as, but not limited to, "about," "substantially," or "substantially" are understood when so modified to not necessarily be absolute or complete, but will be considered close enough to one of ordinary skill in the art to ensure that the specified conditions exist. The degree to which the description can be varied will depend on how much of a change can be implemented and still allow one of ordinary skill in the art to recognize the modified feature as still having the properties and capabilities required of the unmodified feature. Typically, but subject to the foregoing discussion, numerical values ​​modified herein by approximate words such as "about" can vary by at least ±1, 2, 3, 4, 5, 6, 7, 10, 12, or 15% from the stated value.

[0337] In addition, the section headings herein are provided to provide organizational cues consistent with the recommendations under 37 CFR 1.77 or otherwise. These headings should not limit or characterize the invention(s) set forth in any claim that may be derived from this disclosure. Specifically and by way of example, although the heading refers to "Field of the Invention," such claims should not be limited by the language describing the so-called technical field under that heading. In addition, the description of the technology in the "Background of the Invention" section should not be interpreted as an admission that the technology is prior art to any invention(s) in this disclosure. The "Summary" should also not be considered as a characterization of the invention(s) set forth in the issued claims. In addition, any reference to "invention" in the singular in this disclosure should not be used to dispute that there is only a single point of novelty in this disclosure. Multiple inventions may be set forth according to the definitions of multiple claims derived from this disclosure, and such claims accordingly define the invention(s) protected thereby and their equivalents. In all cases, the scope of such claims should be considered on their own merits in light of this disclosure, but should not be limited by the headings set forth herein.

[0338] In light of the present disclosure, all compositions and / or methods disclosed and claimed herein can be made and implemented without undue experimentation. Although the compositions and methods of the present invention have been described with respect to preferred embodiments, it will be apparent to those skilled in the art that changes may be made to the compositions and / or methods described herein and in the steps of the methods or in the sequence of steps of the methods without departing from the concept, spirit and scope of the present invention. All such similar substitutions and modifications apparent to those skilled in the art are considered to be within the spirit, scope and concept of the invention as defined by the appended claims.

[0339] References

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Claims

1. A biodegradable intraocular implant comprising: (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropionamide) (diNACA) in a pharmaceutically acceptable polymer.

2. The intraocular implant of claim 1 further comprising an antioxidant selected from the group consisting of N-acetylcysteine ​​(NAC), N-acetylcysteine ​​amide (NACA), lipoic acid, lipoic acid choline ester, salts thereof, and mixtures thereof, and optionally an antioxidant adjuvant.

3. The intraocular implant of claim 1, wherein the implant is selected from at least one of: a diameter of about 0.1-0.5 mm and a length of about 4-10 mm, a diameter of about 0.2-0.4 mm and a length of about 5-8 mm, a diameter of about 0.3 mm and a length of about 6-7 mm, a diameter of about 0.4 mm and a length of about 7 mm, or a diameter of about 0.05 mm and a length of between 5 and 8 mm or about 5 to 8 mm, or the implant comprises a plurality of openings or holes in the polymer, the coating, or both.

4. The intraocular implant of claim 1, wherein the pharmaceutically acceptable polymer is poly(lactide-co-glycolide), polyurethane polyurea, poly(vinyl ester), poly(methyl methacrylate), poly(vinyl chloride), polyamide, nylon, poly(ethylene terephthalate), rubber, silicone, polyisoprene, polyisobutylene, polybutadiene, polyethylene, polytetrafluoroethylene, poly(vinylidene chloride), polyacrylonitrile, polyvinylpyrrolidone, chlorinated polyethylene, polychlorotrifluoroethylene, poly(ethylene chlorotrifluoroethylene), polytetrafluoroethylene, poly(ethylene tetrafluoroethylene), poly(4 , 4-isopropylidene diphenylene carbonate), polyurethane, polyperfluoroalkoxy, poly(vinylidene fluoride), vinylidene chloride-acrylonitrile copolymer, vinyl chloride-diethyl fumarate copolymer, silicone rubber, poly(dimethylsiloxane), ethylene-propylene rubber, silicone-carbonate copolymer, vinylidene chloride-vinyl chloride copolymer, vinyl chloride-acrylonitrile copolymer, poly(olefins), poly(vinyl-olefins), poly(styrenes), poly(halo-olefins), poly(vinyl) esters, poly(alkyl acrylates), poly(oxides), poly(esters), polyamides and polycarbonates, or mixtures thereof.

5. The intraocular implant of claim 1, wherein the amount of diNACA in the implant is at least 21-65 weight percent (wt%), 1-20 wt%, 5-15 wt%, 7-12 wt%, or about 10 wt%.

6. The intraocular implant of claim 1, wherein the intraocular implant comprises: an antioxidant in the biodegradable polymer as a first intraocular implant; and an adjuvant associated with the biodegradable polymer as a second intraocular implant; wherein the antioxidant is present in the first intraocular implant in an amount of at least about 10 weight percent.

7. The intraocular implant of claim 1, wherein the implant is adapted for placement within the vitreous of an eye of a subject, the antioxidant being present in an amount effective to treat an ocular condition of the eye; and the adjuvant associated with the biodegradable polymer as an intraocular implant is constructed for placement within the vitreous of an eye of a subject, the adjuvant being present in an amount effective to reduce the occurrence of at least one undesirable reaction that would occur when the otherwise identical antioxidant is administered alone; or wherein the antioxidant is present in the intraocular implant in an amount of at least about 10 weight percent.

8. A biodegradable intraocular implant system comprising an antioxidant suitable for treating an ophthalmic disease or condition involving oxidative stress in an animal or human.

9. The biodegradable intraocular implant system of claim 8, wherein the antioxidant comprises (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropionamide) (diNACA) in a matrix of a polymer or in alternating layers, or a combination of (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropionamide) (diNACA) and an adjuvant.

10. The biodegradable intraocular implant system of claim 9, wherein the antioxidant comprises (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropionamide) (diNACA), or the diNACA and the adjuvant are contained in the same implant or in different implants.

11. The biodegradable intraocular implant system of claim 10, wherein the amount of the antioxidant in the implant system is at least 21-65 weight percent (wt%), 1-20 wt%, 5-15 wt%, 7-12 wt%, or about 10 wt%.

12. A method for treating ophthalmic oxidative stress in an animal or human subject, the method comprising: identifying an animal or human patient in need of treatment for ophthalmic oxidative stress in the eye; as well as A therapeutically effective amount of N-acetylcysteine ​​amide (NACA) or (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropionamide) (diNACA) is administered to the animal or human patient as an intravitreal implant (diNACA implant).

13. The method of claim 12, wherein the ophthalmic oxidative stress in the eye is selected from at least one of cataracts, cataracts in subjects without diabetes, corneal endothelial cell loss, age-related macular degeneration, presbyopia, retinitis pigmentosa (RP), Usher syndrome, Stargardt syndrome, glaucoma, diabetic retinopathy, or a retinal disease.

14. The method of claim 12, wherein the diNACA is provided in or together with a pharmaceutically acceptable carrier.

15. The method of claim 12, wherein the diNACA is in a dosage form for a delivery route selected from the group consisting of intravitreal, intrastromal, intracameral, subfascial, retinal, subretinal, retrobulbar, peribulbar, suprachoroidal, subchoroidal, conjunctival, subconjunctival, suprascleral, posterior juxtascleral, anterior juxtascleral, pericorneal, topical, and lacrimal.

16. The method of claim 13, wherein the diNACA is administered at a daily dose of about 0.25, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 25, 30, 40, 45, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140 to 150 mg / Kg.

17. The method of claim 12, wherein the diNACA is administered in a single dose of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 25, 30, 40, 45, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 175, 200, 250, 300, 400, 500, 600, 700, 750, 800 to 900 micrograms.

18. The method of claim 12, wherein the diNACA is administered once every 1, 2, 3, 4, 5, or 6 months.

19. The method of claim 12, wherein the diNACA is administered with a second active agent selected from at least one of ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, NAC, NACA, propyl gallate, alpha-tocopherol, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, or phosphoric acid.

20. The method of claim 12, wherein the amount of diNACA in the implant is at least 21-65 weight percent (wt%), 1-20 wt%, 5-15 wt%, 7-12 wt%, or about 10 wt%.

21. The method of claim 12, wherein the dose for administration is about 1, 10, 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1000, 2500, 5000, 7500, or 10000 micrograms per dose.

22. The method of claim 12, wherein the diNACA implant is at least one of: manually inserted into the eye, injected into the eye, broken up and dissolved or biodegraded in the eye, or administered prophylactically to prevent an ophthalmic disease or condition involving oxidative stress.

23. A non-biodegradable, non-bioerodible or non-bioresorbable intraocular implant comprising: (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropionamide) (diNACA) in a pharmaceutically acceptable polymer.

24. The implant of claim 23, wherein the antioxidant is selected from the group consisting of N-acetylcysteine, N-acetylcysteine ​​amide, (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropionamide) (diNACA), lipoic acid, lipoic acid choline ester, salts thereof, adjuvants and mixtures thereof.

25. The implant of claim 23, wherein the implant is selected from at least one of: about 0.1-0.5 mm in diameter and about 4-10 mm in length, about 0.2-0.4 mm in diameter and about 5-8 mm in length, about 0.3 mm in diameter and about 6-7 mm in length, about 0.4 mm in diameter and about 7 mm in length, or about 0.05 mm in diameter and between or about 5 to 8 mm in length, or the implant comprises a plurality of openings or holes in the polymer, the coating, or both.

26. The implant of claim 23, wherein the polymer is polyurethane polyurea, poly(vinyl ester), poly(methyl methacrylate), poly(vinyl chloride), polyamide, nylon, poly(ethylene terephthalate), rubber, silicone, polyisoprene, polyisobutylene, polybutadiene, polyethylene, polytetrafluoroethylene, poly(vinylidene chloride), polyacrylonitrile, polyvinyl pyrrolidone, chlorinated polyethylene, polychlorotrifluoroethylene, polyethylene chlorotrifluoroethylene, polytetrafluoroethylene, poly(ethylene tetrafluoroethylene), poly(4,4-isopropylidene difluoroethylene), poly(ethylene tetra ... Poly(ethylene carbonate), polyurethane, polyperfluoroalkoxy, poly(vinylidene fluoride), vinylidene chloride-acrylonitrile copolymer, vinyl chloride-diethyl fumarate copolymer, silicone rubber, poly(dimethylsiloxane), ethylene-propylene rubber, silicone-carbonate copolymer, vinylidene chloride-vinyl chloride copolymer, vinyl chloride-acrylonitrile copolymer, poly(olefins), poly(vinyl-olefins), poly(styrenes), poly(halo-olefins), poly(vinyl esters), polyalkyl acrylates, polyoxides, polyesters, polyamides and polycarbonates, or mixtures thereof.

27. The implant of claim 23, wherein the amount of diNACA in the intraocular implant is at least 21-65 weight percent (wt%), 1-20 wt%, 5-15 wt%, 7-12 wt%, or about 10 wt%.

28. The implant of claim 23, wherein the diNACA implant is suitable for administration to the eye at a location selected from the group consisting of intravitreal, intrastromal, intracameral, subfascial, retinal, subretinal, retrobulbar, peribulbar, suprachoroidal, subchoroidal, conjunctival, subconjunctival, suprascleral, posterior juxtascleral, anterior juxtascleral, pericorna!e, topical, and lacrimal.

29. A method for treating cataracts, corneal endothelial cell loss, age-related macular degeneration, presbyopia, retinitis pigmentosa (RP), Usher syndrome, Stargardt syndrome, glaucoma, diabetic retinopathy, cataracts in a subject not suffering from diabetes, or other retinal disease in an eye of an animal or human subject, comprising: obtaining an intravitreal implant (diNACA implant) comprising a therapeutically effective amount of N-acetylcysteine ​​amide (NACA) or (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropionamide) (diNACA); and The diNACA implant is delivered to a predetermined area in, at, or around the eye, and the diNACA implant delivers a therapeutically effective amount of diNACA to a predetermined area of ​​the eye to treat cataracts, corneal endothelial cell loss, age-related macular degeneration, presbyopia, retinitis pigmentosa (RP), Usher syndrome, Stargardt syndrome, glaucoma, diabetic retinopathy, cataracts in subjects without diabetes, or other retinal diseases.

30. The method of claim 29, wherein the diNACA implant is administered to a predetermined area of ​​the eye selected from the group consisting of intravitreal, intrastromal, intracameral, subfascial, retinal, subretinal, retrobulbar, peribulbar, suprachoroidal, subchoroidal, conjunctival, subconjunctival, suprascleral, posterior juxtascleral, anterior juxtascleral, pericorneal, topical, and lacrimal.

31. The method of claim 29, wherein the diNACA is administered at a daily dose of about 0.25, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 25, 30, 40, 45, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140 to 150 mg / Kg.

32. The method of claim 29, wherein the diNACA is administered in a single dose of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 25, 30, 40, 45, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 175, 200, 250, 300, 400, 500, 600, 700, 750, 800 to 900 micrograms.

33. The method of claim 29, wherein the diNACA is administered once every 1, 2, 3, 4, 5, or 6 months.

34. The method of claim 29, wherein the diNACA is administered with a second active agent selected from at least one of ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, NAC, NACA, propyl gallate, alpha-tocopherol, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, or phosphoric acid.

35. The method of claim 29, wherein the amount of diNACA in the implant is at least 21-65 weight percent (wt%), 1-20 wt%, 5-15 wt%, 7-12 wt%, or about 10 wt%.

36. The method of claim 29, wherein the dose for administration is about 1, 10, 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1000, 2500, 5000, 7500, or 10000 micrograms per dose.

37. The method of claim 29, wherein the diNACA implant is manually inserted into the eye.

38. The method of claim 29, wherein the diNACA implant ruptures and dissolves or biodegrades in a predetermined area of ​​the eye.

39. The method of claim 29, wherein the diNACA is administered prophylactically to prevent an ophthalmic disease or condition in or around a predetermined area of ​​the eye.

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