Ophthalmic implant

Abstract

The present invention generally relates to compositions and methods for treating animal or human patients in need of treatment for ophthalmic diseases or conditions involving oxidative stress, and to treatment with ophthalmic implants containing (2R,2R’)-3,3’-disulfanediylbis(2-acetamidopropanamide) (diNACA), such ophthalmic diseases or conditions including, but not limited to, cataracts, cataracts in subjects without diabetes, loss of corneal endothelial cells, age-related macular degeneration, presbyopia, retinitis pigmentosa (RP), Ascher syndrome, Stargardt syndrome, glaucoma, diabetic retinopathy, and / or retinal diseases.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Application No. 63 / 358,946, filed on July 7, 2022, the entire content of which is incorporated herein by reference.

[0002] Reference to Government Grants None.

[0003] 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 treatment with an ophthalmic implant containing (2R,2R’)-3,3’-disulfanediylbis(2 - acetamidopropanamide) (diNACA). Such ophthalmic diseases or conditions include, but are not limited to, cataracts, cataracts in subjects without diabetes, loss of corneal endothelial cells, age - related macular degeneration, presbyopia, retinitis pigmentosa (RP), Ascher syndrome, Stargardt syndrome, glaucoma, diabetic retinopathy, and / or other retinal diseases.

Background Art

[0004] Age-related macular degeneration (AMD) is a term used to describe vision loss or blurring at the center of the visual field. The difficulty in detecting early-stage AMD is the lack of symptoms, which are very gradual and can affect one or both eyes. Not all vision is lost, but vision loss at the center of the visual field makes it difficult to recognize objects, drive, read, or perform normal activities. Typically, AMD is a disease that affects older individuals and is worsened by smoking, high blood pressure, atherosclerosis, elevated cholesterol, obesity, fat intake, and exposure to sunlight. There is also a genetic component to AMD, as shown by sibling studies indicating an increased recurrence ratio, and to date, at least five different genes have shown some connection to AMD. Unfortunately, AMD is a complex disease resulting from various environmental, genetic, and lifestyle factors.

[0005] The clinical signs of AMD typically include distortion of the visual field in the form of metamorphopsia, which is a type of visual distortion where a grid of straight lines appears wavy and parts of the grid may appear blank. Other symptoms of AMD include a slow recovery of visual function as a result of exposure to bright light (e.g., using a light stress test), a dramatic decrease in visual acuity clarity, blurring, difficulty in color discrimination, and loss of contrast sensitivity. AMD shows a processor accumulation of drusen deposits in the macula between the retinal pigment epithelium and the choroid. These drusen are an increase in 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 60 have drusen without any negative effects. Various stages of AMD are known and are generally classified into early AMD, intermediate AMD, late AMD, dry (or non-exudative) AMD, atrophic (or geographic) AMD, and / or wet (or exudative) AMD. Currently, there are approved drug products for treating "wet" AMD, but not for "dry" AMD.

[0006] Diabetic retinopathy (DR) is a major cause of blindness worldwide, and its pathogenesis remains not fully understood. Some studies have shown a close relationship with oxidative stress. (Zhu et al. Effect of antioxidant N-acetylcysteine on diabetic retinopathy and expression of VEGF and ICAM-1 from retinal blood vessels of diabetic rats. Molecular Biol Rep 2012; 39(4): 3727-3735) conducted a study aimed at examining the effect of antioxidants in DR and the expression of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1) from retinal blood 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 given 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 reactive oxygen species content in the retina was detected using a dichlorofluorescein assay. Compared with normal rats, diabetic rats showed significant retinopathy under both electron and light microscopes, accompanied by an increase in the reactive oxygen species content in the retina, and N-acetylcysteine treatment most significantly reduced the pathological changes and also decreased the reactive oxygen species at 5 months. VEGF and ICAM-1 expression was significantly upregulated in retinal blood vessels from diabetic rats, and such upregulation was attenuated by N-acetylcysteine treatment. The expression of both factors returned to basal levels 5 months after treatment with N-acetylcysteine.Long-term N-acetylcysteine treatment shows a protective effect on the retina of diabetes, perhaps by its downregulation of the expression of VEGF and ICAM-1, and the reduction of the content of reactive oxygen species in retinal vascular tissue in diabetic rats (Zhu et al. Effect of antioxidant N-acetylcysteine on diabetic retinopathy and expression of VEGF and ICAM-1 from retinal blood vessels of diabetic rats. Molecular Biol Rep 2012; 39(4): 3727-3735).

[0007] Ocular vitreoretinal surgery includes a group of procedures performed deep inside the eye using lasers or conventional surgical instruments. The goal of vitreoretinal surgery is to preserve, restore, and enhance vision for individuals suffering from one of a range of blindness conditions. The frequency of vitreoretinal surgery is approximately 225,000 cases per year in the United States. Despite the effectiveness of vitreoretinal surgery, it is associated with various unwanted complications. Without a doubt, the most frequently seen complication is cataract formation (clouding or turbidity of the lens that focuses light on the retina). After vitreoretinal surgery, significant cataracts occur in 80% of patients within one year (Belin PJ and Parke DW. Complications of vitreoretinal surgery. Curr Opin Ophthalmol 2020; 31, 167-173. doi: 10.1097 / ICU.0000000000000652).

[0008] The importance of the vitreous humor in protecting the lens from oxygen and nuclear cataracts has been highlighted by studies in which the vitreous gel was either intentionally preserved or destroyed. Surgery to remove the membrane in front of the retina typically involves a vitrectomy, which is immediately followed by nuclear cataracts. However, patients who had a modified form of the normal procedure in which the vitreous gel was not destroyed did not develop nuclear cataracts even after 5 years of follow-up. These studies were important because they showed that they could prevent nuclear cataracts even in patients who had undergone surgery to repair retinal problems by simply preserving the structure of the vitreous humor. Unfortunately, patients who underwent this modified procedure were more likely to have a recurrence of the fibrotic membrane in front of the retina, except for the property of the lens preservation of the modified surgery. Recent studies in animals have shown that liquefaction of the vitreous humor or enzyme-induced detachment of the vitreous humor from the retina increased the level of oxygen in the vitreous humor, resulting in a higher level of oxygen reaching the nucleus of the lens. These studies demonstrate that the gel state of the vitreous humor protects the lens from oxygen and nuclear cataracts. Liquefaction of the vitreous humor, which occurs to varying degrees with age, can be considered a delayed form of vitrectomy. Loss of the gel state of the vitreous humor may increase the exposure of the lens to oxygen, putting the patient at increased risk of nuclear cataracts (Beebe DC, Holekamp NM, Shui YB. Oxidative damage and the prevention of age-related cataracts. Ophthalmic Res. 2010;44(3):155-65. doi: 10.1159 / 000316481. Epub 2010 Sep 9. PMID: 20829639; PMCID: PMC2952186).

[0009] A safe and effective drug therapy to prevent cataract formation resulting from vitreoretinal surgery would be a medical leap forward that prevents the need for subsequent cataract surgery. The accumulation of experimental evidence indicates that oxidative stress is a factor in cataract development (Lim JC, Umapathy A, Donaldson PJ. Tools to fight the cataract epidemic: A review of experimental animal models that mimic age related nuclear cataract. Exp Eye Res. 2016 Apr;145:432-443. doi: 10.1016 / j.exer.2015.09.007. Epub 2015 Sep 25. PMID: 26391448). Therefore, agents that treat oxidative stress should have activity as anti-cataract agents.

[0010] Glaucoma refers to several eye diseases resulting from damage to the optic nerve that leads to vision loss. Primary Open Angle Glaucoma (POAG) is a chronic irreversible optic neuropathy that clinically presents as asymptomatic visual field loss along with a decrease in color and contrast sensitivity, leading to progressive death of retinal ganglion cells (Ster AM, Popp RA, Petrisor FM, Stan C, Pop VI. The Role of Oxidative Stress and Vascular Insufficiency in Primary Open Angle Glaucoma. Clujul Med. 2014;87(3):143-6. doi: 10.15386 / cjmed-295. Epub 2014 Aug 5. PMID: 26528013; PMCID: PMC4508597). POAG is a major global cause of irreversible blindness. However, our approach to its treatment: eye drops to reduce intraocular pressure (IOP) as the first approach, and surgical enhancement of outflow when eye drops are insufficient, has remained essentially unchanged for over 100 years. An increase in IOP is a major risk factor for glaucoma, such as a family history of glaucoma and hypertension. However, the etiology of glaucoma is still under investigation. An increase in IOP is a major (perhaps the most important specific) risk factor associated with glaucomatous neuropathy, but it does not mean the only factor causing glaucomatous neuropathy.Extensive studies have revealed multiple 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 impairment, and toxic effects and oxidative damage caused by reactive oxygen species (ROS) (Ster AM, Popp RA, Petrisor FM, Stan C, Pop VI. The Role of Oxidative Stress and Vascular Insufficiency in Primary Open Angle Glaucoma. Clujul Med. 2014;87(3):143-6. doi: 10.15386 / cjmed-295. Epub 2014 Aug 5. PMID: 26528013; PMCID: PMC4508597). The etiological role of ROS in glaucoma is supported by various experimental findings, including (a) the resistance to aqueous humor outflow is increased by hydrogen peroxide by inducing trabecular meshwork (TM) degeneration; (b) the TM possesses significant antioxidant activity mainly related to the altered superoxide dismutase-catalase and glutathione pathways in glaucoma patients; and (c) the increased intraocular pressure (IOP) and the severity of visual field defects in glaucoma patients are comparable to the amount of oxidative DNA damage affecting the TM (Izzotti A, Bagnis A, Sacca SC. The role of oxidative stress in glaucoma. Mutat Res. 2006 Mar;612(2):105-14. doi: 10.1016 / j.mrrev.2005.11.001. Epub 2006 Jan 18. PMID: 16413223).

[0011] Cataract is any opacity of the lens. Cataract is often considered an inevitable result of aging. Age-related cataract is the cause of nearly half of all blindness worldwide and half of all visual impairments in the United States. In the United States alone, surgery for age-related cataract is the most costly eye surgery procedure, exceeding $3 billion in annual expenditures. Lens opacification can result from protein aggregation, protein phase separation, or disruption of the regular alignment or packing of fiber cells, all of which can lead to increased light scattering. Nuclear opacification may also be involved in increased pigmentation, resulting in decreased light transmission. Oxidative damage is a major cause or consequence of cortical and nuclear cataracts, the most common types of age-related cataract. The overwhelming evidence suggests that exposure to increased levels of molecular oxygen accelerates age-related opacification of the lens nucleus, resulting in nuclear cataract. Factors in the eye that maintain a low oxygen partial pressure in the lens periphery are thus important for protecting the lens from nuclear cataract (Beebe DC, Holekamp NM, Shui YB. Oxidative damage and the prevention of age-related cataracts. Ophthalmic Res. 2010;44(3):155-65. doi: 10.1159 / 000316481. Epub 2010 Sep 9. PMID: 20829639; PMCID: PMC2952186).

[0012] The vitreous is a transparent gel-like substance that fills the cavity of the eye behind the lens and helps to stabilize the various retinal layers and retinal blood vessels. The gel-like characteristics of the vitreous result from a network of collagen fibrils that extend throughout the gel. Since the vitreous gel has no circulating flow and does not mix, this effectively impedes the distribution of signaling molecules or nutrients that can be released from the surrounding tissues.

[0013] The vitreous gel is remarkably stable, but over time, it tends to gradually disintegrate, perhaps as a result of the breakdown or change of the collagen fiber network. Patients with a degenerated vitreous have an increased risk for tractional forces that develop inferiorly in the retina and can predispose them to retinal detachment and disruption of the delicate layer architecture that characterizes the healthy retina. Apart from age-related vitreous liquefaction, other conditions typical of patients with diabetic retinopathy, such as uncontrolled bleeding from unstable retinal blood vessels, may require removal of the vitreous gel. In such conditions, the vitrectomy procedure is used to remove the native gel along with the captured blood components and subsequently replace it with a balanced salt solution. Vitrectomy is a major therapeutic advance in the treatment of retinal diseases, but it poses a high risk for the development of nuclear cataracts. Recent studies have pointed to oxygen as a cataract-inducing byproduct of the vitrectomy procedure. Most of the oxygen in the vitreous gel is thought to originate from the retinal blood vessels. An oxygen gradient exists in the native eye, with the highest levels closest to the retina and relatively low levels farthest near the back of the lens, because of the physical properties that limit its diffusion. When the vitreous humor contents are removed by vitrectomy and replaced with an aqueous saline solution, the physical barrier to oxygen diffusion is disrupted. Since the components in the replacement fluid for the vitreous freely mix, small molecules released from the retinal blood vessels are distributed throughout the vitreous cavity, and in this way, the area behind the lens is exposed to abnormally high levels of oxygen (Petrash JM. Aging and age-related diseases of the ocular lens and vitreous body. Invest Ophthalmol Vis Sci. 2013 Dec 13;54(14):ORSF54-9. doi: 10.1167 / iovs.13-12940. PMID: 24335070; PMCID: PMC3864378).

[0014] Since vitrectomy is a common procedure that causes rapid and certain opacification of the lens nucleus, patients who have undergone vitrectomy provide a "model system" with promise for testing the anti-cataract hypothesis. Success in protecting against the development of nuclear cataracts in patients after vitrectomy would lay the foundation for interventions to prevent these cataracts in subjects with advanced vitreous degeneration (Beebe DC, Holekamp NM, Shui YB. Oxidative damage and the prevention of age-related cataracts. Ophthalmic Res. 2010;44(3):155-65. doi: 10.1159 / 000316481. Epub 2010 Sep 9. PMID: 20829639; PMCID: PMC2952186).

[0015] Presbyopia is a condition in which the ability to focus on nearby objects is diminished. The effects of presbyopia are present in almost all individuals as they enter middle age. Near vision can be restored by the use of reading glasses alone, but there is a high demand for treatments that do not require corrective lenses for practical and professional reasons. The biological basis of presbyopia has been avidly studied over the years. To adjust for near vision, the lens needs to "round up" from an unaccommodated shape. This shape change is made possible when the ciliary muscle contracts and pulls closer the tissue that surrounds the lens in a sphincter-like movement. Accordingly, the body of the lens assumes a more rounded shape, mainly with a change in the radius of curvature of the front surface. The accommodative response reduces the focal length of the lens, which enables clear focusing on nearby objects at the retina. Therefore, the process of accommodation for near vision relies on the change in lens shape in response to contraction of the ciliary muscle (Petrash JM. Aging and age-related diseases of the ocular lens and vitreous body. Invest Ophthalmol Vis Sci. 2013 Dec 13;54(14):ORSF54-9. doi: 10.1167 / iovs.13-12940. PMID: 24335070; PMCID: PMC3864378).

[0016] As the lens ages, the nucleus becomes harder, while the cortex remains soft. Nuclear sclerosis is a major contributing factor to presbyopia (Beebe DC, Holekamp NM, Shui YB. Oxidative damage and the prevention of age-related cataracts. Ophthalmic Res. 2010;44(3):155-65. doi: 10.1159 / 000316481. Epub 2010 Sep 9. PMID: 20829639; PMCID: PMC2952186).

[0017] Flexibility is an important factor underlying the ability of the lens to change its shape. Many researchers have shown that the human lens hardens over time, leading to the hypothesis that presbyopia occurs when the lens becomes too hard to change its shape in response to contraction of the ciliary muscle. Studies by various methods have demonstrated that lens hardness begins to increase significantly from the 30s to the 50s, which is approximately the same age at which loss of accommodation becomes noticeable in the early stages of presbyopia. The molecular basis for the increase in lens hardness is not fully understood. Fibrous cells in the lens nucleus are linked by the arrangement of intercellular adhesion molecules, gap junction complexes, and ball-and-socket-like fittings along their extensive lateral membranes. As the lens ages and much of the lens mass migrates internally to the nuclear region, the cells become firmly fixed together with these intercellular junctions and may possibly contribute to the reduced deformability of the tissue (Petrash JM. Aging and age-related diseases of the ocular lens and vitreous body. Invest Ophthalmol Vis Sci. 2013 Dec 13;54(14):ORSF54-9. doi: 10.1167 / iovs.13-12940. PMID: 24335070; PMCID: PMC3864378).

[0018] The onset of presbyopia in middle age can lead to a potential decrease in productivity in healthy adults if uncorrected or undercorrected. In 2011, there were an estimated 1.272 billion cases of presbyopia worldwide. Among people under the age of 50, a total of 244 million cases of uncorrected or undercorrected cases were associated with a potential productivity loss of $11.023 billion (0.016% of the world's GDP), or assuming people aged <65 were productive, were associated with a potential productivity loss of $25.367 billion (0.037% of the world's GDP). The economic burden is even greater in low-income countries where up to 94% of cases can be uncorrected or undercorrected (Frick KD, Joy SM, Wilson DA, Naidoo KS, Holden BA. The Global Burden of Potential Productivity Loss from Uncorrected Presbyopia. Ophthalmology. 2015 Aug;122(8):1706-10. doi: 10.1016 / j.ophtha.2015.04.014. PMID: 26190438).

[0019] Retinitis pigmentosa (RP) is a group of diseases in which one of a number of mutations causes the death of rod photoreceptors. After the rods die, cone photoreceptors degenerate slowly in a characteristic pattern. The mechanisms of rod cell death, which vary depending on the mutated gene and the rate at which the rods degenerate, are an important prognostic image because the cones do not begin to degenerate until almost all of the rods are eliminated. Rod cell death causes night blindness, but visual impairment and blindness result from cone degeneration, and thus it is important to determine the mechanism by which this occurs. The death of rods reduces oxygen consumption and results in high tissue levels of oxygen outside the retina. Excess oxygen stimulates superoxide radical production by mismatches in the electron transport chain in mitochondria and by stimulation of NADPH oxidase activity in the cytoplasm. High levels of superoxide radicals overwhelm the antioxidant defense system and generate more reactive species, including peroxynitrite, which is extremely harmful and difficult to detoxify. Since drugs or gene transfer that reduce oxidative stress promote cone survival and function maintenance, this results in progressive oxidative damage in cones that contributes to cone cell death and loss of function. Samples of aqueous humor from patients with RP show a significant increase in the carbonyl content of proteins indicating oxidative damage, and a reduction in the ratio of reduced glutathione to oxidized glutathione, indicating depletion of the main components of the antioxidant defense system from ongoing oxidative stress, compared to samples from control patients. The first step in clinical trials is to identify doses of therapeutic agents that reverse these disease biomarkers to assist in the design of very long trials with functional and anatomical endpoints (Campochiaro PA, Mir TA. The mechanism of cone cell death in Retinitis Pigmentosa. Prog Retin Eye Res. 2018 Jan;62:24-37. doi: 10.1016 / j.preteyeres.2017.08.004. Epub 2017 Sep 27. PMID: 28962928).

[0020] N-acetylcysteine (NAC) is a free radical scavenger that is converted to cysteine, a substrate for the synthesis of glutathione, an important component of the endogenous antioxidant defense system (Dilger RN, Baker DH. Oral N-acetyl-L-cysteine is a safe and effective precursor of cysteine. J Anim Sci. 2007 Jul;85(7):1712-8. doi: 10.2527 / jas.2006-835. Epub 2007 Mar 19. PMID: 17371789). NAC is approved for the treatment of acetaminophen overdose and is life-saving when administration is initiated relatively early after ingestion. In untreated patients, the severity of liver oxidative damage is very severe, with extensive liver necrosis and liver failure occurring, which is very noteworthy (Prescott LF, Park J, Ballantyne A, Adriaenssens P, Proudfoot AT. Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine. Lancet. 1977 Aug 27;2(8035):432-4. doi: 10.1016 / s0140-6736(77)90612-2. PMID: 70646); (Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med. 1988 Dec 15;319(24):1557-62. doi: 10.1056 / NEJM198812153192401. PMID: 3059186).Compared to untreated rd10 mice, those given NAC in drinking water showed a dose-dependent and statistically significant reduction in oxidative damage, as well as improved cone survival and function (Lee SY, Usui S, Zafar AB, Oveson BC, Jo YJ, Lu L, Masoudi S, Campochiaro PA. N-Acetylcysteine promotes long-term survival of cones in a model of retinitis pigmentosa. J Cell Physiol. 2011 Jul;226(7):1843-9. doi: 10.1002 / jcp.22508. PMID: 21506115). Over several months of NAC treatment, cone function and survival showed some decline but remained significantly higher than in untreated mice, demonstrating a long-lasting effect. N-acetylcysteine amide (NACA), a precursor of NAC, penetrates the blood-retinal barrier and enters cells better than NAC. Those treated with 7-fold lower doses of N-acetylcysteine amide (NACA) compared to NAC-treated rd10 mice showed higher preservation of cone function and survival (Campochiaro PA, Mir TA. The mechanism of cone cell death in Retinitis Pigmentosa. Prog Retin Eye Res. 2018 Jan;62:24-37. doi: 10.1016 / j.preteyeres.2017.08.004. Epub 2017 Sep 27. PMID: 28962928).

[0021] The Argis II Retinal Prosthesis System was approved by the FDA in 2013 as an implantable device to treat adults with severe vision loss, but it simply produces a sense of light, thereby helping the patient to identify objects and the location or movement of people, and the device does not change the disease.

[0022] One FDA-approved gene therapy for RP is LUXTURNA, a gene therapy based on an adeno-associated virus vector that is indicated for the treatment of patients with confirmed biallelic RPE65 mutation-related retinal dystrophy (LUXTURNA Prescribing Information, 2017 accessed 23Jan2022 at: https: / / www.fda.gov / media / 109906 / download). 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 News Release “FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss”, 2017, accessed 23Jan2022 at: https: / / www.fda.gov / news-events / press-announcements / fda-approves-novel-gene-therapy-treat-patients-rare-form-inherited-vision-loss)), there are no other FDA-approved therapies that stop the progression of the disease or restore vision caused by retinitis pigmentosa. Current treatment approaches are limited to slowing the degenerative process by sun protection and vitamin A supplementation, treating complications (cataracts and macular edema), and helping patients cope with the social and psychological impact of blindness.

[0023] 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 to a greater extent than NAC in a mouse model of RP.

[0024] Thus, although not limited thereto, there remains a need for novel compositions and methods for the treatment of ophthalmic diseases and conditions related to oxidative stress, including age-related macular degeneration, cataracts, corneal endothelial cell protection, glaucoma, diabetic retinopathy, presbyopia, retinitis pigmentosa, and other retinal diseases.

Prior Art Documents

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Summary of the Invention

Means for Solving the Problems

[0027] As embodied and broadly described herein, aspects of the present disclosure relate to biodegradable intraocular implants that include (2R,2R’)-3,3’-disulfanediylbis(2-acetamidopropanamide) (diNACA) in a pharmaceutically acceptable polymer. In one aspect, the implant further includes an antioxidant selected from the group consisting of 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 between 5 - 8 mm or about 5 - 8 mm. In another aspect, the biodegradable polymer is a poly(lactide-co-glycolide) copolymer. In another aspect, diNACA is present in the implant in an amount of at least between about 21 - 65 weight percent (wt%), between 1 - 20 wt%, between 5 - 15 wt%, between 7 - 12 wt%, or about 10 wt%. In another aspect, diNACA is present with an adjuvant. In another aspect, the implant includes a number of openings or pores in the polymer. In another aspect, the intraocular implant includes diNACA in a biodegradable polymer in the form of a first intraocular implant; and an adjuvant associated with a biodegradable polymer in the form of a second intraocular implant; wherein diNACA is present in the first intraocular implant in an amount of at least about 10 weight percent.In another aspect, the implant is suitable for intravitreal placement in an individual's eye, diNACA is present in an amount effective to treat the eye condition of the individual; an adjuvant associated with the biodegradable polymer component in the form of an intraocular implant is structured for intravitreal placement in the individual's eye, and the adjuvant is present in an amount effective to reduce the occurrence of at least one undesirable effect that would be present when administered in the same manner except for diNACA alone; diNACA is present in the intraocular implant in an amount of at least about 10 weight percent. In another aspect, the polymer in the diNACA implant decreases in molecular weight, for example, by hydrolysis, becomes a hydrogel, and then dissolves, as evidenced by a decrease in mass of the implant over time. The process of decreasing molecular weight controls the release of the drug from the implant.

[0028] As embodied and broadly described herein, aspects of the present disclosure relate to a biodegradable intraocular implant system containing an antioxidant suitable for the treatment of ophthalmic diseases or conditions involving oxidative stress in animals or humans. In one aspect, the antioxidant is included in the polymer matrix or alternating layers as a combination of (2R,2R’)-3,3’-disulfanediyldi(2-acetamidopropanamide) (diNACA) or (2R,2R’)-3,3’-disulfanediyldi(2-acetamidopropanamide) (diNACA) and an adjuvant. In another aspect, the antioxidant includes (2R,2R’)-3,3’-disulfanediyldi(2-acetamidopropanamide) (diNACA), or diNACA and the adjuvant are included in the same implant or different implants. In another aspect, diNACA is present in the implant in an amount between at least 21 - 65 weight percent (wt%), between 1 - 20 wt%, between 5 - 15 wt%, between 7 - 12 wt%, or about 10 wt%. In another aspect, the polymer in the diNACA implant decreases in molecular weight, for example, by hydrolysis, becomes a hydrogel, and then dissolves, as evidenced by a decrease in mass of the implant over time. The process of decreasing molecular weight controls the release of the drug from the implant.

[0029] As embodied and broadly described herein, aspects of the present disclosure are methods for the treatment of ophthalmic oxidative stress in an animal or human subject, the methods comprising identifying an animal or human patient in need of treatment for ophthalmic oxidative stress of the eye; and administering to the animal or human patient a therapeutically effective amount of N-acetylcysteine amide (NACA) or (2R,2R’)-3,3’-disulfanediylbis(2-acetamidopropanamide) (diNACA) in an intravitreal implant (diNACA implant). In one aspect, the ophthalmic oxidative stress of the eye is selected from at least one of cataract, cataract in a subject without diabetes, loss of corneal endothelial cells, age-related macular degeneration, presbyopia, retinitis pigmentosa (RP), Usher syndrome, Stargardt syndrome, glaucoma, diabetic retinopathy, or retinal disease. In another aspect, 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, sub-Tenon's, retinal, subretinal, retrobulbar, peribulbar, suprachoroidal, subchoroidal, conjunctival, subconjunctival, episcleral, posterior juxtascleral, anterior juxtascleral, periacular, topical, and lacrimal duct. 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 - 150 mg / Kg. In another aspect, diNACA is administered as 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 - 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 bisulfite, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, NAC, NACA, propyl gallate, α-tocopherol, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, or phosphoric acid. In another aspect, diNACA is present in the implant in an amount of at least between 21 and 65 weight percent (wt%), between 1 and 20 wt%, between 5 and 15 wt%, between 7 and 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, 1,000, 2,500, 5,000, 7,500, or 10,000 micrograms per dose. In another aspect, the dosage for administration is 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 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 degrades, dissolves, or biodegrades in the eye. In another aspect, the polymer in the diNACA implant, as evidenced by a decrease in mass of the implant over time, for example, has a decreasing molecular weight by hydrolysis, becomes a hydrogel, and then dissolves. The process of decreasing molecular weight controls the release of the drug from the implant. In another aspect, diNACA is administered prophylactically to prevent ophthalmic diseases or conditions in which oxidative stress is involved.

[0030] As embodied and broadly described herein, aspects of the present disclosure relate to non-biodegradable, non-biodegradable or non-bioabsorbable intraocular implants that include (2R,2R’)-3,3’-disulfanediylbis(2-acetamidopropanamide) (diNACA) in a pharmaceutically acceptable polymer. In one aspect, the antioxidant is selected from the group consisting of N-acetylcysteine, N-acetylcysteine amide, (2R,2R’)-3,3’-disulfanediylbis(2-acetamidopropanamide) (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 0.05 mm or about 0.05 mm and a length between 5 - 8 mm or about 5 - 8 mm.In another aspect, the biodegradable polymer is a polycarbamate 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-isopropylidenediphenylene carbonate), polyurethane, 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(halo-olefin), poly(vinyl) ester, alkyl acrylate, polyoxide, polyester, polyamide, and polycarbonate, or a mixture thereof. In another aspect, diNACA is present in the implant in an amount of at least between 21 and 65 weight percent (wt%), between 1 and 20 wt%, between 5 and 15 wt%, between 7 and 12 wt%, or about 10 wt%. In another aspect, the polymer in the diNACA implant decreases in molecular weight, for example, by hydrolysis, becomes a hydrogel, and then dissolves, as evidenced by a decrease in mass of the implant over time. The process of decreasing molecular weight controls the release of the drug from the implant. In another aspect, the implant further comprises 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 within the vitreous body, within the stroma, within the anterior chamber, sub-Tenon's, retina, subretinal, posterior to the eye, around the eye, suprachoroidal, subchoroidal, conjunctiva, subconjunctiva, episclera, posterior near the sclera, anterior near the sclera, around the cornea, topical, and the tear duct.

[0031] As embodied and broadly described herein, aspects of the present disclosure are methods for the treatment of a disease or condition of ophthalmic oxidative stress in the eyes of an animal or human subject, the method comprising obtaining an intravitreal implant (diNACA implant) comprising a therapeutically effective amount of N-acetylcysteine amide (NACA) or (2R,2R’)-3,3’-disulfanediylbis(2-acetamidopropanamide) (diNACA), and delivering the diNACA implant, which delivers a therapeutically effective amount of diNACA, to a predetermined region of the eye into, in, or around the eye. In one aspect, the disease or condition is selected from at least one of cataract, cataract in a subject without diabetes, loss of corneal endothelial cells, age-related macular degeneration, presbyopia, retinitis pigmentosa (RP), Usher syndrome, Stargardt syndrome, glaucoma, diabetic retinopathy, or retinal disease. In another aspect, the diNACA implant is administered to a predetermined region of the eye selected from the group consisting of intravitreal, stromal, anterior chamber, sub-Tenon's, retina, subretinal, posterior to the globe, around the globe, suprachoroidal, subchoroidal, conjunctiva, subconjunctiva, episcleral, posterior adjacent to the sclera, anterior adjacent to the sclera, around the cornea, topical, and lacrimal duct. In another aspect, diNACA is administered at a daily dose of about 0.25 - 150 mg / Kg. In another aspect, diNACA is administered at a single dose of about 1 - 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 bisulfite, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, NAC, NACA, propyl gallate, α-tocopherol, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, or phosphoric acid. In another aspect, diNACA is present in the implant in an amount of at least between 21 - 65 weight percent (wt%), between 1 - 20 wt%, between 5 - 15 wt%, between 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, 1,000, 2,500, 5,000, 7,500, or 10,000 micrograms per dosage. In another aspect, the dosage for administration is 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per dosage. In another aspect, the diNACA implant is manually inserted into the eye. In another aspect, the diNACA implant decomposes, dissolves, or biodegrades in a predetermined area of the eye. In another aspect, the polymer in the diNACA implant, as evidenced by the decrease in mass of the implant over time, for example, undergoes a decrease in molecular weight by hydrolysis to become a hydrogel and then dissolves. The process of decreasing molecular weight controls the release of the drug from the implant. In another aspect, diNACA is prophylactically administered to prevent an ophthalmic disease or condition in or around a predetermined area of the eye.

Brief Description of the Drawings

[0032] To more fully understand the features and advantages of the present invention, a detailed description of the present invention is hereby incorporated by reference in conjunction with the accompanying drawings.

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Mode for Carrying Out the Invention

[0033] The fabrication and use of various embodiments of the present invention are discussed in detail below, but it should be understood that the present invention provides many applicable inventive concepts that can be embodied in a wide variety of specific situations. The specific embodiments discussed herein are merely illustrative of specific methods for fabricating and using the present invention and do not limit the scope of the present invention.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present specification, including definitions, will control. Preferred methods and materials are described below, but 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 intended to be limiting.

[0035] The singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. The present disclosure contemplates other embodiments that "comprise", "consist of", and "consist essentially of" the embodiments or elements presented herein, whether explicitly stated or not.

[0036] The conjunctive term "or" includes any and all combinations of one or more of the associated listed elements. For example, the phrase "an apparatus including A or B" can refer to an apparatus including A without B, an apparatus including B without A, or an apparatus including both A and B. The phrase "at least one of A, B, ··· and N" or "at least one or a combination of A, B, ··· N" is defined in its broadest sense to mean one or more elements selected from the group consisting of A, B, ··· and N, which can be any one element alone or in combination with one or more of the other elements, including combinations with additional elements not listed, and any combination of one or more of the elements A, B, ··· or N.

[0037] The modifier "about" used in conjunction with a quantity includes the recited value and has the meaning indicated by the context (e.g., this includes at least the degree of error associated with the measured value of a particular quantity). The modifier "about" is also considered to disclose a range defined by the absolute values of two endpoints. For example, the expression "about 2 to about 4" also discloses the range "2 to 4". The term "about" can refer to plus or minus 10% of the indicated number. For example, "about 10%" can indicate the range 9% to 11%, and "about 1" can mean 0.9 to 1.1. Other meanings of "about" such as rounding can be apparent from the context, and thus, for example, "about 1" can also mean 0.5 to 1.4.

[0038] As used herein, weight percent is abbreviated as "wt.%".

[0039] As used herein, "active oxygen species" or "reactive oxygen species" refers to an anion having the form O2'' of superoxide, or a peroxide anion having a compound containing an O - O single bond, e.g., hydrogen peroxide and lipid peroxide, and is understood as the transfer of one or two electrons. Such superoxides and peroxides are very reactive and can cause damage to cellular components including proteins, nucleic acids, and lipids. - ’’ or a peroxide anion having a compound containing an O - O single bond, for example, hydrogen peroxide and lipid peroxide, and is understood as the transfer of one or two electrons. Such superoxides and peroxides are very reactive and can cause damage to cellular components including proteins, nucleic acids, and lipids.

[0040] As used herein, the term "agent" refers to a therapeutically active compound or a potentially therapeutically active compound, e.g., an antioxidant. An agent can be a previously known compound or an unknown compound. As used herein, an agent is typically a cell - based compound, however, agents can include biological therapeutics, e.g., peptide or nucleic acid therapeutics, e.g., siRNA, shRNA, cytokines, antibodies, etc.

[0041] As used herein, the terms "amelioration" or "treatment" are understood to mean reducing or decreasing at least one sign, symptom, indication, or effect of a particular disease or condition. For example, amelioration or treatment of age-related macular degeneration, glaucoma, and / or diabetic retinopathy may include, but is not limited to, reduction of night vision, reduction of overall visual acuity, reduction of visual field, reduction of cone density in one or more quadrants of the retina, thinning of the retina, particularly the outer granular layer, reduction of a- or b-wave amplitude in scotopic or photopic electroretinogram (ERG); or reduction, delay, or elimination of one or more signs or symptoms of age-related macular degeneration, glaucoma, and / or diabetic retinopathy, including any other clinically acceptable indicator of disease state or progression. Amelioration and treatment may require administration of two or more doses of the agent, either alone or in combination with other therapeutic agents and interventions. Amelioration or treatment does not require that the disease or condition be cured.

[0042] As used herein, the term "antioxidant" refers to a molecule that delays or prevents the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substrate to an oxidizing agent. Such reactions may be promoted by, or may generate, superoxide anions or peroxides. Oxidation reactions can generate free radicals, which initiate a chain reaction that damages cells. Antioxidants terminate these chain reactions by removing free radical intermediates and inhibit other oxidation reactions by oxidizing themselves. As a result, antioxidants are often reducing agents such as thiols, ascorbic acid, or polyphenols. Examples of antioxidants include, but are not limited to, a-tocopherol, ascorbic acid, Mn(III) tetrakis(4-benzoic acid) porphyrin, a-lipoic acid, and n-acetylcysteine.

[0043] As used herein, the term "adjuvant" refers to an agent that can reduce at least one side effect of an antioxidant drug. An adjuvant includes a compound 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.

[0044] As used herein, the term "co - administration" refers to the administration of one or more agents to a subject such that the agents are present and active in the subject at the same time. Co - administration does not require the preparation of a mixture of the agents or the simultaneous administration of the agents.

[0045] As used herein, the term "effective amount" or "effective dose" refers to the amount of an agent that produces the intended pharmacological, therapeutic, or prophylactic result. A pharmacologically effective amount results in the remission of one or more signs or symptoms of a disease or condition or the progression of a disease or condition, or causes the regression of a disease or condition. For example, a therapeutically effective amount preferably reduces vision loss, loss of overall visual clarity, loss of visual field 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 over a defined period, such as 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 5 years or more, compared to an untreated control subject. More than one dose may be required to provide an effective dose.

[0046] As used herein, the terms "effective" and "efficacy" include both pharmacological efficacy and physiological safety. Pharmacological efficacy refers to the ability of a treatment to produce a desired biological effect in a patient. Physiological safety refers to the level of toxicity or other adverse physiological effects (often referred to as side effects) at the cellular, organ, and / or organism level resulting from the administration of a treatment. On the other hand, the term "ineffective" indicates that, in at least an unstratified population, the treatment does not provide a pharmacological effect sufficient for the treatment to be therapeutically useful even in the absence of adverse effects (e.g., the treatment may be ineffective in a subpopulation that can be identified by one or more expression profiles). "Low efficacy" means that the treatment results in a therapeutically significantly low level of pharmacological efficacy and / or a therapeutically high level of adverse physiological effects, such as high hepatotoxicity.

[0047] Thus, in the context of drug administration, a drug that is "effective against" a disease or condition indicates that administration in a clinically appropriate manner results in a beneficial effect, such as improvement of symptoms, cure, reduction of disease signs or symptoms, extension of lifespan, improvement of quality of life, or other effects generally recognized as favorable by physicians knowledgeable in the treatment of a particular type of disease or condition, in at least a statistically significant proportion of patients.

[0048] As used herein, the phrase "oxidative stress-related eye disorders" includes, but is not limited to, age-related macular degeneration, macular degeneration including age-related macular degeneration, glaucoma, and / or diabetic retinopathy, Leber's neuropathy, and optic neuritis.

[0049] As used herein, the term "peroxidase" or "peroxide-metabolizing enzyme" ROOR1 + electron donor (2e-) + 2H+ → ROH + R1OH refers to a large family of enzymes that typically catalyze reactions of the form

[0050] For many of these enzymes, the optimal substrate is hydrogen peroxide where each R is H, while others are more active with organic hydroperoxides such as lipid peroxides. Peroxidases can contain a heme cofactor at their active sites, or a redox-active cysteine or selenocysteine residue.

[0051] As used herein, the phrase “pharmaceutically acceptable carrier” is recognized in the art and includes pharmaceutically acceptable materials, compositions or media suitable for administering the compounds of the invention to a mammal. A carrier includes a liquid or solid diluent, excipient, solvent or encapsulating material involved in carrying or transporting the subject agent from one organ or part of the body to another. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. For example, a pharmaceutically acceptable carrier for administration of cells is typically a carrier acceptable for delivery by injection and does not contain agents such as surfactants or other compounds that can damage the cells being delivered. Some examples of materials that can serve 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 carboxymethyl cellulose, ethyl cellulose 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 glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances used in pharmaceutical formulations, particularly phosphate buffered saline aqueous solution which is preferred for intraocular delivery.

[0052] Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring agents and fragrances, preservatives and antioxidants can also be present in the composition.

[0053] Examples of pharmaceutically acceptable antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, 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 chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0054] The formulations of the present invention are suitable for oral, nasal, topical, transdermal, buccal, sublingual, intramuscular, intraperitoneal, intraocular, intravitreal, posterior juxtascleral, anterior juxtascleral, posterior to the globe, subretinal, and / or other parenteral administration routes. The specific route of administration depends, inter alia, on the specific cells to be targeted. The formulations may be conveniently presented in unit dosage form and may be prepared by any method well known in the pharmaceutical art. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form is generally the amount of the compound that produces a therapeutic effect.

[0055] As used herein, "a plurality" is understood to mean two or more. For example, a plurality refers to at least 2, 3, 4, 5 or more.

[0056] As used herein, the terms "polypeptide" or "peptide" are understood to be two or more independently selected natural or non-natural amino acids connected by a covalent bond (e.g., a peptide bond). A peptide can 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 connected by peptide bonds. The polypeptides described herein include not only full-length proteins (e.g., fully processed proteins), but also shorter amino acid sequences (e.g., fragments of naturally occurring proteins or synthetic polypeptide fragments).

[0057] As used herein, "prevention" is understood to mean, in particular, the limitation of at least one sign or symptom of a disease or condition, the reduction in the rate or degree of onset, or the inhibition of the occurrence of a disease or condition in a subject predisposed to developing the disease or disorder. For example, a subject having a mutation in a gene such as an opsin gene may be at risk of developing age-related macular degeneration, glaucoma, and / or diabetic retinopathy. The age of onset of one or more symptoms of the disease may be determined by a particular mutation in some cases. Prevention can include the delay in the onset of one or more signs or symptoms of age-related macular degeneration, glaucoma, and / or diabetic retinopathy, and it is not necessary to prevent the appearance of at least one sign or symptom of the disease throughout the life of the subject. Prevention may require the administration of two or more doses of a drug or therapeutic agent.

[0058] As used herein, the term "small molecule" refers to a compound, typically an organic compound, having a molecular weight of about 1500 Da, 1000 Da, 750 Da, or 500 Da or less. In certain embodiments, a small molecule does not include polypeptides or nucleic acids that contain only natural amino acids and / or nucleotides.

[0059] As used herein, the term "subject" refers to a living organism, particularly a human. In certain embodiments, the living organism is an animal, and in certain preferred embodiments, the subject is a mammal. In certain embodiments, the subject is a domesticated mammal or a primate including non-human primates. Examples of subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, goats, and sheep. A human subject may also be referred to as a subject or a patient.

[0060] As used herein, a subject "having or suspected of having" a particular disease, condition or syndrome has a sufficient number of risk factors or presents a sufficient number or combination of signs or symptoms of the disease, condition or syndrome such that a qualified individual would diagnose or suspect that the subject has the disease, condition or syndrome. Methods for identifying subjects having or suspected of having conditions such as age-related macular degeneration, glaucoma, and / or diabetic retinopathy are within the ability of one of ordinary skill in the art. Subjects having and suspected of having a particular disease, condition or syndrome are not necessarily two separate groups.

[0061] As used herein, the term "superoxide dismutase" refers to an enzyme that disproportionates superoxide into oxygen and hydrogen peroxide. Examples include, but are not limited to, SOD1, SOD2, and SOD3. Sod1 and SOD3 are two isoforms of the Cu-Zn-containing superoxide dismutase enzyme present in mammals. Cu-Zn-SOD or SOD1 is found in the intracellular space, and extracellular SOD (ECSOD or SOD3) is found primarily in the extracellular matrix of most tissues.

[0062] As used herein, the phrase "therapeutically effective amount" refers to an amount of an agent that, upon single or multiple dosing to a cell or subject, is effective in prolonging the survival of a patient having such a disorder, reducing one or more symptoms or signs of the disorder, preventing or delaying beyond that predicted in the absence of such treatment, etc.

[0063] An agent or other therapeutic intervention can be administered to a subject as a pharmaceutical composition that is a mixture with a conventional excipient, e.g., a pharmaceutically acceptable carrier, either alone or in combination with one or more additional therapeutic agents or therapeutic interventions, or can be administered as a therapeutic treatment.

[0064] The pharmaceutical may be conveniently administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, e.g., as described in Remington’s Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1985). Formulations for parenteral administration may contain conventional excipients such as sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalene, etc. In particular, biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers can be useful excipients for controlling the release of certain agents.

[0065] The present invention is directed to the use of an implant having 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 human, which includes administering to the human a therapeutically effective amount of diNACA. In some embodiments, diNACA is provided in or with a pharmaceutically acceptable carrier. In other embodiments, the diNACA implant is administered intravitreally, subretinally, intravitreally, posterior juxtascleral, anterior juxtascleral, posterior to the globe, intramuscularly, or topically, in or around the eye. The implant of the present invention can be injected into one or more non-limiting locations, such as a predetermined location, including, for example, intravitreally, in a stroma, in the anterior chamber, sub-Tenon's, the retina, subretinally, posterior to the globe, around the globe, suprachoroidal, subchoroidal, the conjunctiva, subconjunctiva, episcleral, posterior juxtascleral, anterior juxtascleral, around the cornea, topically, and the lacrimal duct.

[0066] Administration of a therapeutic agent, such as an antioxidant, by use in one or more intraocular implants can improve the treatment of eye diseases or conditions in which oxidative stress is involved. The implant includes 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, including the delivery of one agent, the dosage regimen may be formulated to provide one drug to the anterior or posterior segment of the eye. For example, for delivery of an ophthalmic drug to the posterior region of the eye, the implant may be introduced as an intravitreal implant inserted into the vitreous cavity.

[0067] In certain embodiments involving the delivery of two or more agents, the dosing regimen may be formulated to provide two or more drugs to the posterior segment of the eye under different dosing regimens. For example, the dosing of the antioxidant in the implant may be discontinuous over the course of treatment, while the non - discontinuous dosing of the adjuvant is administered in the implant over the same entire period. The implant containing the antioxidant and the implant containing the adjuvant may be different implants, or the same implant including means for administering the antioxidant and the adjuvant differently, such means may not contain any of the drugs, may contain one or both of the drugs, or may contain covalent linkage of one or both of the drugs to the biodegradable polymer of the implant by biodegradable linkage, including different coatings or shells, and in this way enable the regulation of the delivery of one or more drugs over the course of treatment. The implant is effective to directly provide a therapeutically effective dosage of one or more agents to the eye region to treat one or more eye diseases or conditions involving oxidative stress. Thus, by a single administration, the therapeutic agents become available at the sites where they are needed, rather than subjecting the patient to repeated infusions or, in the case of self - administered eye drops, ineffective treatment due to only limited and intensive exposure to one or more active agents, and can be maintained for a long period of time.

[0068] As used herein, the term "adjuvant" refers to agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifying agents, salts for affecting osmotic pressure, buffering agents, coloring agents, flavoring agents and / or fragrances, which do not interact detrimentally with the antioxidant of the formulation.

[0069] One such intraocular implant according to the disclosure herein includes a therapeutic component and a drug release sustaining component associated with the therapeutic component. According to the invention, the therapeutic component comprises, consists essentially of, or consists of the antioxidant diNACA. The drug release sustaining component is associated with the therapeutic component for the sustained release of a therapeutically effective amount of the antioxidant into the eye in which the implant is placed. A therapeutic amount of the antioxidant is released into the eye for a period longer than about two months after the implant is placed in the eye.

[0070] For the purposes of this description, we use the following terms as defined in this section, unless the context of the word indicates a different meaning.

[0071] As used herein, "intraocular implant" refers to a device or element or pharmaceutical product that is structured, sized, or otherwise configured to be placed into the "eye," including the subconjunctival space. Intraocular implants are generally biocompatible with the physiological conditions of the eye and do not cause harmful side effects. Intraocular implants can be placed into the eye without disrupting the vision of the eye.

[0072] As used herein, "therapeutic component" refers to a part of an intraocular implant that includes one or more therapeutic agents or substances used to treat a medical condition of the eye. The therapeutic component may be a separate region of the intraocular implant or it may be homogeneously distributed throughout the implant. The therapeutic agents of the therapeutic component are typically ophthalmically acceptable and are provided in a form that does not cause a harmful reaction when the implant is placed in the eye.

[0073] As used herein, "drug release sustaining component" refers to a part of an intraocular implant that is effective in providing sustained or controlled release of a therapeutic agent of the implant. The drug release sustaining component may be a biodegradable polymer matrix, or it may be a coating that covers the core region of the implant containing the therapeutic component.

[0074] As used herein, "associated with" means mixed with, dispersed therein, coupled with, coated with, or surrounding. With respect to an intraocular implant containing 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.

[0075] As used herein, "ocular region" or "ocular site" generally refers to any area of the eye globe including the anterior and posterior segments of the eye, which generally includes, but is not limited to, the eye globe partially or completely juxtaposed to the inside or outside of the eye globe, or any functional (e.g., for vision) or structural tissue found in the tissue or cell layer. Specific examples of areas of the eye in the ocular region include the anterior chamber, posterior chamber, vitreous cavity, choroid, suprachoroidal space, conjunctiva, subconjunctival space, episcleral space, intrascleral space, suprachoroidal space, sclera, pars plana, surgically induced avascular area, macula, and retina.

[0076] As used herein, "ophthalmic disease or eye disease" or "ophthalmic condition or eye condition" is a disease, illness or condition that affects or is involved with one of the eyes or parts or regions of the eyes. Broadly speaking, the eye includes the eyeball, or globe, the tissues and fluids that make up the eye, the muscles around the eye (e.g., oblique and straight muscles), and the part of the optic nerve inside or adjacent to the eye.

[0077] The state in front of the eye is a disease, illness, or condition that affects or is involved with the eye tissue or fluid located in front of the eye region or part (i.e., in front of the eyes), such as the muscles around the eyes, the eyelids, or the eyeball tissue or fluid in front of the posterior wall of the lens capsule or ciliary muscle. Therefore, the state in front of the eye mainly affects or is involved with the conjunctiva, cornea, anterior chamber of the eye, iris, posterior chamber of the eye (in front of the posterior wall of the lens capsule but behind the retina), lens or lens capsule, and the blood vessels and nerves with developed blood vessels or distributed nerves in front of the eye region or part.

[0078] The state in front of the eye may include diseases, illnesses, or conditions such as aphakia; pseudophakia; astigmatism; eyelid spasm; cataract; conjunctival diseases; conjunctivitis; corneal diseases; corneal ulcer; dry eye syndrome; eyelid diseases; lacrimal apparatus diseases; lacrimal duct obstruction; myopia; presbyopia; pupil disorders; refractive disorders, and strabismus. Glaucoma can also be considered a state in front of the eye because the clinical goal of glaucoma treatment may be to reduce the high pressure of the aqueous fluid in the anterior chamber of the eye (i.e., reduce intraocular pressure).

[0079] The state behind the eye is a disease, illness, or condition that mainly affects or is involved with the area or part behind the eye, such as the choroid or sclera (located behind the plane passing through the posterior wall of the lens capsule), vitreous body, vitreous chamber, retina, optic nerve (i.e., optic disc), and the blood vessels and nerves with developed blood vessels or distributed nerves in the area or part behind the eye.

[0080] Therefore, the conditions behind the eye may include diseases, illnesses or conditions such as, for example, acute macular neuroretinopathy; Behçet's disease; choroidal neovascularization; diabetic uveitis; histoplasmosis; infectious diseases, for example, infectious diseases caused by fungi or viruses; macular degeneration, for example, acute macular degeneration, non-exudative age-related macular degeneration and exudative age-related macular degeneration; edema, for example, macular edema, cystoid macular edema and diabetic macular edema; multiple choroiditis; ocular trauma affecting sites or locations behind the eye; eye tumors; retinal disorders, for example, central retinal vein occlusion, diabetic retinopathy (including proliferative diabetic retinopathy), proliferative vitreoretinopathy (PVR), retinal arterial occlusive diseases, retinal detachment, uveitis retinal diseases; sympathetic ophthalmia; Vogt-Koyanagi-Harada (VKH) syndrome; uveal diffusion; conditions behind the eye caused by or affected by laser treatment of the eye; conditions behind the eye caused by or affected by photodynamic therapy, photocoagulation, radiation retinopathy, epiretinal membrane disorders, retinal vein branch occlusion, anterior ischemic optic neuropathy, non-retinopathy diabetic retinal dysfunction, retinitis pigmentosa, and glaucoma. Glaucoma can be considered a condition behind the eye because the treatment goal 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).

[0081] As used herein, the term "biodegradable" refers to a material that degrades into soluble species or, under physiological conditions, degrades into small units or chemical species that are themselves non-toxic (biocompatible) to the subject and can be metabolized, eliminated, or excreted by the subject. The terms biodegradable, bioabsorbable, and biodegradeable as used herein are equivalent and are used interchangeably herein.

[0082] As used herein, the term "non-biodegradable" refers to a material that does not break down into soluble species or, under physiological conditions, does not break down into small units or chemical species that are themselves non-toxic (biocompatible) to the subject and can be metabolized, eliminated, or excreted by the subject. The terms non-biodegradable, non-biodegradable, and non-bioabsorbable as used herein are equivalent and are used interchangeably herein.

[0083] As used herein, the term "biodegradable polymer" refers to one or more polymers that degrade in vivo, where the disintegration and / or breakdown of one or more polymers over time occurs simultaneously with or subsequent to the release of the therapeutic agent. Specifically, hydrogels such as methylcellulose that act to release a drug by swelling of the polymer are specifically excluded from the term "biodegradable polymer". A biodegradable polymer can be a homopolymer, a copolymer, or a polymer containing more than two different polymer units.

[0084] As used herein, the terms "treat", "treating", or "treatment" refer to reducing, dissipating, or preventing an ocular condition, ocular injury or damage, or promoting the healing of injured or damaged ocular tissue.

[0085] As used herein, the term "therapeutically effective amount" refers to the level or amount of an agent necessary to treat an ocular condition or reduce or prevent an ocular injury or damage without causing significant negative or adverse side effects to the eye or area of the eye.

[0086] As used herein, "susceptible to", "tendency to", or "predisposed to" a particular disease or condition, etc., refers to an individual who has a higher likelihood of developing a 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.

[0087] As used herein, the term "lactide" refers to lactide monomers and lactic acid monomers.

[0088] As used herein, the term "glycolide" refers to glycolide monomers and glycolic acid monomers.

[0089] The present invention provides, for example, new drug delivery formulations or preparations for the sustained or controlled release of drugs to the eye to achieve a desired therapeutic effect, and methods of using such formulations and preparations. The drug delivery formulation or preparation is in the form of an implant or implant element that can be placed in the eye.

[0090] An intraocular implant according to the disclosure herein contains an antioxidant drug. The antioxidant drug may be present in or on the same implant or a different implant. The antioxidant drug can reduce oxidative stress in the eye to an acceptable extent.

[0091] Such an intraocular implant may include a therapeutic component and a drug release sustainability component associated with the therapeutic component. According to the present invention, the therapeutic component comprises, consists essentially of, or consists of an antioxidant drug. The drug release sustainability component is associated with the therapeutic component for the sustained release of a therapeutically effective amount of a steroid to the eye in which the implant is placed. A therapeutically effective amount of the antioxidant is preferably released to the eye for about 1 or about 2 months or longer after the implant is placed in the eye.

[0092] 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 that releases the drug by dissolving, disintegrating or degrading at a rate effective for sustained release of a therapeutically effective amount of the antioxidant drug from the implant for a period of about one or two months or greater or longer from the time the implant is placed in the eye site or region of the eye. The intraocular implant is biodegradable or bioresorbable and provides sustained release of the antioxidant drug in the eye for a long period of time, such as several days, several weeks, longer than two months, or about three months or more and up to about six months or more.

[0093] The biodegradable polymer component of the implant may be a mixture of biodegradable polymers, where at least one of the biodegradable polymers is a polylactide or poly(lactide-co-glycolide) polymer having a molecular weight of less than 40 kilodaltons (kD). Additionally or alternatively, the implant may comprise a first biodegradable polymer having terminal free acid groups and a different second biodegradable polymer having terminal free acid groups. Additionally or alternatively, the implant may comprise a first biodegradable polymer having terminal esters and a different second biodegradable polymer having terminal ester groups. Furthermore, the aforementioned implant may comprise a mixture of different biodegradable polymers, each biodegradable polymer having an intrinsic viscosity in the range of about 0.16 deciliters / 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.

[0094] In another embodiment, the intraocular implant comprises a therapeutic component that includes an antioxidant drug, and a polymeric outer layer that coats the therapeutic component. The polymeric outer layer may include one or more holes or apertures or pores that are effective to pass liquid into the implant and to pass steroid out of the implant. The therapeutic component is provided in the core or inner portion of the implant, and the polymeric outer layer coats or encapsulates the core. The polymeric outer layer may include one or more biodegradable portions. The implant can provide a sustained release of steroid for a period of more than about two months or longer, for a period of more than about one year, and further for a period of more than about five years or more than about ten years.

[0095] In one embodiment, the polymeric outer layer of the implant may include two or more layers or coatings of biodegradable material, and each such layer has a different composition or rate of degradation than the layer immediately adjacent thereto. For example, the polymeric outer layer of the implant may include a concentric ring or nested coating that includes a first layer, where the first layer may be, for example, a biodegradable polymer without antioxidant drug, a biodegradable polymer that includes a therapeutically effective amount of antioxidant drug, a biodegradable polymer that includes an amount of adjuvant effective to reduce at least one side effect of the antioxidant drug, and a biodegradable polymer that includes an amount of adjuvant effective to reduce at least one side effect of a therapeutically effective amount of antioxidant drug and steroid, and a biodegradable polymer without any added drug.

[0096] The second layer may also be, for example, a biodegradable polymer without antioxidant drug, a biodegradable polymer that includes a therapeutically effective amount of antioxidant drug, a biodegradable polymer that includes an amount of adjuvant effective to reduce at least one side effect of the antioxidant drug, and a biodegradable polymer that includes an amount of adjuvant effective to reduce at least one side effect of a therapeutically effective amount of steroid and steroid, and a biodegradable polymer without any added drug, and in addition, provided that the first and second layers are positioned adjacent to each other in the biodegradable implant, the first and second layers are not the same, and the first layer is designed to substantially disintegrate before the second layer.

[0097] Additional layers may be present, and preferably, each such layer is not the same as the layer immediately surrounding it.

[0098] It is well known that long-term ophthalmic treatment with drugs must be closely monitored due to potential toxicity and long-term side effects. For example, the adverse reactions listed for conventional ophthalmic dexamethasone preparations include glaucoma (accompanied by optic nerve damage, loss of visual acuity and visual field, and ocular hypertension), posterior subcapsular cataract formation, and secondary eye infections from pathogens including herpes simplex. Additional dangerous side effects during conventional topical treatment with steroids can include hypertension, hyperglycemia, increased susceptibility to infections, and peptic ulcers.

[0099] Age-related macular degeneration (''AMD'') includes a large group of hereditary visual disorders that cause progressive loss of retinal photoreceptor cells, leading to severe visual impairment and often incurable blindness. The most common form of AMD is retinitis pigmentosa, where the first symptom is night blindness, followed by progressive loss of peripheral vision in sunlight, ultimately leading to blindness decades later. As a general pathology, rod photoreceptors die early, while the morphologically changed cone photoreceptors that are insensitive to light persist longer.

[0100] Diabetic retinopathy (DR), sometimes also referred to as diabetic eye disease, where type 2 diabetes causes damage to the retina and is a major cause of blindness. Typically, DR affects up to 80 percent of patients with diabetes. Importantly, the longer a patient has diabetes, the higher the chance 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 patients aged 20 - 64.

[0101] Glaucoma describes several eye diseases resulting from damage to the optic nerve that leads to vision loss. Typical symptoms of glaucoma include, for example, eye pain, blurred vision, moderately dilated pupils, eye redness, and nausea. Increased intraocular pressure is a major risk factor for glaucoma, such as a family history of glaucoma and hypertension. However, the cause of glaucoma is still under investigation.

[0102] (2R,2R’)-3,3’-Disulfanediyldi(2-acetamidopropanamide) (diNACA), also referred to herein as NPI-002, has the chemical structure: [Chemical formula] (2R,2R’)-3,3’-Disulfanediyldi(2-acetamidopropanamide) (diNACA), which is a dimeric form of N-acetyl-L-cysteine amide, can be used in the treatment of ophthalmic diseases and conditions involving oxidative stress, including but not limited to age-related macular degeneration, cataracts, loss or protection of corneal endothelial cells, glaucoma, diabetic retinopathy, presbyopia, and retinitis pigmentosa.

[0103] Glutathione (GSH) is the tripeptide c-L-glutamyl-L-cysteinyl-glycine, which is found in all mammalian tissues. It has several important functions, including detoxification of electrophilic substances, scavenging of ROS to maintain the thiol state of proteins, and regeneration of the reduced forms of vitamins C and E. GSH is the predominant non-protein thiol in mammalian cells and is essential, for example, for maintaining the intracellular redox balance and the essential thiol state of proteins. It is also required for the function of some antioxidant enzymes such as glutathione peroxidase.

[0104] Intracellular GSH levels are determined by the balance between production and loss. Production results from de novo synthesis and the regeneration of GSH from GSSG by GSSG reductase. In general, the GSSG reductase system has sufficient capacity to maintain all intracellular GSH in a reduced state, and thus, it is hardly possible to increase it by enhancing this pathway. The main cause of intracellular GSH loss is its export from the cell. While intracellular GSH levels range from 1 to 8 mM, extracellular levels are only a few μM, and this large concentration gradient essentially prevents the transport of GSH into the cell. When it is exported from the cell, it is rapidly degraded by γ-glutamyl transpeptidase. Inhibition of GSH transporters could theoretically increase intracellular GSH levels, but these transporters are not specific for GSH, and their inhibition can potentially cause problems as it can lead to imbalances in other amino acids and peptides. Therefore, intracellular GSH levels are mainly modulated by changes in synthesis.

[0105] GSH is synthesized in the cytosol of almost all cells by an enzyme step requiring two ATPs: 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 is composed of a 73Kd heavy catalytic subunit (GCLC) and a 30Kd modifier subunit (GCLM) encoded by different genes. GCCL is regulated by non-allosteric competitive inhibition of GSH (Ki = 2.3 mM) and 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, so glutamate is 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, EC6.3.2.3), which is 118Kd and composed of two identical subunits. GS does not appear to be important for the regulation of GSH synthesis under normal conditions, while in response to surgical trauma, although GCL activity did not change, GSH levels and GS activity were reduced, so it may play a role under stressful conditions. Furthermore, an increase in the expression of both GCLC and GS resulted in higher levels of GSH compared to an increase in the expression of GCLC alone. To maximize the effect of increased synthetic enzymes, it is necessary to provide an increase in the level of cysteine. In cultured neurons, 90% of cysteine uptake occurs via the sodium-dependent excitatory amino acid transporter (EAAT) system. There are five EAATs, and cysteine uptake by neurons occurs mainly by EAAT3, more commonly known as excitatory amino acid carrier 1 (EAAC1). Under normal circumstances, most EAAC1 is in the ER and translocates to the cell membrane only when activated.This translocation is negatively regulated by glutamate transporter associated protein 3-18 (GTRAP3-18), and suppression of GTRAP3-18 increased GSH levels in neurons. Thus, cysteine uptake provides an impairment to the GSH synthetic pathway, but fortunately can be bypassed by N-acetylcysteine (NAC), which readily enters cells even in the absence of activated EAAC1. Systemically administered NAC gains access to the CNS, increases GSH levels, and provides benefit in neurodegenerative disorders where oxidative stress is an important part of pathogenesis.

[0106] All cellular compartments, including the cytoplasm, mitochondria, and nucleus, must be protected against oxidative damage. The inventors have previously performed gene transfer of enzymes that detoxify reactive oxygen species, but that approach requires the expression of two enzymes in the cytoplasm and two enzymes in the mitochondria. In contrast, the present invention can diffuse GSH anywhere throughout the cell, so expression of only two enzymes in the cytosol provides protection to all cellular compartments.

[0107] NAC is used for the treatment of acetaminophen overdose at a dose of 140 mg / kg as a loading dose, followed by 17 doses of 70 mg / kg every 4 hours starting 4 hours after the loading dose. In clinical studies, NAC has been orally administered at 400 - 1000 mg once a day and 200 - 600 mg three times a day. However, after an oral dose of 600 mg in humans, NAC is rapidly absorbed and then rapidly eliminated. The plasma half-life of NAC has been reported to be 2.5 hours, and NAC is undetectable 10 - 12 hours after administration. During absorption, NAC is rapidly metabolized to cysteine, which is the direct precursor of glutathione. Based on this evidence, NACA was expected to act in vivo similarly to NAC, including being a precursor and / or carrier of NAC. However, the inventors demonstrate that NACA and diNACA act very differently from NAC for the treatment of age-related macular degeneration, glaucoma, and / or diabetic retinopathy.

[0108] According to one embodiment, the present invention provides a method for preventing, alleviating, 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 the subject's tissue.

[0109] Intraocular implants have been developed that can release drug loads over various periods of time. These implants provide therapeutic levels of steroids and / or adjuvants to the eye, for example, when inserted into the vitreous or subconjunctival space of the eye for a long period of time (e.g., for about 2 months or more). The disclosed implants are effective for treating eye conditions such as posterior eye conditions.

[0110] In one embodiment of the present invention, the intraocular implant comprises a biodegradable polymer matrix. The biodegradable polymer matrix is one type of drug release sustainability component. The biodegradable polymer matrix is effective in forming 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", for example, by co-extrusion of the active agent and the biodegradable polymer, or "active" by being connected or coupled to the polymer by covalent chemical bonds, chelation, strong hydrogen bonds, ionic interactions, etc. The matrix degrades at a rate effective for sustained release of a therapeutically effective amount of steroid for a time longer than about two months from when the implant is placed in the eye region or eye site, such as the vitreous of the eye.

[0111] It will be recognized that the actually preferred amounts of the active compounds used in a given therapy will vary, for example, according to the particular compound utilized, the particular 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 dosing rate for a given protocol of administration can be readily ascertained by one of ordinary skill in the art using conventional dosage determination tests conducted with respect to the foregoing guidelines.

[0112] It is understood that the ranges provided herein are shortened for all values within the range.

[0113] As used herein, embodiments of the invention are defined to include pharmaceutically acceptable derivatives thereof. "Pharmaceutically acceptable derivatives" refers to any pharmaceutical salts, esters, salts of esters or other derivatives of the compounds of the invention that can (directly or indirectly) provide the compounds of the invention upon administration to a recipient. Particularly preferred derivatives are those that increase the bioavailability of the compounds of the invention when such compounds are administered to a mammal (e.g., by facilitating absorption of an orally administered compound into the blood, increasing the serum stability of the compound, or decreasing the clearance rate of the compound), or that enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) compared to the parent species. Derivatives include those in which a group that enhances water solubility or active transport across the intestinal membrane is attached to the structure of the formula described herein.

[0114] Embodiments of the present invention may be modified by adding appropriate functionality to enhance selected biological properties. Such modifications are known in the art and include those that increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to enable administration by injection, alter metabolism, and alter the rate of excretion. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from pharmaceutically acceptable inorganic and organic acids and inorganic and organic bases. Examples of suitable acid salts include acetate, adipate, benzoate, benzenesulfonate, butyrate, citrate, digluconate, dodecyl sulfate, formate, fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, malonate, metasulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, tosylate, and undecanoate. Salts derived from suitable bases include alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium, and N-(alkyl)4+ salts. The present invention also contemplates quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water-soluble or oil-soluble, or dispersible products may be obtained by such quaternization.

[0115] Embodiments of the present invention can be administered, for example, by injection, intravitreally, intravitreally, posterior to the globe, posterior to the sclera near, anterior to the sclera near, subretinally, intravenously, intraarterially, subdermally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, by catheter directly to the affected organ, topically, or in an ophthalmic preparation, and the dosage can range from 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 in a range according to the requirements of a particular drug, more preferably in the range of 0.5 to 10 mg / kg body weight. When the compound is delivered directly to the eye, it is understood that considerations such as body weight have little effect on the dosage.

[0116] The frequency of dosing depends on the agent being administered, the progression of the disease or condition in the subject, and other considerations known to those of skill in the art. For example, the pharmacokinetics and pharmacodynamics considerations for a composition delivered to the eye or even an intraocular compartment are different, for example, the clearance in the subretinal space is very low. Thus, dosing can be once a month, once every three months, once every six months, once a year, once every five years or less frequently. If systemic administration of an antioxidant is to be carried out in conjunction with administration of an expression construct to the subretinal space, the dosing frequency of the antioxidant is expected to be more frequent than that of the expression construct, for example, once or more than once a day, once or more than once a week.

[0117] Dosing may be determined in conjunction with monitoring of one or more signs or symptoms of the disease, 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 particular mode of administration. Typical preparations contain from about 1% to about 95% active compound (w / w). Alternatively, such preparations contain from about 20% to about 80% active compound. Lower or higher dosages than those cited above may be required. The specific dosing regimen and treatment regimen for any particular patient will depend on a variety of factors including the activity of the particular compound being used, age, weight, general health, sex, diet, frequency of administration, rate of excretion, drug combination, disease, condition or severity and course of symptoms, susceptibility of the patient to the disease, condition or symptoms, and the judgment of the treating physician.

[0118] The pharmaceutical composition may be in the form of a sterile injectable preparation, for example, an aqueous or oily suspension for injection. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as TWEEN® 80, etc.) and suspending agents. The sterile injectable preparation may 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. Among the acceptable media and solvents, mannitol, water, Ringer's solution, and isotonic sodium chloride solution can be used. In addition, sterile fixed oils have been conventionally used as solvents or suspending media. For this purpose, any blend of fixed oils containing synthetic mono - or diglycerides may be used. Fatty acids such as oleic acid and its glyceride derivatives are useful in injectable preparations, like natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylenated versions. These oily solutions or suspensions may also contain long - chain alcohol diluents or dispersants, or carboxymethyl cellulose, or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and / or suspensions. Other commonly used surfactants such as TWEEN® or SPAN® and / or other similar emulsifying or bioavailability - enhancing agents commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purpose of the formulation.

[0119] 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 two or three times a day. In another aspect, diNACA is administered together with a second active agent selected from ascorbic acid, cysteine hydrochloride, sodium bisulfite, 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 chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0120] In some embodiments, the dose of diNACA for administration is 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per implanted dose. In another aspect, the dose for administration is 0.1 to 0.25, 0.1 to 0.4, 0.35 to 0.5, 0.5 to 1, 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 2.5, 2.5 to 3.5, 4 to 6, 5 to 8, 6 to 9, 7 to 10 grams per implanted dose. In another aspect, the diNACA implant is administered prophylactically to prevent eye diseases.

[0121] In another embodiment, the present invention is a method for the treatment of age-related macular degeneration, glaucoma, and / or diabetic retinopathy, comprising identifying a human in need of treatment for age-related macular degeneration; and administering to the human a therapeutically effective amount of diNACA sufficient to treat age-related macular degeneration, glaucoma, and / or diabetic retinopathy. As in other embodiments defined above, it will be understood that diNACA is administered at a daily dose of about 0.5 to 150 mg / Kg. In another aspect, diNACA is administered two or three times a day. In another aspect, NACA is administered together with a second active agent as disclosed above.

[0122] In another aspect, the additional dosages of diNACA for administration are 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,000, 2,500, 3,000, 4,000, 5,000, 6,000, 7,000, 7,500, 8,000, 9,000, or 10,000 mg per dosage. In another aspect, the dosages for administration are 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 dosage. In another aspect, NACA is orally delivered via mini - tablets, capsules, tablets, effervescent agents, two - stage release, mixed release, sachets, powders, or liquids. In another aspect, diNACA is prophylactically administered to prevent age - related macular degeneration, glaucoma, and / or diabetic retinopathy.

[0123] The diNACA formulations described herein may also be delivered to the eye via ocular topical, intravitreal injection, posterior sub - Tenon's injection, anterior sub - Tenon's injection, and periocular injection routes. In one embodiment of the invention, the amount of the active agent, or poorly water - soluble agent, or biologic agent is about 0.001% - 30% active agent by weight per volume in the solution for intravitreal administration. In other embodiments, the amount of the active can be 0.05% - 20% by weight per volume, and in some cases, 0.1% - 18% by weight per volume. It is contemplated that any active agent that is poorly water - soluble or slightly soluble can be included in the compositions of the invention. In other examples, highly water - soluble active or inactive agents may also be included in the compositions of the invention.

[0124] For example, the present invention that can be delivered is a thick or viscous medium that enables the sustained release of an active agent. For example, diNACA can be provided in any poly(ethylene glycol) (PEG) having a molecular weight greater than 500, 1000, 15000, or 2000 in the compositions and methods of the present invention. PEGs for use in the compositions and methods of the present invention may also include PEG3000, PEG4000, PEG6000, PEG8000, PEG20000, or higher molecular weight PEGs may be used in the compositions and methods of the present invention.

[0125] The diNACA formulation of the present invention offers several advantages over conventional formulations because PEG has been successful in solubilizing poorly soluble compounds and enables the preparation of effective ophthalmically acceptable intravitreal, posterior juxtascleral (PJ), anterior juxtascleral (AJ), and / or periocular formulations for topical ocular delivery. The bioavailability of the drug can be modulated by controlling the molecular weight of the PEG or the mixture of molecular weights used in the formulation. Additionally, the preparation can be injected using a 27- or 30-gauge needle. The toxicity of the active agent can also be reduced or favorably modulated by extending its release. Another advantage of the present invention is that the stability of biopharmaceuticals is improved in the solid dosage forms based on PEG described herein.

[0126] The formulations of the present invention may further contain lipids in order to modulate drug delivery 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 the lipid is glyceryl palmitostearate. The concentration of the lipid is generally less than 31 weight percent (wt%), but in many cases less than 14 wt%, and in some cases less than 8 wt%.

[0127] The specific dosage level of the active agent for any particular human or animal depends on a variety of factors including the activity of the active compound being used, age, body weight, general health, frequency of administration, route of administration, and the severity of the pathological condition being treated.

[0128] The present invention generally relates to devices and methods for treating a patient's eye, and more particularly to an intraocular implant that provides sustained release of a therapeutic agent to the eye in which the implant is placed. After elution and depletion of the active agent from the implant, the therapeutic effect can no longer be obtained.

[0129] To correct this, the use of a sustained release drug delivery system may be employed. In 2000, Jaffe et al. reported using compressed fluocinolone acetonide pellets coated with silicone and poly(vinyl alcohol) as a fluocinolone sustained release device (Jaffe, G. J. et al., Journal of Ophthalmology and Vision Surgery, Vol 41, No. 11, October 2000). (Jaffe, G. J. et al., Journal of Ophthalmology and Vision Surgery, Vol 41, No. 11, October 2000) obtained release rates of 1.9 ± 0.25 4 / day (6 months) and 2.2 ± 0.6 μg / day (45 days) for the 2 mg device and 15 mg device, respectively. The duration of release for the 2 mg and 15 mg devices was estimated to be 2.7 and 18.6 years, respectively. U.S. Patent Nos. 6,217,895 and 6,548,078 disclose sustained release implants for delivering corticosteroids such as fluocinolone acetonide to the eye. However, the fluocinolone acetonide intravitreal implant made by the control delivery system (the assignee of U.S. Patent Nos. 6,217,895 and 6,548,078) was only partially successful and led to the development of cataracts and an increase in intraocular pressure.

[0130] Additional biocompatible implants for placement in the eye are disclosed in many patents, such as U.S. Patent 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.

[0131] Other intravitreal treatment approaches are described in U.S. Application No. 10 / 966,764, filed October 14, 2004; U.S. Application No. 11 / 039,192, filed January 19, 2005; and U.S. Application No. 60 / 587,092, filed July 12, 2004.

[0132] It would be advantageous to provide an implantable drug delivery system for the eye, such as an intraocular implant, and a method of using such a system that can release a therapeutic agent at a sustained or controlled rate over a long period of time and in amounts with low or no negative side effects.

[0133] The biodegradable polymer may contain a number of hydroxyl groups to which the agent may be connected by biodegradable linkages. A biodegradable or bio-cleavable linkage is defined as a particular chemical moiety or type of group that can be used within a chemical to covalently and reversibly couple or crosslink a therapeutic agent and / or co-agent to a biodegradable polymer contained within an implant. Thus, such linkages may be incorporated into certain embodiments of the present invention that provide for the controlled release of steroids and / or co-agents. In certain embodiments of the present invention, an implant system comprising one or more implants is structured such that the therapeutic agent and co-agent are released at different rates or at different times after implantation of the implant. Bio-cleavable linkages or bonds can be distinguished by their structure and function, and non-limiting examples are provided herein in separate categories or types.

[0134] One such category includes disulfide linkages, which are well known for covalent coupling. Such linkages are stable under oxidative conditions but can be cleaved under reductive conditions. For drug delivery, they may be more useful for shorter periods in vivo because they are cleaved relatively easily. Simple ester linkages are another preferred type that can be readily formed between an acid and an alcohol. Another preferred type is any imido ester formed from an alkyl imidate. Also included are maleimide linkages by sulfhydryl or amine used to incorporate biodegradable linkages.

[0135] Another category in the present invention includes acid-cleavable biodegradable linkages. Biodegradable linkages for such release of active agents and other moieties are preferred. One such type is the acid-sensitive (or acid-labile) hydrazone linkage described in (Greenfield, et al., Cancer Res. 50, 6600-6607 (1990)) and its references.

[0136] Other types of acid-labile linkages include polyortho or diortho ester linkages, examples of such linkages are disclosed in (Heller, et al., Methods In Enzymology 112, 422-436 (1985), Heller et al. Adv. Polymer Sci. 107, 41 (1993)) and (Ahmad, et al., J. Amer. Chem. Soc. 101, 2669 (1979)), as well as their references. Also, the acid-labile phosphonamide linkages disclosed in (Rahil, et al, J. AM. CHEM. SOC. 103, 1723 (1981)) and (Jeong, et al, Bioconj. Chem. 14, 473 (2003)) may also be useful.

[0137] The implant can be placed in the eye region to treat various eye conditions, including those affecting the anterior or posterior regions of the eye. For example, the implant can be used to treat many eye conditions, including but not limited to macular degeneration and retinal dystrophies, uveitis, retinitis, choroiditis, vascular diseases, and exudative diseases, proliferative disorders, infectious disorders, genetic disorders, tumors, trauma, and surgery, retinal breaks or holes. In particular, the treatment of retinal conditions is particularly advantageous by means of insertion, injection or other intravitreal delivery, or subconjunctival delivery of such implants.

[0138] The kit according to the invention can comprise the present implant and one or more instructions for using the implant. For example, the instructions can describe how to administer the implant to a patient and the types of conditions that can be treated with the implant.

[0139] The kit can also include an injector device used to deliver the implant to the eye. The kit, implant, and injector are sterile.

[0140] Any and all features described herein, and any and all combinations of two or more of such features, are included within the scope of the invention, provided that the features included in such combinations are not mutually inconsistent. Additionally, any feature or combination of features may be specifically excluded from any embodiment of the invention.

[0141] Additional aspects and advantages of the invention are set forth in the following description and claims, particularly when considered in conjunction with the accompanying drawings and examples.

[0142] The antioxidant in the implant is preferably about 10 to 90% by weight of the implant. More preferably, the antioxidant is about 50 to about 80% by weight of the implant, or 10% to 49% of the implant, or 20% to 60% of the implant. In a preferred embodiment, the antioxidant constitutes about 30% by weight of the implant. In a preferred embodiment, the antioxidant constitutes about 35% by weight of the implant. In a preferred embodiment, the antioxidant constitutes about 40% by weight of the implant. In a preferred embodiment, the antioxidant constitutes about 45% by weight of the implant. In a preferred embodiment, the antioxidant constitutes about 50% by weight of the implant. In another embodiment, the antioxidant constitutes about 70% by weight of the implant.

[0143] Suitable polymeric materials or compositions for use in the implant include materials that are compatible with the eye, i.e., biocompatible with the eye, such that they do not cause substantial interference with the function of the eye or physiology. Such materials are preferably at least partially, more preferably substantially completely, biodegradable, bioabsorbable or biodegradeable.

[0144] Examples of useful polymeric materials include, but are not limited to, such materials derived from and / or containing organic esters and organic ethers which, upon degradation, yield 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. Also, polymeric materials derived from and / or containing anhydrides, amides, orthoesters, etc., either by themselves or in combination with other monomers, may be used. The polymeric material may be a ring-opening polymer or an addition polymer or a condensation polymer, preferably a condensation polymer. The polymeric material may or may not be cross-linked, for example, it may be lightly cross-linked at most, for example, less than about 5% or less than about 1% of the polymeric material being cross-linked. In most cases, in addition to carbon and hydrogen, the polymer contains at least one of oxygen and nitrogen, preferably oxygen. Oxygen may be present as oxy, for example, hydroxy or ether, carbonyl, for example, non-oxocarbonyl such as carboxylic acid ester, etc. Nitrogen may be present as amide, cyano and amino. Polymers described in Heller, Biodegradable Polymers in Controlled Drug Delivery, In: CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 1, CRC Press, Boca Raton, Fla. 1987, pp 39-90, which describe encapsulation for controlled drug delivery, may be used in the present implant.

[0145] Additional desired materials are polymers of hydroxy aliphatic carboxylic acids, either homopolymers or copolymers, and polysaccharides. Desired polyesters 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. As used herein, the term lactide relates to lactide and lactic acid. As used herein, the term glycolide relates to glycolide and glycolic acid. Generally, by using L-lactate or D-lactate, polymers or polymeric materials that degrade slowly and / or are bioabsorbed are achieved, while biodegradation and / or bioabsorption are substantially enhanced by the racemate of the lactate.

[0146] Among these, useful polysaccharides include, but are not limited to, calcium alginate and functionalized cellulose, in particular, carboxymethyl cellulose esters characterized by being water-insoluble and having, for example, a molecular weight of about 5 kD to 500 kD.

[0147] Other desired polymers include, but are not limited to, poly(vinyl alcohol), polyesters, polyethers, and combinations thereof, which can be biocompatible, biodegradable and / or bioabsorbable and / or bioerodible.

[0148] Some preferred characteristics of the polymers or polymeric materials for use in the present invention can include biocompatibility, compatibility with therapeutic components, ease of use of the polymer in making the drug delivery formulations or preparations of the present invention, a half-life in a physiological environment of at least about 5 hours, preferably longer than about 1 day, not significantly increasing the viscosity of the vitreous humor, and water-insolubility.

[0149] The biodegradable polymer materials included to form the matrix are desirably made enzyme or hydrolysis labile. Water-soluble polymers can be cross-linked with hydrolytically or biodegradably labile cross-links to provide useful water-insoluble polymers. The degree of stability can vary widely depending on the monomer selection, whether homopolymers or copolymers are used, the polymer mixtures used, and whether the polymers contain terminal acid groups.

[0150] Equally important to the control of polymer biodegradation, and thus to the implant's sustained release profile, is the relative average molecular weight of the polymer composition used in the implant. The same or different polymer compositions of different molecular weights can be included in the implant to modulate the drug release profile. In certain implants, the relative average molecular weight of the polymer ranges from about 10 to about 70 kD, generally from about 10 to about 55 kD, more generally from about 10 to about 45 kD, and most generally less than about 40 kD.

[0151] In some implants, copolymers made from glycolide monomers and lactide monomers are used, where the rate of biodegradation is controlled by the ratio of glycolide monomers to lactide monomers incorporated into the polymer chain. The most rapidly degraded copolymers have an incorporation of approximately equal amounts of glycolide and lactide. Homopolymers, or copolymers with unequal ratios, take longer to resorb. The ratio of glycolide to lactide incorporated also affects the fragility of the implant, where a more flexible implant is desirable for larger shapes. The percentage of lactide monomers incorporated into poly(lactide-co-glycolide) (PLG) copolymers can be from 0 to 100%, preferably from about 15 to 85%, more preferably from about 35 to 65%. In some implants, 50 / 50 PLG copolymers are used.

[0152] The biodegradable polymer matrix of the intraocular implant may comprise a mixture of two or more biodegradable polymers. For example, the implant may comprise a mixture of a first biodegradable polymer and a different second biodegradable polymer. One or more of the biodegradable polymers may have terminal acid groups. One or more of the biodegradable polymers may have ester end groups. In certain implants, the matrix comprises a first biodegradable polymer having terminal acid groups and a different second biodegradable polymer having terminal acid groups. The first biodegradable polymer may be poly(DL-lactide-co-glycolide). The second biodegradable polymer may be poly(DL-lactide).

[0153] Release of the drug from the bioabsorbable polymer is the result of several mechanisms or combinations of mechanisms. Some of these mechanisms include desorption from the implant surface, dissolution, diffusion through the porous channels of the hydrated polymer, and erosion. Erosion can be bulk or surface, or a combination of both. As discussed herein, the matrix of the intraocular implant can release the drug at a rate effective for sustained release of a therapeutically effective amount of steroid for longer than 3 months after implantation in the eye. In certain implants, a therapeutic amount of the drug is released for longer than 4 months after implantation. For example, the implant may contain an antioxidant, and the matrix of the implant degrades at a rate effective for sustained release of a therapeutically effective amount of the antioxidant for about 3 months after placement in the eye. As another example, the implant may contain an antioxidant, and the matrix releases the drug at a rate effective for sustained release of a therapeutically effective amount of the antioxidant for longer than 3 months, for example, from about 3 months to about 6 months.

[0154] The rate of drug release 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 include a substantially homogeneous matrix mixed with an active agent. When drying and formulating the matrix into an intraocular implant, the active agent may be distributed substantially homogeneously in the matrix. In such an embodiment, the drug release characteristics are largely determined by the nature of the solvent and the rate of matrix degradation.

[0155] In another embodiment, the implant may include a layer or shell of biodegradable polymer formulated differently, in which a therapeutic agent and / or adjuvant can be associated and released. The concentrations of the polymer, therapeutic agent and / or adjuvant may vary between layers, or the biodegradable polymer may be formulated to deliver such agents at different rates, according to different release profiles, or over different periods than other layers or the core portion of the implant. Each layer may be formulated differently from at least one other layer due to, but not limited to, differences in drug concentration within different layers, the absence or presence of therapeutic agents and / or adjuvants within different layers, differences in the means by which the drug associates with the polymer matrix in different layers, or the chemistry and density of the biodegradable material.

[0156] Therefore, the drug release from the present implant may be related to the amount of drug present in the implant, the properties of the polymer of the implant, such as the molecular weight of the polymer and the ratio of glycolide and lactide incorporated into the polymer. In one embodiment of the present implant, one or more drugs, such as antioxidants and / or adjuvants, are released at a first rate during a first period that is substantially independent of the properties of the polymer, and one or more drugs are released at a second rate during a second period after the first period that depends on the properties of the polymer of the implant. For example, the implant includes a steroid and a polymer component, which releases an antioxidant from the implant for a period of about 30 days mainly due to steroid dissolution, and releases the steroid from the implant 30 days later mainly due to the properties of the polymer.

[0157] One example of a biodegradable intraocular implant includes an antioxidant (and / or adjuvant) associated with a biodegradable polymer matrix, which includes 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 is effective for the sustained release of a therapeutically effective amount of at least one agent for a period longer 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 may be poly(D,L-lactide), and the polylactide may include a polymer having a terminal free acid group. In one particular embodiment, the matrix of the implant includes a mixture of poly(lactide-co-glycolide) and polylactide. Each of the poly(lactide-co-glycolide) and polylactide may have a terminal free acid group.

[0158] Another example of a biodegradable intraocular implant includes an antioxidant (and / or adjuvant) associated with a biodegradable polymer matrix, which includes a mixture of different biodegradable polymers, and each biodegradable polymer has 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 include two different biodegradable polymers, and each biodegradable polymer has an intrinsic viscosity of about 0.25 dL / g.

[0159] Other implants may include a biodegradable polymer matrix of a biodegradable polymer, and at least one of the polymers has an intrinsic viscosity of about 0.25 dL / g to about 0.35 dL / g. Additional implants may include a mixture of biodegradable polymers, where each polymer has an intrinsic viscosity of about 0.50 dL / g to about 0.70 dL / g.

[0160] Release of antioxidants (and / or adjuvants) from an intraocular implant comprising a biodegradable polymer matrix may include an initial burst release of the agent and a subsequent gradual increase in the amount of agent released, or the release may include an initial delay in the release of the steroid and a subsequent increase in release. When the implant degrades substantially completely, the percentage of agent released is about 100. Compared to existing implants, in one embodiment, the implants disclosed herein release at least one agent (antioxidant and / or adjuvant) of about 100% until about 2 months after being placed in the eye or until not completely released. Thus, the implants of the present invention exhibit a cumulative release profile that may have a gentler slope or a lower rate of release over a longer period than existing implants.

[0161] The implant can provide a therapeutically effective amount of antioxidant over a long period or a series of such periods without requiring so many doses. Thus, the implant may contain 1, 2, 3, 4, or 5 micrograms of antioxidant, which is gradually released over time without causing substantial ocular toxicity or other adverse side effects. The antioxidants may, in one embodiment, be alternating within different shells of the implant, such that it is delivered only over a specific period with a period in which substantially little (or no) antioxidant is delivered where delivery is interrupted. In this way, continuous exposure of the eye to the antioxidant and side effects that may be associated with such constant delivery can be avoided or reduced. In another embodiment, the intravitreal implant comprises an antioxidant and a biodegradable polymer associated with the antioxidant in the form of an intravitreal implant that releases the antioxidant in an amount associated with reduced toxicity compared to the toxicity associated with administration of the antioxidant in a liquid composition.

[0162] In certain instances, it may be desirable to provide a relatively constant rate of antioxidant release from the implant over the life of the implant. For example, it may be desirable for the steroid to be released in an amount of from about 0.01 μg to about 2 μg per day over the life of the implant. However, the release rate may vary to increase or decrease depending on the formulation of the biodegradable polymer matrix. Additionally, the steroid release profile may include one or more linear portions and / or one or more non-linear portions. Preferably, the release rate is greater than zero when the implant begins to degrade or disintegrate.

[0163] It may be desirable to include delivery of an adjuvant in combination with intravitreal or subconjunctival delivery of the antioxidant to reduce or eliminate at least one side effect as compared to delivery of the steroid in the same manner except for the absence of the adjuvant. The adjuvant and the antioxidant may be included in the same implant or co-administered with different implants during the same treatment period.

[0164] The implant may be integrated, i.e., may have one or more active agents homogeneously distributed throughout the polymer matrix, or may be encapsulated, where the active agent is encapsulated by the polymer matrix. Due to ease of manufacture, integrated implants are typically preferably of the core / shell reservoir type encapsulation form. However, the higher control afforded by encapsulated or reservoir-type implants may be beneficial in some situations where the therapeutic level of the drug is within a narrower window. Additionally, the therapeutic components containing the antioxidant may be distributed in a heterogeneous pattern within the matrix. For example, the implant may include a portion having a higher concentration of antioxidant and / or adjuvant as compared to a second portion of the implant.

[0165] In another embodiment of the present invention, the intraocular implant includes a therapeutic component containing an antioxidant and a drug release persistence component including one or more coatings covering the core region of the implant. The therapeutic component and / or adjuvant is provided in the core region. The polymer outer layer may be relatively impermeable to the therapeutic component and the eye fluid. Alternatively, the polymer outer layer may initially be impermeable to the therapeutic component and the eye fluid, but then become permeable to the therapeutic component or the eye fluid as the outer layer degrades. Thus, the polymer outer layer may include a polymer such as polytetrafluoroethylene, ethylene tetrafluoroethylene propylene, polylactide, polyglycolide, silicone, or a mixture thereof.

[0166] It can be understood that the aforementioned implant includes a reservoir of one or more therapeutic agents, such as antioxidants and / or adjuvants.

[0167] In some implants, the drug release persistence component includes a polymer outer layer covering the therapeutic component and / or adjuvant, and the outer layer includes a number of openings or pores through which the therapeutic component can pass from the drug delivery system to the external environment of the implant, such as the ocular region of the eye. The pores allow liquid to enter the interior of the implant and dissolve the drug contained therein. The release of the therapeutic agent and / or adjuvant from the implant can be affected by the solubility of the drug in the liquid, the size of the pores, and the number of pores. In certain implants, the size and number of the pores are effective in providing substantially all of the desired release characteristics of the implant. Thus, additional excipients may not be necessary to achieve the desired results. However, in other implants, excipients may be provided to further enhance the release characteristics of the implant.

[0168] A variety of biocompatible, substantially impermeable polymer compositions can be used to prepare the outer layer of the implant. Some of the relevant factors considered in selecting the polymer composition include the compatibility of the polymer with the biological environment of the implant, the compatibility of the drug with the polymer, ease of manufacture, half-life in the physiological environment for at least several days, does not significantly enhance the viscosity of the vitreous humor, lack of cytotoxicity, and the desired rate of release of the agent. The composition can be varied depending on the relative importance of these characteristics. Some such polymers and methods for their preparation are well known in the art. See, for example, U.S. Patent Nos. 4,304,765; 4,668,506; 4,959,217; 4,144,317, and 5,824,074, Encyclopedia of Polymer Science and Technology, Vol. 3, published by Interscience Publishers, Inc., New York, latest edition, and Handbook of Common Polymers by Scott, J. R. and Roff, W. J., published by CRC Press, Cleveland, Ohio, latest edition.

[0169] The desired polymer can be non-biodegradable, non-biodegradable, or non-bioabsorbable. The desired polymer can be a homopolymer, copolymer, linear, branched, or cross-linked derivative. Some exemplary polymers include polycarbamate or polyurea, cross-linked poly(vinyl acetate), ethylene-vinyl ester copolymers having an ester content of 4 to 80%, such as ethylene-vinyl acetate (EVA) copolymer, ethylene-vinyl hexanoate copolymer, ethylene-vinyl propionate copolymer, ethylene-vinyl butyrate copolymer, ethylene-vinyl pentanoate copolymer, ethylene-vinyl pivalate copolymer, ethylene-vinyl diethylacetate copolymer, ethylene-vinyl 3-methylbutyrate copolymer, ethylene-vinyl 3,3-dimethylbutyrate copolymer, and ethylene-vinyl benzoate copolymer, or mixtures thereof.

[0170] Additional examples include poly(methyl methacrylate), polybutyl acrylate, 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-isopropylidenediphenylene carbonate), polyurethane, polyperfluoroalkoxy, poly(vinylidene fluoride), vinylidene chloride-acrylonitrile copolymer, vinyl chloride-diethyl fumarate copolymer, silicone, medical grade silicone rubber (such as SILASTIC® Medical Grade ETR Elastomer Q7-4750 or Dow Corning® MDX 4-4210 Medical Grade Elastomer); and polymers such as cross-linked copolymers of polydimethylsilane silicone polymers.

[0171] Further examples of polymers include 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(halo-olefin), polyvinyl, for example, poly(vinyl acetate), crosslinked polyvinyl alcohol, crosslinked poly(vinyl butyrate), ethylene ethyl acrylate copolymer, poly(ethyl hexyl acrylate), poly(vinyl chloride), poly(vinyl acetal), plasticized ethylene vinyl acetate copolymer, polyvinyl alcohol, poly(vinyl acetate), ethylene vinyl chloride copolymer, polyvinyl ester, polyvinyl butyrate, polyvinyl formal, polyacrylate, polymethacrylate, poly(oxide), polyester, polyamide, and polycarbonate, or mixtures thereof.

[0172] In some embodiments, an implant having an outer coating (with or without pores) can be biodegradable, where the outer layer degrades after the drug has been released for the desired duration. The biodegradable polymer composition can include any of the biodegradable polymers or combinations thereof identified above. In some implants, the polymer is polytetrafluoroethylene (commercially known as TEFLON®), ethyl vinyl alcohol, or ethylene vinyl acetate, all of which are non-biodegradable, non-biodegradable, or non-bioabsorbable.

[0173] Antioxidant-containing implants that exhibit a desired release time typically have orifices that are configured to have a total area of less than 1% of the total surface area of the implant. Implants formed substantially in a cylindrical shape have a first end, a second end, and a body portion between the first and second ends. Typically, the implants disclosed herein are sealed at the first and second ends. One or more holes are formed in the body portion of the implant. The holes typically have a diameter of at least about 250 μm and less than about 500 μm. For example, the holes may have a diameter of about 250 μm, 325 μm, 375 μm, or 500 μm. Smaller holes may be provided in other implants. Typically, two or three holes are provided in the outer layer of the implant. The holes may be spaced apart by a distance of about 1 mm to about 2 mm for an implant having a length of about 7 mm to about 10 mm.

[0174] 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 an ocular region of an eye for more than 1 year, for example, for more than 5 years, and even for about 10 years.

[0175] The implant may include a coating formed around a core containing a therapeutic agent. The core may include a therapeutic agent (or therapeutic components and adjuvants) associated with a biodegradable polymer matrix, or the core may be formed by filling a pre-formed coating, such as a tube.

[0176] The antioxidant and / or adjuvant can be placed, respectively, as a dry powder, particles, granules, or as a compressed solid, within a preformed coating. One or more agents may also be present in solution. Additionally, the core can include a biodegradable polymer matrix and a mixture of one or more agents, such as a matrix containing the implant described above. The polymer used in the matrix with the therapeutic agent and / or adjuvant is biocompatible with the body's tissues and body fluids and can be biodegradable or substantially insoluble in body fluids. Any of the biocompatible polymer compositions described above can be used to prepare the matrix. The amount of polymer in the core can be from about 0% to 80 wt% by weight. These polymers are commercially available and methods for preparing the polymer matrix are well known in the art. See, for example, U.S. Patent No. 5,882,682.

[0177] A biocompatible, substantially impermeable outer layer can be obtained by coating the core with the polymer composition described above. The coating can be applied using an organic solvent, which is then removed from the coating by vacuum to leave a dry coating. A polymer at a concentration of about 10 to about 80 weight percent is dissolved or suspended in an organic solvent at an appropriate temperature, such as from 60 degrees Celsius to 90 degrees Celsius for a poly(lactic acid) or polylactide polymer. The resulting mixture can be cut, shaped, injection molded, extruded, or poured or sprayed onto a preformed core into any shape or size for implantation. Spraying can be completed in a rotary pan coater or a fluidized bed coater until the desired coating thickness is achieved.

[0178] Alternatively, the core may be dip-coated or melt-coated. This type of coating is particularly useful for waxes and oils. In another embodiment, the core may be compression-coated, where a suitable polymer composition may be compressed over a pre-formed core. In another aspect, an adhesive coating, such as shellac or poly(vinyl acetate phthalate) (PVAP), is applied to the core prior to applying the impermeable coating to improve adhesion of the impermeable coating to the core. These techniques are well known in the art. See, for example, Handbook of Common Polymers, by J. R. Scott and W. J. Roff, Section 64, (1971) published by CRC Press, Cleveland, Ohio.

[0179] When the outer layer is injection molded or extruded into 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 hole is drilled in the device. Optionally, the hole is drilled or pre-formed in the wall, or the hole is sealed with a cut-out tab such as breaking or cutting open at the time of use.

[0180] Alternatively, a device without a core may be loaded with a therapeutic agent, for example, by immersing the device in a solution containing the therapeutic agent for a time sufficient for absorption of the therapeutic agent. The device may comprise hollow fibers, and the therapeutic agent and / or adjuvant may be loaded directly into the fibers and the device may then be sealed. If the activity of the therapeutic agent and / or adjuvant is not impaired, the device filled with the therapeutic agent may then be dried or partially dried for storage until use. This method may find particular application where the activity of the selected therapeutic agent is sensitive to exposure to solvents, heat or other modes of conventional solvent evaporation, molding, extrusion, or other methods described above.

[0181] The holes may be made by using a mechanical process or a laser-based process to drill holes of appropriate size through the walls of the device. In some implants, a digital laser marking system is used to drill the holes. This system allows a series of openings to be drilled simultaneously on both sides of the dosage form at a rate suitable for the production of the dosage form. The process utilizes a digital laser marking system (e.g., DigiMark™ variable marking system, available from Directed Energy, Inc.) to produce an unlimited number of holes in the surface or coating of the dosage form at a rate that is actually suitable for the production of the dosage form.

[0182] The steps involved in this laser drilling process are as follows: focus the digital laser marking system on a later stage; move the dosage form onto the laser stage of the digital laser marking system and apply pulses to these laser tubes necessary to drill the desired openings along a linear array on the dosage form, move the dosage form forward on the laser stage, and, if necessary, pulse the digital laser marking system again to produce an additional linear array of openings; then remove the dosage form from the later stage.

[0183] Holes and equipment for forming holes are disclosed in U.S. Patent Nos. 3,845,770; 3,916,899; 4,063,064 and 4,008,864. Holes formed by leaching are disclosed in U.S. Patent Nos. 4,200,098 and 4,285,987. A laser drilling machine equipped with a light wavelength detection system for orienting the device is described in U.S. Patent Nos. 4,063,064 and 4,088,864.

[0184] The intraocular implant may have a size of 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 for administration by needle, or greater than 1 mm, or greater than 2 mm, for example, 3 mm or up to 10 mm for administration by surgical implantation. For a needle injection implant, the implant may have any suitable length as long as the diameter of the implant allows it to move through the needle. For example, an implant having a length of about 6 mm to about 7 mm has been injected into the eye. The implant administered by needle must have a diameter that is less than the inner diameter of the needle. In certain implants, the diameter is less than about 500 μm. The vitreous chamber in humans can accommodate relatively large implants of various shapes having, for example, a length of 1 to 10 mm. The implant may be a cylindrical pellet (e.g., rod) having a diameter dimension of about 0.2 mm to 0.75 mm. Or, 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.

[0185] The implant can also be at least somewhat flexible so as to facilitate both the insertion of the implant in the eye, for example, in the vitreous body, and the accommodation of the implant. The total weight of the implant is typically up to about 100, 150, 150, 250, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,000, 2,500, 3,000, 4,000, 5000 μg, more preferably about 500, 600, 700, 750, 800, 900, 1,000 μg. For example, the implant can be about 500 μg or about 1,000 μg. For non-human individuals, the dimensions and total weight of the implant can be larger or smaller depending on the type of individual. For example, a human has a vitreous volume of approximately 3.8 mL as compared to approximately 30 mL for a horse and approximately 60 - 100 mL for an elephant. Implants sized for use in humans can be scaled up or down according to other animals, for example, about 8 times larger for an implant for a horse or, for example, about 26 times larger for an implant for an elephant.

[0186] An implant can be prepared that can have a core of one material and a surface with one or more layers of the same or different compositions, where the layers can be cross-linked or can be of different molecular weights, different densities or porosities, etc. For example, if it is desired to rapidly release an initial bolus of a drug, the core can be a polylactide coated with a poly(lactide-co-glycolide) copolymer so as to enhance the rate of initial degradation. Alternatively, the core can be a poly(vinyl alcohol) coated with a polylactide, such that upon degradation of the outer polylactide, the core dissolves and is rapidly washed out of the eye.

[0187] Implants, particularly those having antioxidants and / or adjuvants associated with a biodegradable polymer matrix, can be of any form, including fibers, sheets, films, microspheres and microparticles, spheres, circular disks, plaques, etc. The upper limit of the implant size is determined by factors such as the tolerance to the implant, size limits in insertion, ease of handling, etc. When a sheet or film is used, the sheet or film has a thickness of about 0.1 - 1.0 mm and is at least about 0.5 mm × 0.5 mm, usually in the range of about 3 - 10 mm × 5 - 10 mm for ease of handling. When fibers are used, the diameter of the fibers is generally in the range of about 0.05 - 3 mm, and the length of the fibers is generally in the range of about 0.5 - 10 mm. The spheres can range in diameter from about 0.5 μm to 4 mm, with an equivalent volume for other shaped particles.

[0188] In certain embodiments of the present invention, use in the case of microparticle implants can be particularly advantageous. Methods of making such microparticles include combining, associating, or mixing a therapeutic agent and / or an adjuvant with one or more biodegradable polymers. The mixture can then be extruded or compressed to form a single composition. The single composition can then be processed to form microparticles suitable for replacement in the vitreous or subconjunctival space.

[0189] Alternatively, methods of making the microparticles can also include forming the microparticles using a water-in-oil emulsion process. Such methods can be particularly useful for forming microparticles, nanoparticles, etc. Thus, embodiments of the present invention relate to inserts containing microparticles made using a water-in-oil emulsion process.

[0190] A population of microparticles or nanoparticles can be placed in ocular regions such as, but not limited to, the vitreous body, stroma, anterior chamber, sub-Tenon's capsule, retina, subretinal space, posterior segment of the eye, periorbital area, suprachoroid, subchoroid, conjunctiva, subconjunctiva, episclera, posterior juxtascleral area, anterior juxtascleral area, corneal periphery, locally, and / or the tear duct, etc., for treating various ocular conditions. For example, microparticles can be administered intravitreally in a manner effective to deliver a therapeutic component and / or adjuvant to the tissues of the posterior segment, thereby reducing damage to the tissues of the posterior segment while reducing at least one side effect compared to administration of a steroid alone in the same manner. Alternatively, subconjunctival administration of the microparticles of the present invention is highly effective for delivering a therapeutic component to the retina and other tissues of the posterior segment for the treatment of neurodegenerative conditions such as age-related macular degeneration (AMD), such as "wet type" or "dry type" AMD, macular edema, etc.

[0191] The use of microparticles (or microspheres), etc. provides an excellent means for interrupting the delivery of antioxidants in the implants of the present invention. For example, in one embodiment, different lots (including microparticles of the same or different sizes) are made, each having different properties, such as different rates of disintegration; different drug contents (e.g., some may contain antioxidants and adjuvants, while others may contain only adjuvants; some may be made of one biodegradable polymer having a fast dissolution rate, while others may be made of different biodegradable polymers having a slower dissolution rate). During the treatment period, by manipulating the microparticles such that the dosage of the antioxidant is "pulsed", for example, from an initial substantially optimal therapeutically effective dosage, to a subsequent period lacking the antioxidant at a substantially optimal therapeutically effective dosage, and optionally to another treatment period where the antioxidant at a substantially optimal therapeutically effective dosage is administered again, at least one of the toxic side effects of long-term antioxidant use can be reduced. Some microparticles can be loaded with an adjuvant alone or in combination with an antioxidant, such that the dosage of the adjuvant, although the dosage of the antioxidant may vary, provides a substantially constant (or at least slowly decreasing) dosage of the adjuvant to the ocular tissue during the treatment period.

[0192] Thus, combinations of different microparticles in intravitreal or subconjunctival injections or insertions administered separately provide a powerful way to separately tailor the administration of antioxidants and adjuvants. Methods for making the microparticles are provided in U.S. Application No. 11 / 303,462, and U.S. Application No. 10 / 837,260.

[0193] The size and shape of the implant can also be used to control the rate of release, the duration of treatment, and the drug concentration at the site of implantation. Larger implants deliver proportionally higher doses but may have a slower release rate depending on the surface-to-mass ratio. The specific size and shape of the implant are selected to conform to the site of implantation.

[0194] The ratios of antioxidant and / or adjuvant, polymer, and any other modifiers may be determined empirically by formulating several implants having various ratios. The rate of release can be measured using USP-approved methods for dissolution or release testing (USP23; NF18 (1995) pp. 1790 - 1798). For example, using the infinite sink method, a weighed sample of the implant is added to a measured volume of solution containing 0.9% NaCl in water, where the solution volume is such that the drug concentration is less than 5% of saturation after release. The mixture is maintained at 37° C. and gently stirred to keep the implant in suspension. The appearance of the dissolved drug as a function of time can be followed by various methods known in the art, such as spectrophotometric, HPLC, mass spectrometry, etc., until the absorbance is constant or more than 90% of the drug is released.

[0195] The intravitreal implants containing antioxidants disclosed herein may also contain one or more additional ophthalmologically acceptable therapeutic agents.

[0196] The implant is injected into the vitreous of each patient's eye through the pars plana using an applicator with a 22-gauge needle. The patient is monitored after administration of the implant. [Example 1]

[0197] Inhibition of cataract by diNACA in the rat lens method Lenses were excised from 3-week-old male or female Wistar rats using existing Animal Ethics Approval for tissue collection. The rats were euthanized using CO2, enucleated, and the lenses were dissected from the eyeballs and incubated for 6 hours in either Dulbecco's modified eagle's medium (low glucose; DMEM) with glutamine without phenol red and a 1% penicillin, streptomycin, neomycin mixture or Medium 199 under normoxic conditions with 5% CO2. At the end of the 6-hour incubation, the lenses were imaged under dark field and bright field microscopes, and only clear and transparent lenses were used for further experiments.

[0198] Control group: The lenses were incubated for an additional 18 hours, during which dark field and bright field images were acquired. The lenses were placed in fresh medium and then incubated for an additional 24 hours in DMEM or M199 with 1% PSN. Images were then acquired to evaluate lens transparency.

[0199] 10 mM diNACA pretreatment group: After the first 6-hour incubation, the clear lenses were cultured in 10 mM diNACA (NPI-002) for 18 hours. Images were acquired, 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 acquired to evaluate lens transparency.

[0200] 10 mM NACA pretreatment group: After the first 6-hour incubation, the clarified lenses were cultured in 10 mM NACA (NPI-001) for 18 hours. Images were acquired, 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 acquired to evaluate lens transparency.

[0201] Results. Addition of 1 μg / mL glucose oxidase (GO) after 24 hours resulted in cataract formation by 48 hours (some of the grid lines were barely visible from the bright-field image (Figure 1)). NPI-002 (diNACA) alone without oxidant maintained lens transparency slightly better than NPI-001 (NACA) alone. After 6 hours, clarified and transparent lenses were assigned to either no treatment or 24 hours of 10 mM DiNACA. NACA-treated lenses developed subtle thin peripheral opacities at the edges (Figure 1A - opacities marked by ). However, the lower grid was clearly visible, but surprisingly, the diNACA-treated lenses remained completely clear and transparent (Figure 1B). * (marked by ). [Example 2]

[0202] NACA or diNACA pretreatment of lenses in the GO cataract model reduced lens opacity Method: Isolated rat lenses were pretreated with NACA or diNACA, followed by GO.

[0203] Results: Pretreatment with 10 mM NACA (NPI-001) followed by GO cataract induction resulted in a reduction in opacity compared to cataract induction alone (n = 8; Figures 2A-2L, comparison panels F-I, and F’-I’). Opacity appeared reduced in the NACA group compared to the GO group (Figures 2A-2L, comparison panels 2F-2I), and the lower grid appeared clearer in the NACA group compared to the GO group (Figures 2A-2L, comparison panels 2F’-2I’). These observed differences suggest that pretreatment with 10 mM NACA may help reduce lens opacity induced by GO. Pretreatment with 10 mM diNACA followed by GO cataract induction also reduced lens opacity (n = 7; Figures 2A-2L, comparison panels 2F and 2L) and improved grid visibility (Figures 2A-2L, comparison panels F’ and L’) compared to GO cataract induction alone.

[0204] Conclusion: Since slight ring opacity occurred after exposure to NACA that did not occur with diNACA, rat lenses showed better tolerance to exposure to diNACA than to NACA. [Example 3]

[0205] diNACA inhibition of cataract in isolated porcine lenses. Method: The lenses were harvested from fresh eyes of pigs. These lenses were first incubated for 2 hours in 4 - 5 mL of TC - 199 medium and 1% porcine serum in a 12 - well plate. At the end of the incubation, the lenses were imaged under a dark - field microscope, and only the clear and transparent lenses were used for further experiments. The lenses were pre - incubated with NAC, NACA, and diNACA for 24 hours. After the pretreatment, the lenses were transferred to a medium containing hydrogen peroxide (H2O2) and GO to maintain a constant H2O2 level during incubation, in the same manner as the published method (Wang GM, Raghavachari N, Lou MF. Relationship of protein - glutathione mixed disulfide and thioltransferase in H2O2 - induced cataract in cultured pig lens. Exp Eye Res. 1997 May;64(5):693 - 700. doi: 10.1006 / exer.1996.0251. PMID: 9245898). At the end of the 6 - hour incubation, the lenses were imaged under a dark - field microscope (Figure 3).

[0206] Results and conclusions. NAC, NACA, and diNACA pretreatment prevented H2O2 - induced cataract in a dose - dependent manner, suggesting that these compounds may have the potential for anti - cataract effects. Surprisingly, diNACA had a better protective effect on the lenses compared to NAC and NACA. [Example 4]

[0207] Summary of the anti - cataract effect of diNACA in an ex vivo lens model. The anti - cataract effects of NPI - 002 in isolated rat lenses and isolated pig lenses are equivalent (Figure 4). NPI - 002 prevented oxidation - induced cataract caused by two different oxidizing reagents (GO in rats; H2O2 in pigs) in two different species in studies by two independent investigation groups. [Example 5]

[0208] Study on the 3-week safety and pharmacokinetics of a single-dose intravitreal (IVT) implant of NPI-002 in rabbits. A study was conducted to evaluate intravitreal injection of di-NACA and NACA solutions as suspensions or implants in rabbits. The objectives were to evaluate safety and whether the implants could deliver diNACA, NACA, and NAC to the eye tissues. A sterile intravitreal implant containing diNACA was prepared (formulation 1896-08, immediate-release implant; Figure 7). Female New Zealand white rabbits were administered 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 substance. Figure 8 shows the dimensions of the implant.

[0209] Before installation in the study, ophthalmic examinations including slit-lamp examination and indirect ophthalmoscopy were performed on each rabbit. The eye findings were scored according to the modified McDonald-Shadduck Scoring.

[0210] Clinical ophthalmic examinations were performed at baseline and on days 8 and 23 after dosing. Overall health observations were made daily. Body weights were recorded at baseline and before the end.

[0211] Subjects were assigned as shown in Table 1. Sterile NPI-002 or placebo IVT implants were pre-loaded into 22G angled needles and wire plungers (1 implant / needle) and injected into the VH. NPI-002 suspension and NPI-001 solution were prepared in sterile phosphate buffer and injected into the VH.

[0212] Animals were euthanized on day 8, 15, or 23, eye tissues were collected and submitted for bioanalysis of diNACA, NACA, and NAC. Delivery of IVT di-NACA was associated with minimal eye findings on the day of dosing. Observation of conjunctival bulge, eye grease, and minimal bleeding was determined to be related to the injection procedure and resolved in most eyes on the day following dosing. Mild to moderate conjunctival congestion, swelling, and eye grease observed on day 8 by clinical ophthalmic examination resolved by day 23, suggesting that these findings were associated with the use of a 22-gauge needle for the IVT injection procedure.

[0213] Delivery of di-NACA as a suspension or implant, placebo implant, and NACA as a solution via IVT injection was associated with minimal eye findings on the day of dosing. Observation of conjunctival bulge, eye grease, and minimal bleeding was determined to be related to the injection procedure and resolved in most eyes on the day following dosing.

Table 1

[0214] Mild to moderate conjunctival congestion, swelling, and eye grease observed on day 8 by clinical ophthalmic examination resolved by day 23, suggesting that these findings were associated with the use of a large 22G needle for the IVT injection procedure. In addition, choroid / retinal inflammation was also observed in three eyes that received di-NACA implants, due to the implant reaching the retina, and this was also procedure-related. Vitreous cells and flare detected on days 8 and 23 may have been test substance-related particles as they were mostly absent or only few in number in the vitreous humor on day 23 compared to day 8. A few of these reflective particles were attached behind the lens capsule.

[0215] No adverse effects on general test substance administration, eye health, or body weight were observed.

[0216] Intravitreal delivery of the NPI-002 implant resulted in significant levels of diNACA, NACA, and NAC in the vitreous humor after 1 week (Figure 5).

[0217] In summary, delivery of NACA solutions and suspensions or di-NACA or placebo implants as implants generally showed sufficient tolerance when administered via intravitreal (IVT) injection.

[0218] Intravitreal delivery of the NPI-002 implant resulted in significant levels of diNACA, NACA, and NAC in rabbit vitreous humor after 1 week, thereby demonstrating that diNACA is a prodrug for NACA and NAC, its main metabolites and pharmacologically active species. [Example 6]

[0219] Three-month toxicity study of a single dose of the NPI-002 intravitreal (IVT) implant in rabbits. A study was conducted to evaluate the safety of the diNACA (NPI-002) IVT implant. The study included four groups of six rabbits (NZ white): (1) an untreated control group; (2) a drug-treated group in which one immediate-release NPI-002 implant was injected into each eye; (3) a drug-treated group in which one immediate-release and one sustained-release NPI-002 implant were injected into each eye (Figure 6); (4) a placebo group in which one placebo implant was injected into the left eye and two placebo implants were injected into the right eye. Clinical ophthalmic 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 electroretinogram testing were performed at baseline and 3 months. Blood samples were collected. For groups 1-3, the left eyes were dissected, fixed, and processed for histological and immunohistochemical examinations to evaluate safety / toxicity. The right eyes were dissected and used for bioanalytical analysis. For group 4, the left and right eyes were dissected, fixed, and processed for histological and immunohistochemical examinations.

[0220] Overall, the implant injections proceeded with very few complications. The overall health and body weight of all 24 rabbits were satisfactory throughout the study period. The most commonly encountered welfare incident was related to small wounds encountered from transient attacks between rabbits. All rabbits reached the designed endpoints of the study at 3 months. Blood samples were taken for future analysis. Of the 48 eyes, 30 eyes were taken for postmortem histopathological diagnosis while 18 eyes were dissected for future pharmacokinetic analysis. No adverse effects of the NPI-002 implant were observed on overall health. Weight gain was normal. There was no evidence from clinical ophthalmic examinations that the NPI-002 implant caused adverse effects in either the anterior or posterior compartments of the eye, either acutely or chronically. There was no evidence from rebound intraocular pressure measurements that the NPI-002 implant caused changes in intraocular pressure. There was no evidence from electroretinogram examinations that the NPI-002 implant had an adverse effect on the electrical function of the retina. There was no evidence from fundus imaging or SD-OCT scans that the NPI-002 implant caused adverse effects on the morphology of the retina. Overall, no differences were observed between the untreated control, placebo injection, and NPI-002 injection cohorts from the perspective of the various parameters evaluated. No differences were observed among the animals that received either one or two NPI-002 implants.

[0221] This study demonstrated the safety of one or two NPI-002 implants in the vitreous cavity of albino rabbits. No drug-related toxicity was observed at the clinical, retinal imaging, electroretinogram examination, or histological examination levels. These findings provide reconfirmation to proceed to a human phase 1 / 2 clinical trial to examine the safety and efficacy of one or two intravitreal NPI-002 implants per eye in the attenuation of vitrectomy-induced cataracts. [Example 7]

[0222] Local ocular administration of repeated doses of NPI-002 in rabbits. A study was conducted to evaluate the effects of topical ocular administration of diNACA or NACA in rabbits. An ophthalmic formulation containing either 1% diNACA or 1% NACA was developed and used for repeated topical instillation into Dutch Belted rabbits. Three animals per group were dosed four times a day at approximately 8:00 AM, 11:00 AM, 2:00 PM, and 4:00 PM on days 1 - 6 and once at approximately 8:00 AM on day 7 via bilateral topical administration with each test substance. Ocular tolerance was evaluated by means of scoring conjunctival edema, ocular discharge, and hyperemia (Draize scoring) at baseline and prior to the first daily dosing. Ocular tissues were harvested at necropsy (day 7). A validated analytical LC - MS method was developed and used to quantify NACA levels in aqueous humor (AH). No severe adverse findings were observed after topical ocular administration.

[0223] Mild ocular discharge was observed infrequently in all groups and mild hyperemia was observed in the vehicle group. No signs of conjunctival edema were seen in any of the dosing groups. Since vehicle treatment showed mild ocular irritation at similar or higher frequencies as indicated by ocular discharge or hyperemia, the ocular irritation seen in the test agent dosing groups may not be contributed by the test agent itself but rather by the vehicle. NACA levels reached in the aqueous humor after dosing with either 1% diNACA or 1% NACA were observed (Table 2). The presence of diNACA in the AH demonstrated that diNACA penetrated the eye after topical ocular administration. The presence of NACA in the AH demonstrated that diNACA served as a prodrug for delivering NACA to the AH. It is unclear whether diNACA is cleaved to NACA at the ocular surface or after penetration into the AH. [Table 2] [Example 8]

[0224] Manufacture of the implant. The NPI - 002 IVT implant manufacturing process flow is presented in Figure 7.

[0225] The process for manufacturing the IVT implant is as follows. Using a Fisher Pharma Mini Twin-Screw extruder, set the temperature of the feed port chiller to 17°C and the temperatures of zones 1 and 2 to 127°C each. Set the extrusion speed to 5 rpm and add the NPI-002 and 8515 9E-PLG blend to the feed hopper of the extruder. Note: The blend of NPI-002 and 8515 9E-PLG is pre-done (blended for 5 minutes at a 46 speed setting) using a Turbula blender. Once all of the NPI-002 and 8515 9E-PLG blend has been added to the extruder, increase the screw rpm to 15 and recirculate the NPI-002 / 8515 9E-PLG material in the extruder for 10 - 12 minutes. Then, set the screw to 5 - 10 rpm and pass the extrudate through the die of the extruder. When the extrudate exits the die, it is conveyed by a conveyor passing through a Beta Lasermike to control the diameter of the extrudate to around 0.38 - 0.41 mm and collected as a bulk rod. The bulk rod is then cut to the length of the IVT implant.

[0226] Use the drug content method to determine the amounts of NPI-002 and impurities in the implant. Incubate the NPI-002 implant in acetonitrile to dissolve the PLG. Then add a diluent to extract the NPI-002. Analyze the extracted NPI-002 against a reference standard of NPI-002 using a reverse phase gradient HPLC method with UV detection at 214 nm. The HPLC conditions are shown in Table 3.

Table 3

[0227] Clinical study of NPI-002 intravitreal implant in subjects after vitrectomy. Since vitrectomy is a common procedure that causes rapid and certain opacification of the lens nucleus, patients undergoing vitrectomy provide a "model system" with the potential to test this hypothesis. Success in protecting against the development of nuclear cataracts in vitrectomized patients would lay the groundwork for interventions to prevent these cataracts in subjects with advanced vitreous degeneration (Beebe DC, Holekamp NM, Shui YB. Oxidative damage and the prevention of age-related cataracts. Ophthalmic Res. 2010;44(3):155-65. doi: 10.1159 / 000316481. Epub 2010 Sep 9. PMID: 20829639; PMCID: PMC2952186).

[0228] Predictive Example. NPI-002 Intravitreal Implant for Delaying Cataract Progression. Description of the Study. Brief Summary: This study examines the safety and efficacy of the NPI-002 intravitreal implant after vitrectomy.

Table 4

[0229] Study Design: Type of Study: Intervention (Clinical Trial) Estimated Enrollment: 30 Participants Allocation: Random Intervention Model: Parallel Assignment Masking: Double (Participants, Outcome Assessors) Primary Purpose: Prevention Official Title: Safety and Efficacy of the NPI-002 Intravitreal Implant for Delaying Cataract Progression in Patients Undergoing Vitrectomy

[0230] Arms and Interventions:

Table 5

[0231] Outcome measure Primary evaluation item: 1. Lens densitometry [Time frame: 6 months] Change from baseline Eligible age for the study: 18 years or older Eligible gender for the study: All Acceptance of healthy volunteers: No

[0232] Criterion Inclusion criteria: 1. Eligible for vitrectomy 2. Natural lens in the eye of the study at the time of vitrectomy 3. Presence of some cataracts, evaluated preoperatively

[0233] Exclusion criteria: 1. Previous intraocular surgery in the eye of the study 2. Atrophy or defect / coloboma of the clear ciliary body 3. Not on a stable dose of drug therapy for other conditions 4. Requirement for oral corticosteroids is expected during the study 5. Evidence or history of uveitis or ocular ischemia (ischemic retinopathy) 6. Evidence or history of proliferative diabetic retinopathy 7. Previous panretinal photocoagulation 8. Moderate or severe uncontrolled glaucoma 9. Currently a smoker 10. Use of oxygen supplementation 11. Current lung disease causing a decrease in oxygen saturation. 12. Sensitivity to thiol compounds. 13. Participation in another clinical trial. [Example 12]

[0234] Rabbit study of diNACA intraocular implant This example shows the measured values of NAC, NACA, di-NACA, and GSH in plasma samples obtained at baseline and 3 months after implant delivery. Additionally, the measured values of NAC, NACA, di-NACA, and GSH in aqueous humor, vitreous humor, lens, retina, and RPE / choroid 3 months after implant delivery were also determined.

Table 6

[0235] Blood collection. Blood was not obtained from the animals in Group 1 (control). Blood was collected again from each of the animals in Groups 2, 3, and 4 at the time of implant delivery and at the study endpoint (3 months after implant delivery). The blood was placed into pre-chilled tubes containing K2EDTA as an anticoagulant, inverted several times to mix, and kept on wet ice until centrifugation. The blood samples were centrifuged at a temperature of 4°C at approximately 3,000 x g for 5 minutes. 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 at -60°C to -80°C. Prior to snap-freezing, the plasma was acidified with formic acid to stabilize NPI-002 (0.5% of the plasma volume).

[0236] Tissue collection. Tissues were collected for pharmacokinetic evaluation.

[0237] The right eyes were collected from the respective rabbits 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.

[0238] Subsequently, the tissues were dissected: aqueous humor (AH); vitreous humor (VH); lens; retina; and choroid / retinal pigment epithelium (RPE).

[0239] Samples from each eye were separated and not combined. Samples were collected in individual pre-labeled and pre-weighed polypropylene tubes. The weight of each sample was recorded. AH and VH (but not other eye tissues) were acidified with formic acid to stabilize NPI-002 (0.2% of the volume of the body fluid). The samples were snap-frozen in liquid nitrogen and placed on dry ice until storage in a freezer set to maintain at -60°C to -80°C. All samples were frozen on dry ice and transported to Agilex, the sponsor-designated laboratory, for analysis. A total of 18 samples each of AH, VH, lens, retina, and choroid / RPE were collected and provided for analysis.

[0240] Analyte concentrations in plasma. NAC plasma levels in the placebo group were 43.6 ng / mL at baseline and 38.2 ng / mL three months after implant delivery. NAC plasma levels in both implant groups were approximately 65 ng / mL at baseline. An increase in plasma NAC was not detected in either group three months after implant delivery. In fact, NAC levels decreased somewhat in both groups. NACA was essentially undetectable in all groups at both baseline and three months after implant delivery. Levels of di-NACA were extremely low in all groups at both baseline and three months after implant delivery.

[0241] GSH plasma levels in the placebo group were 9,782 ng / ml at baseline and 18,270 ng / ml three months after implant delivery. GSH plasma levels in the single and double implant groups were 10,427 ng / mL and 6,513 ng / ml at baseline, respectively, and 9,747 ng / mL and 10,377 ng / mL three months after implant delivery, respectively.

[0242] These data demonstrate that when intravitreal implants containing di-NACA were analyzed 3 months after surgery, the plasma levels of NAC, NACA, di-NACA, or GSH did not increase. Although a statistically significant difference was found between the baseline and 3-month data for some parameters, such results are unlikely to represent a true cause-effect relationship.

Table 7

[0243] NAC: As shown in Figure 9A, NAC was undetectable in the aqueous humor in all three groups. In the vitreous humor, NAC was undetectable in the control group but was present at low levels (typically below the lower limit of quantification of the assay) in samples from both treatment groups.

[0244] As shown in Figure 9B, NAC was undetectable in the lens samples in all three groups. In the retina, NAC was essentially undetectable in the untreated and single (immediate-release) implant groups, although there was significant variability between samples, and was very elevated in the double implant group. In the RPE / choroid, NAC was undetectable in the untreated group and in all but one sample in the single (immediate-release) implant group, and was not at the levels measured in the corresponding retina samples but was very elevated in the double implant group. Again, there was significant variability between animals.

[0245] NACA: As shown in Figure 10A, NACA was present at very low levels in the aqueous humor of the control group. In both treatment groups, the concentration of NACA increased but remained very low. In the vitreous humor, NACA was present at very low levels (approximately 3 ng / mL) in the control group but was dramatically higher (approximately 15,000 - 20,000 ng / mL) in both treatment groups.

[0246] As shown in Figure 10B, NACA was undetectable in the lens samples in all three groups. In the retina, NACA was undetectable in the untreated group and did not increase much in the single (quick-release) implant group. The gap between the elevated vitreous levels and low retinal levels in the single implant group is surprising. In the double implant group, NACA was, on average, very elevated, however, there was large variation between samples, with one of the six samples showing an abnormally high level (30 times higher than the next highest sample, which itself was 25 times 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, did not increase much in the single implant group, but was very elevated in the double implant group, though not to the magnitude measured in the corresponding retinal samples. Again, there was large variation between animals in the double implant group, with the same two animals showing high and very high levels of NACA.

[0247] di-NACA: As shown in Figure 11A, di-NACA was undetectable in the aqueous humor of the control group, but in both treatment groups, the concentration of di-NACA was 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), where NACA was also essentially undetectable, but was dramatically elevated in both treatment groups (approximately 9000 - 13000 ng / mL).

[0248] As shown in Figure 9B, di-NACA was undetectable in the lens samples in all three groups. In the retina, di-NACA was undetectable in the untreated group and essentially undetectable in the single implant group, but moderately elevated (125 ng / g tissue weight) in the double implant group. The difference between the high levels in the vitreous and low levels in the retina in both treatment groups is surprising. In the RPE / choroid, the results showed the same pattern as the retina: di-NACA was undetectable in the untreated group, barely detectable in the single implant group, and slightly elevated (78 ng / g tissue weight) in the double implant group.

[0249] GSH: As shown in Figure 12A, GSH was present at high concentrations (approximately 14,000 ng / mL) in the aqueous humor of the control group. This level of GSH corresponded to a molar concentration of 45 μM, which is roughly similar to the value of 25 μM reported in the literature (Richer SP and Rose RC (1998). Water soluble antioxidants in mammalian aqueous humor: interaction with UV B and hydrogen peroxide. Vision Research 38: 2881-2888). The GSH concentration was higher in both the single and double implant groups (approximately 37,000 - 47,000 ng / mL). In the vitreous humor, GSH was present at a concentration of approximately 17,000 ng / mL in the control group. The GSH concentration was somewhat higher in both the single and double implant groups (approximately 19,000 - 25,000 ng / mL).

[0250] As shown in Figure 12B, 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 the single or double implant groups in any of the tissues.

[0251] Abstract. The levels of NAC, NACA, and di-NACA were low in the aqueous humor of all groups. This is not particularly surprising considering the rapid turnover of aqueous humor. However, it is interesting that the 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.

[0252] In the vitreous humor, the data indicate that implants containing NPI-002 (di-NACA) dramatically increased the vitreous humor levels of NACA and di-NACA when analyzed 3 months post-surgery. Interestingly, the levels of both compounds were higher in the double implant group, although the difference between the single and double implant groups was not particularly prominent. The increase in the levels of di-NACA and NACA in the vitreous humor of the treatment groups did not translate into statistically significantly higher GSH levels.

[0253] In the RPE / choroid, the results for NAC, NACA, and di-NACA were at slightly lower levels but were essentially similar to those of the retina.

[0254] It is contemplated that any embodiment discussed herein can be implemented with respect to any method, kit, reagent, or composition of the invention, and vice versa. Furthermore, the methods of the invention can be achieved using the compositions of the invention.

[0255] It will be understood that the specific embodiments described herein are illustrative and not intended as limitations of the invention. The main features of the invention can be used in various embodiments without departing from the scope of the invention. Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, many equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of the invention and are included in the claims.

[0256] All publications and patent applications cited in this specification represent the level of those skilled in the art to which the present invention pertains. All publications and patent applications are hereby incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0257] The use of the terms "a" or "an" may mean "one" when used in conjunction with the term "comprising" in the claims and / or the specification, although this is also consistent with the meanings of "one or more", "at least one", and "one or more than one". The use of the term "or" in the claims is used to mean "and / or" for the purposes of this disclosure to support only alternatives and definitions that refer to "and / or", unless explicitly indicated to refer to only alternatives or that the alternatives are mutually exclusive. Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for the device, method used to determine the value, or the variation that exists among the subjects being studied.

[0258] As used in this specification and the claims, the words "comprising" (and any form of comprising such as "comprise" and "comprises"), "having" (and any form of having such as "have" and "has"), "including" (and any form of including such as "includes" and "include") or "containing" (and any form of containing such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. In any embodiment 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 not only particular integers or steps but also those that do not materially affect the characteristics or functions of the invention recited in the claims. As used herein, the term "consisting of" is used to indicate the presence of only the recited integers (e.g., features, elements, characteristics, properties, methods / method steps or limitations) or groups of integers (e.g., features, elements, characteristics, properties, methods / method steps or limitations). Each of the compositions of the present invention may comprise, consist essentially of, or consist of diNACA, as outlined above in this specification.

[0259] As used herein, the term "or combinations thereof" refers to all variations and combinations of the listed items preceding this term. For example, "A, B, C, or combinations thereof" is intended to include at least one of A, B, C, AB, AC, BC, or ABC, and, where order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing this example, combinations containing repetitions of one or more items or terms are explicitly included, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, etc. One of ordinary skill in the art will typically understand that there is no limitation on the number of items or terms in any combination, unless otherwise apparent from the context.

[0260] As used herein, by way of non-limiting example, approximating words such as "about," "substantially," or "substantially" are meant that when a condition is modified by them, the condition is understood not necessarily to be absolute or complete, but is expected to be considered close enough for one of ordinary skill in the art to conclude that the condition exists. The range within which the description can vary depends on how large a change can occur, and the modified characteristic still has what one of ordinary skill in the art would recognize as the necessary characteristics and capabilities of the unmodified characteristic. Generally, subject to the preceding discussion, numerical values herein modified by approximating words such as "about" can vary by at least ±1, 2, 3, 4, 5, 6, 7, 10, 12, or 15% from the stated value.

[0261] In addition, section headings in this specification are provided for consistency with the suggestions under 37 CFR § 1.77 or, alternatively, to provide organizational cues. These headings do not limit or characterize the invention claimed in any claim that may issue from this disclosure. In particular, by way of example, where a heading refers to a "Technical Field," a claim of that nature should not be limited by the language under that heading intended to describe the so-called technical field. Further, the description of technology in the "Background Art" section should not be construed as an admission that the technology is prior art to any invention of this disclosure. The "Summary" is also not to be regarded as reflecting features of the invention as claimed in issued patent claims. Still further, any reference in this disclosure to the singular "invention" should not be used to argue that there is only a single novel point in this disclosure. Multiple inventions may be presented according to limitations of multiple claims arising from this disclosure, and accordingly, such claims define the inventions and their equivalents protected thereby. In all instances, the scope of such patent claims should be considered in view of the merits of the claims themselves in view of this disclosure, but should not be constrained by headings set forth herein.

[0262] All compositions and / or methods disclosed and claimed herein can be made and executed without undue experimentation in view of this disclosure. While the compositions and methods of the invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and / or methods and steps or the order of steps of the method described herein without departing from the concept, spirit, and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope, and concept of the invention as defined by the appended claims.

[0263] References 1. Ahmad, et al., J. Amer. Chem. Soc. 101, 2669 (1979). 2. Beebe DC, Holekamp NM, Shui YB. Oxidative damage and the prevention of age-related cataracts. Ophthalmic Res. 2010;44(3):155-65. doi: 10.1159 / 000316481. Epub 2010 Sep 9. PMID: 20829639; PMCID: PMC2952186. 3. Belin PJ and Parke DW. Complications of vitreoretinal surgery. Curr Opin Ophthalmol 2020; 31, 167-173. doi: 10.1097 / ICU.0000000000000652. 4. Campochiaro PA, Mir TA. The mechanism of cone cell death in Retinitis Pigmentosa. Prog Retin Eye Res. 2018 Jan;62:24-37. doi: 10.1016 / j.preteyeres.2017.08.004. Epub 2017 Sep 27. PMID: 28962928. 5. Dilger RN, Baker DH. Oral N-acetyl-L-cysteine is a safe and effective precursor of cysteine. J Anim Sci. 2007 Jul;85(7):1712-8. doi: 10.2527 / jas.2006-835. Epub 2007 Mar 19. PMID: 17371789. 6. 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Invest Ophthalmol Vis Sci. 2013 Dec 13;54(14):ORSF54-9. doi: 10.1167 / iovs.13-12940. PMID: 24335070; PMCID: PMC3864378. 19. Prescott LF, Park J, Ballantyne A, Adriaenssens P, Proudfoot AT. Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine. Lancet. 1977 Aug 27;2(8035):432-4. doi: 10.1016 / s0140-6736(77)90612-2. PMID: 70646. 20. Rahil, et al, J. AM. CHEM. SOC. 103, 1723 (1981). 21. Richer SP and Rose RC (1998). Water soluble antioxidants in mammalian aqueous humor: interaction with UV B and hydrogen peroxide. Vision Research 38: 2881-2888. 22. Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med. 1988 Dec 15;319(24):1557-62. doi: 10.1056 / NEJM198812153192401. PMID: 3059186. 23. Ster AM, Popp RA, Petrisor FM, Stan C, Pop VI. The Role of Oxidative Stress and Vascular Insufficiency in Primary Open Angle Glaucoma. Clujul Med. 2014;87(3):143-6. doi: 10.15386 / cjmed-295. Epub 2014 Aug 5. PMID: 26528013; PMCID: PMC4508597. 24. Wall GM; Johnson D; Rubenstein A; Tucker R; Bolger J. Method for Preparation of N-Acetyl Cysteine Amide and Derivatives Thereof. U.S. Patent No. 10,590,073 (U.S.), issued March 17, 2020. 25. Wall GM. Prodrug for the treatment of disease and injury of oxidative stress. PCT / US21 / 14819 specification. Filed January 23, 2021. 26. Wall GM. Methods of Making Deuterium-Enriched N-acetylcysteine Amide (D-NACA) and (2R, 2R')-3,3'-Disulfanediyl BIS(2-Acetamidopropanamide) (DINACA) and Using D-NACA and DINACA to Treat Diseases Involving Oxidative Stress. Australian Patent No. 2018365900, issued on June 18, 2020. 27. Wang GM, Raghavachari N, Lou MF. Relationship of protein-glutathione mixed disulfide and thioltransferase in H2O2-induced cataract in cultured pig lens. Exp Eye Res. 1997 May;64(5):693-700. doi: 10.1006 / exer.1996.0251. PMID: 9245898. 28. Zhu et al. 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Claims

Claim 1 A biodegradable intraocular implant comprising (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropanamide) (diNACA) in a pharmaceutically acceptable polymer. Claim 2 The intraocular implant according to 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 any antioxidant adjuvant. Claim 3 The intraocular implant according to claim 1, wherein the implant is selected from at least one of a diameter of about 0.1 to 0.5 mm and a length of about 4 to 10 mm, a diameter of about 0.2 to 0.4 mm and a length of about 5 to 8 mm, a diameter of about 0.3 mm and a length of about 6 to 7 mm, a diameter of about 0.4 mm and a length of about 7 mm, or a length between about 5 to 8 mm or a length of about 5 to 8 mm with a diameter of about 0.05 mm, or the implant comprises a plurality of openings or pores in the polymer, in the coating, or in both. Claim 4 The pharmaceutically acceptable polymer is poly(lactide-co-glycolide), polycarbamate 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-isopropylidenediphenylene 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(olefin), poly(vinyl-olefin), poly(styrene), poly(halo-olefin), poly(vinyl) ester, poly(alkyl acrylate), poly(oxide), poly(ester), polyamide, and polycarbonate, or a mixture thereof, the intraocular implant according to claim 1.

5. The intraocular implant according to claim 1, wherein diNAcA is present in the implant in an amount between at least about 21 to 65 weight percent (wt%), between 1 to 20 wt%, between 5 to 15 wt%, between 7 to 12 wt%, or about 10 wt%.

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

7. The implant is suitable for intravitreal placement in an individual's eye, the antioxidant is present in an amount effective to treat the eye condition of the eye; and an adjuvant associated with a biodegradable polymer as an intraocular implant structured for intravitreal placement in an individual's eye is present in an amount effective to reduce the occurrence of at least one undesirable effect that would be present when the adjuvant is administered in the same manner except that the antioxidant is administered alone; or the antioxidant is present in the intraocular implant in an amount of at least about 10 weight percent, the intraocular implant according to claim 1.

8. A biodegradable intraocular implant system comprising an antioxidant suitable for the treatment of ophthalmic diseases or conditions involving oxidative stress in an animal or human.

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

10. The biodegradable intraocular implant system according to claim 9, wherein the antioxidant comprises (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropanamide) (diNACA), or the diNACA and an adjuvant are included in the same implant or different implants.

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

12. A method for the treatment of ophthalmic oxidative stress in an animal or human subject, comprising: identifying the animal or human patient in need of treatment for ophthalmic oxidative stress of the eye; and administering to the animal or human patient a therapeutically effective amount of N-acetylcysteine amide (NACA) or (2R,2R')-3,3'-disulfanediylbis(2-acetamidopropanamide) (diNACA) in an intravitreal implant (diNACA implant). The method as described above.

13. The method according to claim 12, wherein ocular oxidative stress of the eye results in at least one of cataract, cataract in a subject without cataract and diabetes, loss of corneal endothelial cells, age-related macular degeneration, presbyopia, retinitis pigmentosa (RP), Ascher syndrome, Stargardt syndrome, glaucoma, diabetic retinopathy, or retinal disease.

14. The method according to claim 12, wherein diNAcA is provided in a pharmaceutically acceptable carrier or together with a pharmaceutically acceptable carrier.

15. The method according to claim 12, wherein diNAcA is in a dosage form for a delivery route selected from the group consisting of intravitreal, intrastromal, intracameral, sub-Tenon's, retinal, subretinal, posterior to the eye, around the eye, suprachoroidal, subchoroidal, conjunctival, subconjunctival, episcleral, posterior near the sclera, anterior near the sclera, around the cornea, topical, and lacrimal duct.

16. The method according to claim 13, wherein 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 according to claim 12, wherein diNAcA is administered as 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 according to claim 12, wherein diNAcA is administered once every 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months.

19. The method according to claim 12, wherein diNAcA is administered together with at least one second active agent selected from ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, NAC, NACA, propyl gallate, α-tocopherol, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, or phosphoric acid.

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

21. The method of claim 12, wherein the dosage for administration is about 1, 10, 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 micrograms per dosage.

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

23. A non-biodegradable, non-biodegradable or non-bioabsorbable intraocular implant comprising (2R,2R')-3,3'-disulfanediyldi(2-acetamidopropanamide) (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'-disulfanediyldi(2-acetamidopropanamide) (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 having a diameter of about 0.1 to 0.5 mm and a length of about 4 to 10 mm, a diameter of about 0.2 to 0.4 mm and a length of about 5 to 8 mm, a diameter of about 0.3 mm and a length of about 6 to 7 mm, a diameter of about 0.4 mm and a length of about 7 mm, or a diameter of 0.05 mm or about 0.05 mm and a length between 5 and 8 mm or about 5 to 8 mm, or the implant comprises a plurality of openings or pores in the polymer, in the coating, or in both.

26. The implant according to claim 23, wherein the polymer is polycarbamate polyurea, poly(vinyl ester), poly(methyl methacrylate), poly(vinyl chloride), polyamide, nylon, polyethylene terephthalate, rubber, silicone, polyisoprene, polyisobutylene, polybutadiene, polyethylene, polytetrafluoroethylene, poly(vinylidene chloride), polyacrylonitrile, polyvinyl pyrrolidone, chlorinated polyethylene, polychlorotrifluoroethylene, chlorotrifluoroethylene-ethylene copolymer, polytetrafluoroethylene, poly(ethylene-tetrafluoroethylene), poly(4,4'-isopropylidenediphenylene carbonate), polyurethane, polyperfluoroalkoxy, poly(vinylidene fluoride), vinylidene chloride-acrylonitrile copolymer, vinyl chloride-diethyl fumarate copolymer, silicone rubber, polydimethylsiloxane, ethylene-propylene rubber, silicone-carbonate copolymer, vinylidene chloride-vinyl chloride copolymer, vinyl chloride-acrylonitrile copolymer, poly(olefin), poly(vinyl-olefin), poly(styrene), poly(halo-olefin), poly(vinyl ester), polyalkyl acrylate, polyoxide, polyester, polyamide, and polycarbonate, or a mixture thereof.

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

28. The implant according to claim 23, wherein the diNACA implant is suitable for administration to the eye at a site selected from the group consisting of the vitreous body, the stroma, the anterior chamber, sub-Tenon's space, the retina, subretinal, posterior to the globe, around the globe, suprachoroidal, subchoroidal, the conjunctiva, subconjunctival, episcleral, posterior to the episcleral vicinity, anterior to the episcleral vicinity, around the cornea, topical, and the lacrimal duct.

29. A method for the treatment of cataracts, loss of corneal endothelial cells, age-related macular degeneration, presbyopia, retinitis pigmentosa (RP), Ascher syndrome, Stargardt syndrome, glaucoma, diabetic retinopathy, cataracts in a subject without diabetes, or other retinal diseases in the 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-acetamidopropanamide) (diNACA); and Delivering the diNACA implant containing a therapeutically effective amount of diNACA to a predetermined region of the eye in, on, or around the eye to treat cataracts, loss of corneal endothelial cells, age-related macular degeneration, presbyopia, retinitis pigmentosa (RP), Usher syndrome, Stargardt syndrome, glaucoma, diabetic retinopathy, cataracts in a subject without diabetes, or other retinal diseases The method comprising the above.

30. The method according to claim 29, wherein the diNACA implant is administered to a predetermined region of the eye selected from the group consisting of intravitreally, in the stroma, in the anterior chamber, sub-Tenon's, on the retina, subretinally, posterior to the globe, around the globe, suprachoroidally, subchoroidally, in the conjunctiva, subconjunctivally, episclerally, posterior to the vicinity of the sclera, anterior to the vicinity of the sclera, around the cornea, locally, and in the lacrimal duct.

31. The method according to 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 - 150 mg / Kg.

32. The method according to claim 29, wherein the diNACA is administered as 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 - 900 micrograms.

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

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

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

36. The method of claim 29, wherein the dosage for administration is about 1, 10, 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 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 degrades and dissolves or biodegrades in a predetermined region of the eye.

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

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