Gel formulations for topical ocular use

Abstract

A gel formulation for topical ophthalmic use, the gel formulation comprising a compound of formula (I).

Description

Gel formulation for topical ophthalmic use. Technical Field

[0001] This invention relates to a pharmaceutically usable formulation and its use in the treatment of eye conditions. More particularly, this invention relates to a gel formulation for topical ocular use containing a therapeutically active benzylsulfonamide derivative, and its use in the treatment of eye conditions. Background Technology

[0002] Throughout this disclosure, various non-patent publications are mentioned by first author and year of publication. Full citations of these publications are presented in the references section preceding the claims. The disclosures of these references and any patent publications mentioned herein are hereby incorporated in their entirety by reference.

[0003] International application PCT / EP2019 / 061950, published as WO 2019 / 215291 A1, discloses certain benzenesulfonamide derivatives and their use in treatment, particularly in treating conditions or symptoms associated with nicotinamide adenine dinucleotide phosphate oxidase 4 or 2 (NOX4 or NOX2). This application discloses the activity of such derivatives in modulating various conditions affecting the eye, such as diseases involving lens epithelial-mesenchymal transition and retinal diseases.

[0004] Oxidative stress has been shown to be involved in a variety of ocular conditions, including those affecting the anterior and / or posterior segments of the human eye (Shu, 2023). Therefore, the production of reactive oxygen species (ROS) and oxidative stress may contribute to the development and progression of eye-related conditions such as age-related macular degeneration, glaucoma, retinopathy, retinal ischemia-reperfusion injury, cataracts, and corneal conditions and diseases. Oxidative stress has also been shown to be frequently involved in inflammation associated with ocular diseases (Dammak, 2021), where an imbalance between the production of reactive oxygen species (ROS) and their elimination through protective mechanisms may lead to chronic inflammation.

[0005] Extensive evidence suggests that the ROS-producing enzyme NOX, particularly NOX4 and NOX2, is involved in the pathophysiological mechanisms contributing to the progression of eye diseases. Interactions between NOX, oxidative stress, inflammation, and hypertensive eye diseases have been demonstrated, highlighting the importance of NOX in the oxidative and inflammatory pathogenesis of various eye diseases, including age-related macular degeneration, glaucoma, retinopathy, retinal ischemia-reperfusion injury, cataracts, corneal conditions and diseases, and retinal neurodegeneration.

[0006] Age-related macular degeneration (AMD) is a multifactorial disease and a leading cause of irreversible blindness in the elderly. Based on the presence or absence of neovascularization, it is generally classified into two categories: dry or non-neovascular AMD and wet or neovascular AMD (nAMD).

[0007] Oxidative stress and choroidal vascular dysfunction have been shown to be crucially involved in the pathogenesis of AMD, including dry AMD. The retina is one of the most oxygen-consuming tissues in the human body, and the local oxygen metabolic environment within the retina plays a vital role in maintaining retinal homeostasis between oxygen supply and consumption. During the retinal process of converting light into vision, reactive oxygen species (ROS) are produced as normal metabolic byproducts. However, when ROS production exceeds the capacity of the antioxidant system, the balance of redox homeostasis is disrupted, and oxidative stress occurs. NOX4 has been found in retinal pigment epithelial (RPE) cells and is associated with increased ROS production in these cells. Therefore, excessive ROS production in the RPE induced by NOX4 may contribute to the oxidative damage seen in AMD, including the formation of drusen and degenerative changes in photoreceptor cells. Evidence has also been presented that ROS and vascular dysfunction may co-contribute to the pathology of wet AMD, and NOX4 has been demonstrated as a link between vascular endothelial growth factor (VEGF) and ROS in human choroidal endothelial cells (Ruan, 2021).

[0008] Currently, there is no effective treatment for dry AMD, although antioxidant therapy has been shown to offer protection against oxidative damage. On the other hand, treatment for wet AMD includes anti-VEGF medications, usually administered via ocular injection. However, such injections are both painful and associated with potential degenerative changes in healthy endothelium.

[0009] Glaucoma is a type of eye disease characterized by elevated intraocular pressure and damage to the optic nerve. Similar to AMD, it can lead to vision loss. While the disease can occur at any age, it is more common in older adults and is one of the leading causes of blindness in people over 60.

[0010] There are two main types of glaucoma: open-angle glaucoma (or primary open-angle glaucoma) and angle-closure glaucoma (also known as "closed-angle glaucoma" or "narrow-angle glaucoma"). Open-angle glaucoma is the most common type of glaucoma and occurs when impaired drainage of the aqueous humor leads to increased intraocular pressure, causing damage to the optic nerve. Angle-closure glaucoma occurs when the iris blocks the drainage angle of the eye, causing a sudden increase in intraocular pressure, which can lead to blindness if not treated urgently.

[0011] Mounting evidence points to the crucial role of reactive oxygen species (ROS) in the pathogenesis of glaucoma, see, for example, (Izzotti, 2006) and (Fan Gaskin, 2021). Therefore, it has been shown that vascular changes commonly associated with glaucoma may contribute to oxidative damage, and that oxidative stress, also occurring in retinal cells, involves neuronal death affecting the optic nerve, particularly in open-angle glaucoma. Kimura, 2017, reported the prevention of glaucomatous retinal degeneration in mouse models of glaucoma and optic neuritis using drugs with antioxidant properties.

[0012] NOX4 has been identified as one of the major sources of reactive oxygen species (ROS) in glaucoma. Therefore, in studies on acute intraocular hypertension (AOH)-induced retinal ischemia / hypoxia in mice, NOX4 was shown to be highly expressed in the mouse retina, particularly in the retinal ganglion cell layer (GCL) (Liao, 2023). NOX4 inhibition has been shown to reduce excessive ROS production, inhibit the release of inflammatory factors, suppress glial cell activation and proliferation, inhibit leukocyte infiltration, reduce retinal cell senescence and apoptosis in damaged areas, reduce retinal degeneration, and improve retinal function. Based on these observations, the authors conclude that targeted inhibition of NOX4 could provide a novel treatment for acute glaucoma.

[0013] There are four main types of retinopathy: retinopathy of prematurity, hypertensive retinopathy, central serous retinopathy, and (the most common type) diabetic retinopathy. Diabetic retinopathy is a common complication of diabetes in patients with diabetes, affecting the retina due to persistently high blood glucose levels. Studies have demonstrated that oxidative stress is a key factor in the pathogenesis of diabetic retinopathy (Kang, 2020). NOX4 has been found in the retinas of diabetic patients and in animal models of diabetes, and it is believed that ROS produced by NOX4 contributes to retinal vascular dysfunction and damage in diabetic retinopathy (Dionysopoulou, 2023). Therefore, NOX4 is also a potential target for the treatment of retinopathy, particularly diabetic retinopathy. Evidence has also been presented regarding the importance of NOX4 as a major ROS-producing enzyme system in oxidative and inflammatory processes associated with hypertensive eye diseases, including hypertensive retinopathy (Santana-Garrido, 2021).

[0014] In addition to hypertensive retinopathy, hypertensive eye diseases also include hypertensive choroidal disease and hypertensive optic neuropathy. Therefore, NOX4 inhibition may be potentially useful for these diseases.

[0015] Increasing evidence supports the role of neurodegeneration and inflammation in ischemic retinopathy (Barber, 1998; Krady, 2005; Antonetti, 2012), and pathogenic factors involved in the development of ischemic retinopathy include oxidative stress and glutamate excitotoxicity. Therefore, retinal ischemia is associated with increased glutamate levels, leading to overactivation of glutamate receptors (Louzada-Junior, 1992; Osborne, 2004), thus making excitotoxicity an important pathological mechanism involved in ischemic retinopathy. Ischemia-induced glutamate release and activation of N-methyl-D-aspartate (NMDA) receptors lead to intracellular Ca2+ release. 2+Increased levels of NOX4 lead to the death of retinal ganglion cells and axons (Choi, 1988), subsequently damaging the optic nerve and impairing vision. However, loss of amacrine cells has also been observed in ischemic retinal diseases such as diabetic retinopathy (Gastiner, 2006) and is considered to represent an early event of retinal ischemia. Dionospoulou, 2020, disclosed that intravitreal administration of (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate hydrobromide (AMPA) increased ROS levels in the rat retina, the increase being NOX-mediated, and that NOX inhibition could provide neuroprotection and / or anti-inflammatory effects in a retinal model of AMPA excitotoxicity. However, Dionospoulou, 2020, taught that local treatment with a NOX4 selective inhibitor does not protect amacrine cells expressing bNOS in the retina and suggested that this may be due to a lack of NOX4 expression in bNOS-positive amacrine cells.

[0016] The most common form of retinopathy, diabetic retinopathy, has been divided into an early non-proliferative phase involving both vascular and neural components, and a late proliferative phase involving neovascularization. Vascular changes in the retina include increased permeability, loss of pericytes and endothelial cells, vascular tortuosity, leukocyte stasis and capillary blockage, loss, and hemorrhage. Neural changes include abnormal regulation of cellular function in both glial cells (Müller cells) and neurons (inner retinal layer). There remains no accurate animal model of diabetic retinopathy to characterize the aforementioned pathological processes. However, excessive VEGF formation is a significant pathological effect in these processes.

[0017] VEGF is a highly potent vascular permeability factor, and analyses of diabetic retinopathy and the vitreous body indicate that VEGF upregulation is associated with the presence of diabetic macular edema. Animal model studies support the central role of VEGF in diabetes-related blood-retinal barrier disruption. Intraocular injection of VEGF into the eyes of cynomolgus monkeys, rabbits, or rats resulted in vasodilation and tortuosity, and vascular-retinal permeability (Tolentino, 1996; Edelman, 2005; Ishida, 2003). Transgenic mice overexpressing VEGF in photoreceptors were also produced (Lai, 2005). In these animals, pathological changes consistent with those seen in the early stages of nonproliferative diabetic retinopathy (microaneurysms, retinal vascular leakage, and vascular tortuosity) were observed.

[0018] Retinal ischemia-reperfusion injury is known to be sensitive to ischemia-reperfusion (I / R) damage due to its high oxygen consumption. Conditions such as retinal artery or vein occlusion can lead to ischemia (lack of blood flow) in the retina, followed by reperfusion injury when blood flow is restored, i.e., retinal ischemia-reperfusion injury. NOX4-derived ROS are involved in oxidative stress and retinal damage associated with ischemia-reperfusion injury (Chen 2018), and NOX4 is also a potential target for the treatment of retinal ischemia-reperfusion injury.

[0019] Cataracts are complete or partial clouding of the lens of the human eye, either on, within, or in the lens capsule, that impairs vision. Several types of cataracts exist, including those affecting the center of the lens (nuclear cataracts), those affecting the periphery of the lens (cortical cataracts), those affecting the posterior part of the lens (posterior subcapsular cataracts), and congenital cataracts. While congenital cataracts can have serious visual consequences, early-onset cataracts contribute to a relatively small percentage of visual impairments, while age-related cataracts account for almost half of all blindness cases worldwide. Cataracts can be treated with ophthalmic surgery, but restenosis of the lens after cataract surgery is not uncommon. Oxidative stress in the eye has been shown to play a significant role in the onset and progression of cataracts (Kaur, 2012), and oxidative damage is a major cause, particularly for cortical and nuclear cataracts (the most common type of age-related cataracts) (Beebe, 2010). For example, Santana-Garrido, 2021 has shown that NOX is involved in the pathogenesis of cataracts.

[0020] Corneal diseases and conditions: Corneal diseases can generally be classified into three main types: keratitis, corneal ectasia, and corneal dystrophy.

[0021] Keratitis is an inflammation of the cornea, which can be infectious or non-infectious. Infectious keratitis is primarily bacterial, although inflammation of the cornea can also be caused by viruses, fungi, and parasites. Non-infectious keratitis can be caused by conditions such as eye injury and dryness of the ocular surface.

[0022] Corneal ectasia is a group of non-inflammatory eye diseases involving bilateral thinning of the cornea. Keratoconus is a specific type of corneal ectasia in which the cornea thins and weakens, leading to bulging and deformation. Corneal ectasia sometimes occurs as a complication of certain surgical procedures, including laser-assisted in situ keratomileusis (LASIK) and corneal transplantation.

[0023] Corneal dystrophy is a group of inherited disorders involving abnormal deposition of proteins, fluid, or other substances in one or more layers of the cornea. Fuchs' dystrophy is the most common type of corneal dystrophy. Other types include epithelial basement membrane dystrophy, lattice keratopathy, and granular keratopathy.

[0024] Other corneal conditions and diseases include bullous keratopathy, corneal abrasion, herpetic ophthalmopathy, iridocorneal endothelial syndrome, keratoconjunctivitis, and pterygium.

[0025] Oxidative stress is known to contribute to various corneal and ocular surface (or corneal-endothelial) conditions and diseases, including a range of conditions belonging to the major categories mentioned above (keratitis, corneal ectasia, and corneal dystrophy), such as keratitis, keratoconus, Fuchs' endothelial dystrophy, and, for example, pterygium and dry eye (Cejka, 2015; Yin, 2018). Increased NOX4 expression has been reported in corneal-endothelial diseases compared to normal corneas (Matthaei, 2014), and NOX4 regulation has been suggested as a therapeutic strategy for regulating corneal-endothelial cell homeostasis and treating corneal diseases.

[0026] Chemical damage caused by alkaline agents (such as NH3, KOH, NaOH, etc.) or acidic agents (such as H2SO4, H2SO3, HF, etc.) can lead to ocular trauma, including corneal burns and injuries. While first-line treatment typically involves rinsing the eye to remove the problematic substance and restore physiological pH composition, subsequent medical interventions may be necessary to enhance corneal epithelial recovery and collagen synthesis, while also minimizing collagen breakdown and controlling inflammation. A serious complication following corneal injury is neovascularization, a condition characterized by the invasion of new blood vessels into the cornea, caused by an imbalance between angiogenic and anti-angiogenic factors that maintain corneal transparency. While corneal neovascularization can be caused by chemical damage as mentioned above, other risk factors involved in the pathogenesis of this condition include contact lens wear, ocular surface diseases, prior surgery, and herpes. It has been shown that NOX expression increases in corneal epithelial cells after alkali burns, and NOX inhibition effectively attenuates alkali burn-induced ROS production and reduces corneal neovascularization induced by alkali burns. Li, 2022, disclosed that NOX4 inhibition can reduce inflammation and corneal neovascularization by clearing excess ROS. Therefore, NOX inhibition, especially NOX4 inhibition, could provide a novel treatment for corneal neovascularization.

[0027] Improved treatment of ocular diseases associated with NOX4 and / or NOX2 activity remains needed. Convenient and effective methods for topical ocular delivery of medications for treating ocular diseases are also required. Summary of the Invention

[0028] The first aspect relates to a gel formulation for topical use in the eye, said gel formulation comprising a compound of formula (I). Or a pharmaceutically acceptable salt thereof, wherein R1 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, hydroxyl and halogen; each R 1a R1 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, hydroxyl and halogen; R2 is selected from C1-C6 alkyl, C1-C6 alkoxy, halogen and hydroxyl; R3, R4, R5 and R6 are independently selected from H and F; and any alkyl group is optionally substituted with one or more halogens.

[0029] Another aspect involves gel formulations, as defined herein, used for the prevention or treatment (e.g., treatment) of eye diseases in mammalian patients.

[0030] Another aspect involves gel formulations as defined herein, which are used for the prevention or treatment (e.g., treatment) of conditions that achieve beneficial effects by inhibiting intraocular NADPH oxidases, such as NOX2 or NOX4, particularly NOX4.

[0031] Another aspect involves gel formulations as defined herein, used for the prevention or treatment (e.g., treatment) of conditions that achieve beneficial effects by inhibiting VEGF within the eye.

[0032] Another aspect involves gel formulations as defined herein, used for the prevention or treatment of ocular conditions or diseases, such as those mentioned above (see the heading “Background Art”), for example, selected from the following eye diseases: age-related macular degeneration, glaucoma, retinopathy, retinal ischemia-reperfusion injury, cataract, corneal disease, bullous keratopathy, corneal abrasion, herpetic ophthalmopathy, iridocorneal endothelial syndrome, keratoconjunctivitis, pterygium, and ophthalmitis.

[0033] Another aspect of the invention relates to the use of compounds of formula (I) as defined herein in the manufacture of gel formulations for the prevention or treatment (e.g., treatment) of ocular conditions or ailments such as those mentioned above (see the title “Background Art”), for example selected from the following eye diseases: AMD, glaucoma, retinopathy, retinal ischemia-reperfusion injury, cataract, corneal disease, bullous keratopathy, corneal abrasion, herpetic ophthalmopathy, iridocorneal endothelial syndrome, keratoconjunctivitis, pterygium, and ophthalmitis.

[0034] Another aspect relates to a method for preventing or treating (e.g., treating) an ocular condition or symptom in a mammalian patient, such as those mentioned above (see the title “Background Art”), for example, selected from the following eye diseases: AMD, glaucoma, retinopathy, retinal ischemia-reperfusion injury, cataract, corneal disease, bullous keratopathy, corneal abrasion, corneal alkali or acid burns, ocular neovascularization (e.g., corneal or retinal neovascularization), herpetic ophthalmopathy, iridocorneal endothelial syndrome, keratoconjunctivitis, pterygium, and ophthalmitis.

[0035] Another aspect relates to a dosing container for containing gel formulations as defined herein, which can be used for topical ocular application.

[0036] Further aspects of the invention will become apparent from the detailed description and embodiments. Attached Figure Description

[0037] Figure 1 is a graph showing the number (% of control) of amacrine cells expressing bNOS in ocular tissues from diabetic rats (diabetic + Example 1) treated with topical ocular application of 20 μL / eye of the gel formulation of Example 1 and from healthy (control) or diabetic (diabetic) rats treated with topical ocular application of a gel formulation similar to Example 1 but without API (20 μL / eye).

[0038] Figure 2 is a graph showing the number (% of control) of amacrine cells expressing bNOS in ocular tissue from diabetic rats (diabetes + API in DMSO) treated with the same API (10 mg / ml) as in Example 1 (in DMSO as a medium) and in ocular tissue from healthy (control) or diabetic (diabetic) rats treated with DMSO medium only.

[0039] Figure 3 is a graph showing the mean gray value (% of control) of NFL immunoreactivity in ocular tissues from diabetic rats (diabetic + Example 1) treated with topical ocular application of 20 μL / eye of the gel formulation of Example 1 and from healthy (control) or diabetic (diabetic) rats treated with topical ocular application of a gel formulation similar to Example 1 but without API (20 μL / eye).

[0040] Figure 4 is a graph showing the mean gray value (% of control) of NFL immunoreactivity in ocular tissues from diabetic rats (diabetes + API in DMSO) treated with the same API (10 mg / ml) as in Example 1 (in DMSO as a medium) and in ocular tissues from healthy (control) or diabetic (diabetic) rats treated with DMSO medium only.

[0041] Figure 5 shows the number / area (μm²) of caspase-3 positive cells in the ocular tissues of diabetic rats (diabetic + Example 1) treated with topical ocular application of 20 μL / eye of the gel formulation of Example 1 and healthy (control) or diabetic (diabetic) rats treated with topical ocular application of a gel formulation similar to Example 1 but without API (20 μL / eye). 2 (The graph shows the percentage of the comparison).

[0042] Figure 6 shows the number / area (μm²) of caspase-3 positive cells in ocular tissues from diabetic rats (diabetes + API in DMSO) treated with the same API (10 mg / ml) as in Example 1 (in DMSO as the medium), and in ocular tissues from healthy (control) or diabetic rats treated with DMSO as the medium only. 2 (The graph shows the percentage of the comparison).

[0043] Figure 7 is a graph showing the mean gray value (% of control) of GFAP immunoreactivity in ocular tissues from diabetic rats (diabetic + Example 1) treated with topical ocular application of 20 μL / eye of the gel formulation of Example 1 and from healthy (control) or diabetic (diabetic) rats treated with topical ocular application of a gel formulation similar to Example 1 but without API (20 μL / eye).

[0044] Figure 8 is a graph showing the mean gray value (% of control) of GFAP immunoreactivity in ocular tissues from diabetic rats (diabetes + API in DMSO) treated with the same API (10 mg / ml) as in Example 1 (in DMSO as a medium) and in ocular tissues from healthy (control) or diabetic (diabetic) rats treated with DMSO medium only.

[0045] Figure 9 shows the number / area (μm²) of reactive Iba-1 positive cells in the ocular tissues of diabetic rats (diabetic + Example 1) treated with topical ocular application of 20 μL / eye of the gel formulation of Example 1 and healthy (control) or diabetic rats (diabetic) treated with topical ocular application of a gel formulation similar to that of Example 1 but without API (20 μL / eye). 2 (The graph shows the percentage of the comparison).

[0046] Figure 10 shows the number / area (μm²) of reactive Iba-1 positive cells in ocular tissues from diabetic rats (diabetes + API in DMSO) treated with the same API (10 mg / ml) as in Example 1 (in DMSO as the medium), and in ocular tissues from healthy (control) or diabetic rats treated with DMSO medium only. 2 (The graph shows the percentage of the comparison).

[0047] Figure 11 is a graph showing the TNF-α levels (pg / mg total protein) in the ocular tissues of diabetic rats (diabetic + Example 1) treated with topical ocular application of 20 μL / eye of the gel formulation of Example 1 and diabetic rats (diabetic) treated with topical ocular application of a gel formulation similar to Example 1 but without API (20 μL / eye).

[0048] Figure 12 is a graph showing the TNF-α levels (pg / mg total protein) in the eye tissue of diabetic rats (diabetes + API in DMSO) treated with the same API (10 mg / ml) as in Example 1 (in DMSO as a medium) and in the eye tissue of diabetic rats (diabetic) treated with DMSO medium only.

[0049] Figure 13 is a graph showing the VEGF levels (pg / mg total protein) in the ocular tissues of diabetic rats (diabetic + Example 1) treated with topical ocular application of 20 μL / eye of the gel formulation of Example 1 and diabetic rats (diabetic) treated with topical ocular application of a gel formulation similar to Example 1 but without API (20 μL / eye).

[0050] Figure 14 is a graph showing the VEGF levels (pg / mg total protein) in the eye tissue of diabetic rats (diabetes + API in DMSO) treated with the same API (10 mg / ml) as in Example 1 (in DMSO as a medium) and in the eye tissue of healthy (control) or diabetic (diabetic) rats treated with DMSO medium only.

[0051] Figure 15 is a graph showing the number (%) of amacrine cells expressing bNOS in ocular tissues of rats treated by intravitreal injection of PBS (50 mM) (control); AMPA, 8.4 mM (AMPA); or AMPA (8.4 mM) and compound AF (0.1 mM) (AMPA + compound AF).

[0052] Figure 16 is a graph showing the mean gray value (%) of GFAP immunoreactivity in ocular tissues of rats treated by intravitreal injection of PBS (50 mM) (control); AMPA, 8.4 mM (AMPA); or AMPA (8.4 mM) and compound AF (0.1 mM) (AMPA + compound AF).

[0053] Figure 17 shows the number / area (μm²) of Iba-1 positive cells in ocular tissues of rats treated by intravitreal injection of PBS (50 mM) (control); AMPA, 8.4 mM (AMPA); or AMPA (8.4 mM) and compound AF (0.1 mM) (AMPA + compound AF). 2 (The graph shows the percentage of the comparison).

[0054] Figure 18 is a graph showing the mean gray value (% of control) of NFL immunoreactivity in ocular tissues from untreated rats (control); rats treated with intravitreal injection of streptozotocin (70 mg / kg, in citrate buffer) (diabetic); and rats treated with intravitreal injection of streptozotocin (70 mg / kg, in citrate buffer, day 0) followed by topical ocular treatment with DMSO solution of compound AF (10 mg / ml, 20 μL / eye) daily for 14 days starting from day 1.

[0055] Figure 19 shows the number of bNOS-expressing amacrine cells (control) in ocular tissues from untreated rats (control); rats treated with intravitreal injection of streptozotocin (70 mg / kg in citrate buffer) (diabetic); and rats treated with intravitreal injection of streptozotocin (70 mg / kg in citrate buffer, day 0) followed by topical ocular treatment with a DMSO solution of compound AF (10 mg / ml, 20 μL / eye) daily for 14 days starting from day 1 (diabetic + compound AF) (control %).

[0056] Figure 20 is a graph showing the Bcl-2 / GAPDH ratio in the ocular tissue of rats (diabetic + compound AF) treated by intravitreal injection of streptozotocin (70 mg / kg, in citrate buffer, day 0) followed by topical ocular treatment with a DMSO solution of compound AF (10 mg / ml, 20 μL / eye) daily for 14 days starting from day 1.

[0057] Figure 21 is a graph showing the mean gray value (% of control) of GFAP immunoreactivity in ocular tissues from untreated rats (control); rats treated with intravitreal injection of streptozotocin (70 mg / kg, in citrate buffer) (diabetic); and rats treated with intravitreal injection of streptozotocin (70 mg / kg, in citrate buffer, day 0) followed by topical ocular treatment with DMSO solution of compound AF (10 mg / ml, 20 μL / eye) daily for 14 days starting from day 1.

[0058] Figure 22 shows the number / area (μm²) of Iba-1 positive cells in ocular tissues from untreated rats (control); rats treated with intravitreal injection of streptozotocin (70 mg / kg, in citrate buffer) (diabetic); and rats treated with intravitreal injection of streptozotocin (70 mg / kg, in citrate buffer, day 0) followed by topical ocular treatment with a DMSO solution of compound AF (10 mg / ml, 20 μL / eye) daily for 14 days starting from day 1 (diabetic + compound AF). 2 (The graph shows the percentage of the comparison).

[0059] Figure 23 illustrates the induction of vascular leakage by intravitreal injection of rhVEGF165 followed by topical application of Example 1 (1) or the corresponding gel formulation without API (2), or intravitreal injection of Eylea. ® (3) or Kenacort ® A graph of in vitro retinal fluorescence (arbitrary unit × step size) measured in the eyes of four groups of rabbits treated with Retard (4). Detailed Implementation

[0060] Definitions: Generally, any terms used herein should be given in their general sense as accepted within the art to which this invention pertains. However, for clarity, some definitions will be given below, and unless otherwise stated or apparent from the context, these definitions shall apply throughout the specification and the appended claims.

[0061] Unless otherwise stated or obvious from the context, the article “a / an” is used in this document to refer to one or more of the grammatical objects of the article (i.e., at least one). For example, “a / an element” generally means one or more elements.

[0062] As used in this article, “improvement” or “relief” of a condition or state should mean relief or reduction of the symptoms of the condition or state.

[0063] As used herein, the term "antioxidant" refers to an agent that can protect other compounds (e.g., APIs) from oxidation. Pharmaceutically useful antioxidants should be chemically and pharmacologically inert and non-toxic at the amounts used.

[0064] As used herein, “API” stands for “active pharmaceutical ingredient”, which, in conjunction with this disclosure, is a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0065] The term "disease or condition affecting the eye" includes, for example, cataracts (including diabetic cataracts), restenosis of the lens after cataract surgery, diabetes, and other forms of retinopathy.

[0066] As used herein, the term "dosing container" refers to a container suitable for containing a volume of a formulation as provided herein, such as a bottle, vial, tube, flask, etc., where the volume corresponds to a single dose or to more than one dose (multiple dose). Dosing containers may include devices that allow an appropriate amount of the formulation to be applied to a patient's eye, or such devices may be provided separately from the container.

[0067] As used herein, an "effective" amount, or "therapeutic effective amount," means an amount of component that, when used in the manner disclosed herein, is sufficient to produce the indicated therapeutic response without excessive adverse side effects (such as toxicity, irritation, or allergic reactions), commensurate with a reasonable benefit / risk ratio. Effective amounts can vary based on factors known in the art, such as disease state, age, sex, and weight of the person or animal being treated.

[0068] The term "excipient" refers to pharmaceutically acceptable chemicals, such as those known to a person of ordinary skill in the pharmaceutical field as aiding in the administration of medical reagents. Excipients are compounds that can be used to prepare pharmaceutical compositions, are generally safe and non-toxic, and are neither biologically nor otherwise undesirable, and include excipients acceptable for both veterinary and human pharmaceutical use.

[0069] As used herein, the term “eye disease” (which is considered synonymous with “ocular disorder”, “eye disease”, “eye condition”, “eye disease”, or “eye ailment”) refers to a disease affecting the eyes of a mammalian subject (i.e., an animal or a human, preferably a human).

[0070] As used herein, the term "gel" refers to a substantially dilute cross-linked system containing a liquid phase that does not exhibit flow in a steady state. It is a solid or semi-solid system of at least two components, consisting of condensed material surrounding and permeated by the liquid phase.

[0071] The term "wetting agent" refers to a hydrophilic compound that can retain moisture in a formulation.

[0072] As used herein, the terms “inhibition” or “inhibiting” when used in relation to the subject’s disease progression or complications mean the prevention or reduction of the subject’s disease progression and / or complications.

[0073] In the context of this invention, the term "inhibitor" is defined as a molecule that completely or partially inhibits the activity of another molecule (e.g., an enzyme).

[0074] The term "mammal" refers to a human or any mammal, such as a primate, farm animal, pet animal, or laboratory animal. Examples of such animals include monkeys, cows, sheep, horses, pigs, dogs, cats, rabbits, mice, rats, etc. Preferably, the mammal is a human.

[0075] As used herein, the term “eye” refers to the eye, and, for example, the expression “eye preparation” refers to a preparation suitable and appropriate for application to the eye of a subject (such as a human).

[0076] "Optional" or "optionally" means that the event or situation described below may or may not occur, and the description includes both scenarios in which the event or situation occurs and scenarios in which the event or situation does not occur.

[0077] The term "weight molar osmolality" refers to the number of osmotically active solute particles dissolved in one kilogram of solvent (usually water).

[0078] "Pharmaceutical acceptable" means that it can be used to prepare pharmaceutical compositions that are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and include those suitable for veterinary and human use.

[0079] As used in this article, "preservatives" refers to additives that both inhibit the growth of microorganisms and kill microorganisms in preparations exposed to the environment.

[0080] The term "solubilizing agent" (or alternatively "solubilizer") refers to a compound that, when added to a solvent phase or formulation, increases the solubility of another compound in that solvent phase or formulation.

[0081] In formulations, the term "solubilizing effective amount" for a substance ("solubilizer") refers to an amount sufficient to solubilize another component of the composition. For example, "API solubilizing effective amount" is an amount sufficient to solubilize an API (in the case of this invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof).

[0082] Unless otherwise stated or obvious from the context, the term “subject” as used herein refers to an individual mammal.

[0083] The term "surfactant" refers to a compound that reduces the surface tension (or interfacial tension) between two liquids, between a gas and a liquid, or between a liquid and a solid. Surfactants are amphiphilic compounds, meaning they contain both a hydrophobic portion ("hydrophobic tail") and a hydrophilic portion ("hydrophilic head" or "polar head"). Most commonly, surfactants are classified according to their hydrophilic head. "Nonionic surfactants" have no charged groups on their heads; "cationic surfactants" have a net positive charge on their hydrophilic heads, while "anionic surfactants" have a net negative charge on their hydrophilic heads.

[0084] As used herein, the term "tonic modifier" (or alternatively "tonic agent") refers to a compound that contributes to the osmotic concentration of a solution. It is preferable to adjust the osmotic concentration of ocular preparations to minimize patient discomfort during ocular application.

[0085] As used in “topical application”, “topical” means a portion of the body surface (including mucous membranes) on which the (medication) is applied topically. For example, “topical ocular application” means application to the eyes of a subject. “Topical ocular preparation” means a preparation suitable for topical ocular application.

[0086] As used in this article, “treatment” encompasses, for example, the suppression, regression, or cessation of a disease, symptom, or condition, or the improvement or relief of the symptoms of a disease, symptom, or condition.

[0087] As used herein, the term "unit dose" refers to the amount of the formulation of the invention administered to a subject in a single administration, or the amount of a compound of formula (I) or a salt thereof contained in said amount of the formulation of the invention. For example, the unit doses disclosed herein may be administered only once, or periodically, such as once daily, twice daily, three times daily, four times daily, five times daily, every other day, once weekly, twice weekly, three times weekly, four times weekly, five times weekly, or six times weekly.

[0088] As used in this article, the term "viscosity" refers to dynamic viscosity.

[0089] The term "viscosity agent" (which in the technical field of this invention may also be referred to as viscosity enhancer, thickener, viscosity modifier, viscosity imparter, thickening agent, thickener, etc.) refers to a reagent that can increase the viscosity of a liquid when mixed with it.

[0090] The term "alkyl" refers to the general formula C n H 2n+1 Straight-chain or branched alkyl groups.

[0091] The term "cycloalkyl" refers to a general formula C n H 2n-1 Cyclic alkyl groups.

[0092] The expression "Cm-Cn" in conjunction with, for example, alkyl or cycloalkyl portions indicates that the portion contains a number of carbon atoms in the range of m to n, where n is greater than m.

[0093] The term "Cm-Cn alkyl" refers to an alkyl group containing m to n carbon atoms, where n is an integer greater than m and m is at least 1. For example, methyl is a C1 alkyl group.

[0094] The term "alkoxy" refers to the part of the following formula Where R is an alkyl group.

[0095] The term "Cm-Cn alkoxy" refers to an alkoxy group in which the alkyl group is a Cm-Cn alkyl group. For example, a methoxy group is a C1 alkoxy group.

[0096] As used herein, the term "halogen" generally refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), preferably fluorine (F), chlorine (Cl) or bromine (Br).

[0097] The term "hydroxyl group" refers to the HO- moiety.

[0098] The first aspect of the compound of formula (I) relates to a gel formulation for topical application to the eye, the gel formulation comprising a compound of formula (I) as defined herein.

[0099] In compounds of formula (I), R1 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, hydroxyl and halogen.

[0100] In some embodiments, R1 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and halogen. In some embodiments, R1 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, and halogen. In some embodiments, R1 is selected from C1-C6 alkyl. In some embodiments, R1 is selected from halogen.

[0101] When R1 is a C1-C6 alkyl group, R1 may more particularly be a C1-C4 alkyl group or a C1-C3 alkyl group. In some embodiments, when R1 is a C1-C6 alkyl group, R1 may more particularly be methyl or isopropyl. In some embodiments, when R1 is a C1-C6 alkyl group, R1 may more particularly be methyl. In some of these embodiments, any such alkyl group is halogenated; for example, R1 is selected from methyl and trifluoromethyl.

[0102] When R1 is a C1-C6 alkoxy, R1 may more particularly be a C1-C4 alkoxy or a C1-C3 alkoxy. In some embodiments, when R1 is a C1-C6 alkoxy, R1 may more particularly be a methoxy. In some of these embodiments, any such alkoxy group is halogenated; for example, R1 is selected from methoxy and trifluoromethoxy groups.

[0103] When R1 is a halogen, such a halogen can be selected from, for example, F, Cl, and Br. In some embodiments, any such halogen is selected from Cl and Br, for example, Br. In some embodiments, R1 is Br.

[0104] In some embodiments, R1 is selected from C1-C3 alkyl, cyclopropyl, C1-C3 alkoxy, hydroxy, and halogen. In some embodiments, R1 is selected from methyl, trifluoromethyl, ethyl, isopropyl, cyclopropyl, methoxy, hydroxy, and halogen; for example, selected from methyl, trifluoromethyl, isopropyl, cyclopropyl, methoxy, hydroxy, Cl, and Br.

[0105] In the compound of formula (I), each R 1a Independently selected from C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, and halogen. In some embodiments, each R 1a Independently selected from C1-C6 alkyl, hydroxyl, and halogen compounds. In some embodiments, each R... 1a Independently selected from C1-C6 alkyl groups and halogens. In some embodiments, each R... 1a Independently selected from C1-C6 alkyl groups. In some embodiments, each R 1a Independently selected from halogens. In some embodiments, at least one R 1a Selected from halogens.

[0106] When any R 1a When it is a C1-C6 alkyl group, such R 1a More specifically, it can be C1-C4 alkyl or C1-C3 alkyl. In some embodiments, when any R 1a When it is a C1-C6 alkyl group, such R 1a More specifically, methyl groups. In some of these embodiments, any such alkyl group is halogenated, for example fluorinated, such as trifluoromethyl.

[0107] When any R 1a When it is a C1-C6 alkoxy group, such R 1a More specifically, it can be C1-C4 alkoxy or C1-C3 alkoxy. In some embodiments, when any R 1a When it is a C1-C6 alkoxy group, such R 1aMore specifically, methoxy. In some of these embodiments, any such alkyl group is halogenated, for example fluorinated, such as trifluoromethoxy.

[0108] When any R 1a When it is a halogen, such halogens can be selected from, for example, F, Cl, and Br. In some embodiments, any such halogen is selected from Cl and Br, for example, Cl. In some embodiments, the two R... 1a Both are Cl.

[0109] In some implementations, each R 1a It is independently selected from methyl, trifluoromethyl, hydroxyl and Cl; for example, methyl, hydroxyl and Cl; or selected from methyl and Cl, for example selected from Cl.

[0110] In compounds of formula (I), R2 is selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and hydroxyl groups. In some embodiments, R2 is selected from C1-C6 alkyl, halogen, and hydroxyl groups. In some embodiments, R2 is selected from C1-C6 alkyl and halogen groups. In some embodiments, R2 is selected from C1-C6 alkyl groups. In some embodiments, R2 is selected from halogen groups.

[0111] When R2 is a C1-C6 alkyl, R2 can more particularly be a C1-C4 alkyl or a C1-C3 alkyl. In some embodiments, when R2 is a C1-C6 alkyl, R2 is more particularly methyl. In some of these embodiments, any such alkyl group is halogenated; for example, R2 is selected from methyl and trifluoromethyl.

[0112] When R2 is a C1-C6 alkoxy, R2 may more particularly be a C1-C4 alkoxy or a C1-C3 alkoxy. In some embodiments, when R2 is a C1-C6 alkoxy, R2 may more particularly be a methoxy.

[0113] When R2 is a halogen, such halogen can be selected from, for example, F, Cl, and Br. In some embodiments, any such halogen is selected from F and Cl. In some embodiments, any such halogen is selected from Cl and Br. In some embodiments, any such halogen is Cl. In some embodiments, any such halogen is Br.

[0114] In some embodiments, R2 is selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy, hydroxy, F, Cl, and Br.

[0115] As mentioned herein, any alkyl group (including as part of an additional portion such as an alkoxy group) may optionally be substituted with one or more halogens, such as one or more halogens selected from F and Cl, particularly F. In some embodiments, any mentioned methyl or methoxy group also includes a corresponding halogen group, such as a trifluoro group.

[0116] In some embodiments, R1 is selected from C1-C3 alkyl, C1-C3 alkoxy, hydroxy, and halogen; and each R 1a It is independently selected from C1-C3 alkyl groups and halogens.

[0117] In some embodiments, R1 is selected from C1-C3 alkyl groups and halogens; and each R 1a It is independently selected from C1-C3 alkyl groups and halogens.

[0118] In some implementations, R1 is selected from halogens; and each R 1a It is independently selected from halogens.

[0119] In some implementations, R1 is Br; and each R 1a It is Cl.

[0120] In some embodiments, R1 is selected from C1-C3 alkyl, C1-C3 alkoxy, hydroxy, and halogen; each R 1a R2 is independently selected from C1-C3 alkyl and halogen; and R2 is selected from C1-C3 alkyl, C1-C6 alkoxy, halogen and hydroxyl.

[0121] In some embodiments, R1 is selected from C1-C3 alkyl groups and halogens; each R 1a R2 is independently selected from C1-C3 alkyl and halogen; and R2 is selected from C1-C3 alkyl, halogen and hydroxyl.

[0122] In some implementations, R1 is selected from halogens; each R 1a R2 is independently selected from halogens; and R2 is selected from C1-C3 alkyl groups.

[0123] In some implementations, R1 is Br; each R 1a It is Cl; and R2 is a methyl group.

[0124] In the compounds of formula (I), each of R3, R4, R5, and R6 is independently selected from H and F. In some embodiments, at least two of R3, R4, R5, and R6 are H. In some embodiments, at least three of R3, R4, R5, and R6 are H. In some embodiments, R3 and R4 are H. In some embodiments, R3, R4, and R5 are H. In some embodiments, R3, R4, R5, and R6 are all H. In some specific embodiments, R3 and R4 are H, and R5 and R6 are F. In some further specific embodiments, R3, R4, and R5 are H, and R6 is F. In still further embodiments, at least one of R3, R4, R5, and R6 is F; for example, at least one of R5 and R6 is F. In still further embodiments, R3 and R4 are H; and R5 and R6 are selected from H and F.

[0125] For example, in some implementations, R1 is Br; each R 1a R1 is Cl; R2 is as defined herein, for example, R2 is methyl; R3 and R4 are H, and R5 and R6 are independently selected from H and F.

[0126] In some embodiments, the compound of formula (I) is selected from any of the compounds shown in Table 1, which may be referred to herein as "compound A-AF".

[0127] Table 1 The compounds shown in Table 1 have been described in WO 2019 / 215291 A1, in which their NOX2 and / or NOX4 inhibitory activities are also disclosed.

[0128] In some embodiments, the compound of formula (I) is 4-bromo-2,6-dichloro-N-[2-(2-methylphenyl)ethyl]benzene-1-sulfonamide (compound J). In some embodiments, the compound of formula (I) is 4-hydroxy-N-[2-(2-hydroxyphenyl)ethyl]-2,6-dimethylbenzenesulfonamide (compound AF). Compound J is a highly selective NOX4 inhibitor, while compound AF is a highly selective NOX2 inhibitor.

[0129] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt as defined herein, which possesses the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or acid addition salts formed with organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheponic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucoconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, and trimethylacetic acid; or salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth metal ion, or aluminum ion; or salts coordinated with an organic or inorganic base. Acceptable organic bases include, for example, diethanolamine, ethanolamine, N-methylglucosamine, triethanolamine, morpholine, and tromethamine. Acceptable inorganic bases include, for example, ammonia, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

[0130] Gel formulations according to the present invention generally comprise a therapeutically effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in a carrier in gel form.

[0131] The topical ophthalmic formulations provided herein are pharmaceutical gel formulations and contain a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof (the compound or salt may be collectively referred to herein as API), the concentration of which is suitable for providing a therapeutically effective amount of the API by topical application (ophthalmic application) of an appropriate volume of the gel, such as 1-5 drops, or 1-3 drops, or 1 drop (or droplet) of gel, to the eye of the subject.

[0132] In some embodiments, the concentration of the API in the formulation is from about 0.1% (w / w) of the formulation (i.e., 100 g of the formulation contains 0.1 g of the compound of formula (I) in the form of a free base or the corresponding amount of its salt) to about 10% (w / w); for example, from about 0.2 to about 10% (w / w), from about 0.5 to about 10% (w / w), from about 1 to about 10% (w / w), from about 2 to about 10% (w / w), or from about 5 to about 10% (w / w).

[0133] In some other embodiments, the concentration of the API in the formulation is in the range of about 0.1% (w / w) to about 5% (w / w) of the formulation; for example, about 0.2% to about 5% (w / w), about 0.5% to about 5% (w / w), about 1% to about 5% (w / w), or about 2% to about 5% (w / w).

[0134] In some other embodiments, the concentration of the API in the formulation is in the range of about 0.1% (w / w) to about 2% (w / w) of the formulation; for example, about 0.2% to about 2% (w / w), about 0.5% to about 2% (w / w), or about 1% to about 2% (w / w).

[0135] In some embodiments, the gel formulations provided herein contain an API as defined herein, in the form of a suspension in a gel carrier. In such embodiments, an advantageous feature of the gel formulations of the present invention is the high homogeneity of the suspension throughout the gel formulation and its high stability against sedimentation over time.

[0136] In some embodiments, the gel formulation of the present invention has a pH in the range of 6.8 to 8.5; a weight molar osmotic pressure concentration in the range of 200 to 600 mOsm / kg H2O; and a dynamic viscosity in the range of 500 to 2000 mPa·s, measured at 100 rpm and 25°C.

[0137] The formulations provided herein have a pH of about 6.8 to about 8.5. In some embodiments, the pH is at most 8.4. For example, in some embodiments, the formulation has a pH of 6.8 to 8.4, 7.0 to 8.4, 7.2 to 8.4, 7.4 to 8.4, or 8.0 to 8.4. In some embodiments, the pH is at most 8.0. For example, in some embodiments, the formulation has a pH of 6.8 to 8.0, 7.0 to 8.0, 7.2 to 8.0, or 7.4 to 8.0. In some other embodiments, the formulation has a pH in the range of 6.8 to 7.8, or 6.8 to 7.6, or 6.8 to 7.4. In some other embodiments, the formulation has a pH in the range of 7.0 to 7.8, or 7.0 to 7.6, or 7.0 to 7.4. In some other embodiments, the formulation has a pH in the range of 7.2 to 7.8, or 7.2 to 7.6, or 7.2 to 7.4. In some implementations, the formulation has a pH of approximately 7.4.

[0138] pH measurement method: pH values ​​were measured using Hanna HI 8424, Mettler Toledo InLab. ® Microelectrode measurement.

[0139] Ideally, pharmaceutical formulations for ocular application should preferably have a weight molar osmolality in the range of 200 to 600 mOsm / kg H2O so as not to cause discomfort when applied to the eye, although values ​​slightly outside this range are tolerable when the dosage applied to the eye is small.

[0140] In some embodiments, the weight molar osmotic pressure concentration of the gel formulation of the present invention ranges from about 200 to about 550 mOsm / kg H2O, about 200 to about 500 mOsm / kg H2O, about 200 to about 450 mOsm / kg H2O, or about 200 to about 400 mOsm / kg H2O or about 200 to about 350 mOsm / kg H2O.

[0141] In some embodiments, the weight molar osmotic pressure concentration of the gel formulation of the present invention ranges from about 300 to about 600 mOsm / kg H2O, about 300 to about 550 mOsm / kg H2O, about 300 to about 500 mOsm / kg H2O, about 300 to about 450 mOsm / kg H2O, about 300 to about 400 mOsm / kg H2O, or about 300 to about 350 mOsm / kg H2O.

[0142] In some embodiments, the weight molar osmotic pressure concentration of the gel formulation of the present invention ranges from about 400 to about 600 mOsm / kg H2O, about 400 to about 550 mOsm / kg H2O, about 400 to about 500 mOsm / kg H2O, or about 400 to about 450 mOsm / kg H2O.

[0143] In some embodiments, the weight molar osmotic pressure concentration of the gel formulation of the present invention ranges from about 450 to about 600 mOsm / kg H2O, about 450 to about 550 mOsm / kg H2O, or about 450 to about 500 mOsm / kg H2O.

[0144] In some embodiments, the weight molar osmotic pressure concentration of the gel formulation of the present invention ranges from about 500 to about 600 mOsm / kg H2O or from about 500 to about 550 mOsm / kg H2O.

[0145] In some embodiments, the weight molar osmotic pressure concentration of the gel formulation of the present invention ranges from about 250 to about 500 mOsm / kg H2O, about 250 to about 450 mOsm / kg H2O, about 250 to about 400 mOsm / kg H2O, about 250 to about 375 mOsm / kg H2O, about 250 to about 350 mOsm / kg H2O, or about 250 to about 325 mOsm / kg H2O.

[0146] In some embodiments, the weight molar osmotic pressure concentration of the gel formulation of the present invention ranges from about 260 to about 375 mOsm / kg H2O, about 270 to about 375 mOsm / kg H2O, about 280 to about 375 mOsm / kg H2O, or about 290 to about 375 mOsm / kg H2O.

[0147] In some embodiments, the weight molar osmotic pressure concentration of the gel formulation of the present invention ranges from about 260 to about 350 mOsm / kg H2O, about 270 to about 350 mOsm / kg H2O, about 280 to about 350 mOsm / kg H2O, or about 290 to about 350 mOsm / kg H2O.

[0148] In some embodiments, the weight molar osmotic pressure concentration of the gel formulation of the present invention ranges from about 260 to about 320 mOsm / kg H2O, about 270 to about 320 mOsm / kg H2O, or about 280 to about 320 mOsm / kg H2O, or about 285 to about 315 mOsm / kg H2O, or about 290 to about 310 mOsm / kg H2O, or about 295 to about 305 mOsm / kg H2O, for example about 300 mOsm / kg H2O.

[0149] It should be noted that some excipients used in the preparation of gel formulations, such as the solubilizers and buffers used, can also act as osmotic (tension) agents. However, if desired, one or more additional tension agents, such as mannitol, sorbitol, glycerol, polyethylene glycol (PEG), polypropylene glycol (PPG), or sorbitol, can be added to the gel formulation in an amount sufficient to adjust the weight molality of the gel formulation to the desired range, although in some embodiments such additional agents are considered not necessary. Those skilled in the art will be able to readily measure and (if necessary) adjust the weight molality of the gel formulation.

[0150] The gravimetric osmolality concentration was measured using a Roebling 13 / 13DR osmometer according to the manufacturer's instructions.

[0151] When measured at 100 rpm at 25°C using the methods described herein, the gel formulations provided herein have a dynamic viscosity in the range of about 500 mPa·s to about 2000 mPa·s. In some embodiments, the viscosity is in the range of about 500 mPa·s to about 1900 mPa·s, about 500 mPa·s to about 1800 mPa·s, about 500 mPa·s to about 1700 mPa·s, about 500 mPa·s to about 1600 mPa·s, about 500 mPa·s to about 1500 mPa·s, about 500 mPa·s to about 1400 mPa·s, about 500 mPa·s to about 1300 mPa·s, or about 500 mPa·s to about 1200 mPa·s.

[0152] In some embodiments, the viscosity is in the range of about 600 mPa.s to about 2000 mPa.s, about 600 mPa.s to about 1900 mPa.s, about 600 mPa.s to about 1800 mPa.s, about 600 mPa.s to about 1700 mPa.s, about 600 mPa.s to about 1600 mPa.s, about 600 mPa.s to about 1500 mPa.s, about 600 mPa.s to about 1400 mPa.s, about 600 mPa.s to about 1300 mPa.s, or about 600 mPa.s to about 1200 mPa.s.

[0153] In some embodiments, the viscosity is in the range of about 700 mPa.s to about 2000 mPa.s, about 700 mPa.s to about 1900 mPa.s, about 700 mPa.s to about 1800 mPa.s, about 700 mPa.s to about 1700 mPa.s, about 700 mPa.s to about 1600 mPa.s, about 700 mPa.s to about 1500 mPa.s, about 700 mPa.s to about 1400 mPa.s, about 700 mPa.s to about 1300 mPa.s, or about 700 mPa.s to about 1200 mPa.s.

[0154] In some embodiments, the viscosity is in the range of about 800 mPa.s to about 2000 mPa.s, about 800 mPa.s to about 1900 mPa.s, about 800 mPa.s to about 1800 mPa.s, about 800 mPa.s to about 1700 mPa.s, about 800 mPa.s to about 1600 mPa.s, about 800 mPa.s to about 1500 mPa.s, about 800 mPa.s to about 1400 mPa.s, about 800 mPa.s to about 1300 mPa.s, or about 800 mPa.s to about 1200 mPa.s.

[0155] In some embodiments, the viscosity is in the range of about 900 mPa.s to about 2000 mPa.s, about 900 mPa.s to about 1900 mPa.s, about 900 mPa.s to about 1800 mPa.s, about 900 mPa.s to about 1700 mPa.s, about 900 mPa.s to about 1600 mPa.s, about 900 mPa.s to about 1500 mPa.s, about 900 mPa.s to about 1400 mPa.s, about 900 mPa.s to about 1300 mPa.s, or about 900 mPa.s to about 1200 mPa.s.

[0156] In some embodiments, the viscosity is in the range of about 1000 mPa.s to about 2000 mPa.s, about 1000 mPa.s to about 1900 mPa.s, about 1000 mPa.s to about 1800 mPa.s, about 1000 mPa.s to about 1700 mPa.s, about 1000 mPa.s to about 1600 mPa.s, about 1000 mPa.s to about 1500 mPa.s, about 1000 mPa.s to about 1400 mPa.s, about 1000 mPa.s to about 1300 mPa.s, or about 1000 mPa.s to about 1200 mPa.s.

[0157] The viscosity was measured as described in this paper. The viscosity was dynamic and was measured at 25°C and 100 rpm using a Brookfield DV-II+ viscometer with barrel / needle SC4-16 / 8R.

[0158] In some embodiments, the gel formulation of the present invention has a pH in the range of 6.8 to 8.5; a weight molar osmotic pressure concentration in the range of 200 to 600 mOsm / kg H2O; and a dynamic viscosity in the range of 500 to 2000 mPa·s, measured at 100 rpm and 25°C.

[0159] In some other embodiments, the gel formulations provided herein have a pH in the range of 6.8 to 7.5, for example 6.8 to 7.4 or 6.8 to 7.2; a weight molar osmotic pressure concentration in the range of 250 to 400 mOsm / kg; and a dynamic viscosity in the range of 500 to 1700 mPa·s.

[0160] In some other embodiments, the gel formulations provided herein have a pH in the range of 6.8 to 7.2; a weight molar osmotic pressure concentration in the range of 250 to 400 mOsm / kg; and a dynamic viscosity in the range of 500 to 1500 mPa·s, for example 600 to 1500 mPa·s, such as in the range of 700 to 1500 mPa·s, for example 800 to 1500 mPa·s.

[0161] In some other embodiments, the gel formulations provided herein have a pH in the range of 6.8 to 7.2; a weight molar osmotic pressure concentration in the range of 250 to 400 mOsm / kg; and a dynamic viscosity in the range of 700 to 1700 mPa·s, for example, 700 to 1500 mPa·s, such as in the range of 700 to 1200 mPa·s, for example, in the range of 700 to 1000 mPa·s, for example, at least 800 mPa·s.

[0162] In some exemplary embodiments, the gel formulations provided herein have a pH in the range of 6.8 to 7.5, for example 6.8 to 7.4 or 6.8 to 7.2; a weight molar osmotic pressure concentration in the range of 250 to 400 mOsm / kg; and a dynamic viscosity in the range of 500 to 1700 mPa·s.

[0163] In some other embodiments, the gel formulations provided herein have a pH in the range of 6.8 to 7.2; a weight molar osmotic pressure concentration in the range of 250 to 400 mOsm / kg; and a dynamic viscosity in the range of 500 to 1500 mPa·s, for example 600 to 1500 mPa·s, such as in the range of 700 to 1500 mPa·s, for example 800 to 1500 mPa·s.

[0164] In some other embodiments, the gel formulations provided herein have a pH in the range of 6.8 to 7.2; a weight molar osmotic pressure concentration in the range of 250 to 400 mOsm / kg; and a dynamic viscosity in the range of 700 to 1700 mPa·s, for example, 700 to 1500 mPa·s, such as in the range of 700 to 1200 mPa·s, for example, in the range of 700 to 1000 mPa·s, for example, at least 800 mPa·s.

[0165] The gel formulations for topical ocular use provided herein comprise compounds of formula (I) as defined above, or pharmaceutically acceptable salts thereof, and one or more excipients.

[0166] Topical ocular gel formulations provided herein typically contain a compound of formula (I) as defined herein, in the form of a solution or suspension in an aqueous gel medium, said solution or suspension comprising one or more pharmaceutically acceptable excipients. Typically, said excipients include one or more solubilizers, one or more buffers, and one or more viscosity modifiers.

[0167] Solubilizing gel formulations typically contain at least one solubilizer for a compound of formula (I) or a pharmaceutically acceptable salt thereof. The at least one solubilizer may be selected, for example, from dimethyl sulfoxide (DMSO) and surfactants, such as nonionic surfactants, for example from Tween. ® Series of surfactants, such as Tween ® 20 (CAS No. 9005-64-5), Tween ® 40 (CAS No. 9005-66-7) or Tween ® 80 (CAS No. 9005-65-6). For example, the surfactant could be Tween. ® 80 (polyoxyethylene (80) dehydrated sorbitan monooleate), also known as polysorbate 80, Kolliphor ® 80, etc. In some embodiments, the gel formulation contains DMSO and nonionic surfactants (such as Tween). ® Surfactants, such as Tween ® At least one of the following (80), optionally combined with one or more other solubilizers, such as cyclodextrin derivatives (e.g., hydroxypropyl-β-cyclodextrin), tetraethylene glycol, ethanol, or polyvinyl alcohol. Optionally, the solubilizer may include oils such as PEG300 or PEG400 (CAS No. 25322-68-3) or silicone oil (CAS No. 63148-62-9).

[0168] In some embodiments, the solubilizer comprises DMSO and polyoxyethylene dehydrated sorbitan monooleate (such as Tween). ®At least one of (80), such as a mixture of DMSO and polyoxyethylene sorbitan monooleate. For example, the solubilizer may comprise a mixture of DMSO and a nonionic surfactant, said mixture containing the two components in a weight ratio of 1:10 to 10:1, such as 1:8 to 8:1, 1:5 to 5:1. In some embodiments, the solubilizer is a mixture containing DMSO and polyoxyethylene sorbitan monooleate in a weight ratio of 1:10 to 1:1, such as 1:10 to 1:2, 1:10 to 1:3, or 1:10 to 1:4. In some embodiments, the solubilizer is a mixture containing DMSO and polyoxyethylene dehydrated sorbitan monooleate, wherein the weight ratio of DMSO to polyoxyethylene dehydrated sorbitan monooleate is 1:8 to 1:1, for example 1:8 to 1:2, or 1:8 to 1:3, or 1:8 to 1:4, for example 1:6 to 1:1, for example 1:6 to 1:2, or 1:6 to 1:3, or 1:6 to 1:4. In some of these embodiments, the nonionic surfactant is polyoxyethylene dehydrated sorbitan monooleate, such as polyoxyethylene (80) dehydrated sorbitan monooleate.

[0169] In some embodiments, the composition comprises a solubilizer (including one or more additional solubilizers) and an API, wherein the weight ratio of the solubilizer to the API is 1:1 to 15:1, or 2:1 to 15:1, or 3:1 to 15:1, or 4:1 to 15:1, or 5:1 to 15:1, or 1:1 to 10:1, or 2:1 to 10:1, or 3:1 to 10:1, or 4:1 to 10:1, or 5:1 to 10:1; or 5:1 to 8:1; or 1:1 to 8:1, or 2:1 to 8:1, or 3:1 to 8:1, or 4:1 to 8:1, or 5:1 to 8:1.

[0170] Viscosity gel formulations typically contain at least one viscosity agent. Suitable viscosities as used herein include those providing gel formulations comprising a compound of formula (I) and having a viscosity (expressed as dynamic viscosity) within the range defined above. Such viscosities may be selected from, for example, various cellulose polymer derivatives, such as hydroxyethyl cellulose (HEC), (hydroxypropyl)methylcellulose, methylcellulose, and carboxymethyl cellulose derivatives, optionally in combination with one or more additional viscosities, such as those selected from polyvinyl alcohol, poly(acrylic) homopolymers or copolymers (carbomer), and polyvinylpyrrolidone. The viscosity agent is preferably a high-viscosity cellulose derivative, such as a high-viscosity carboxymethyl cellulose derivative, for example, high-viscosity sodium carboxymethyl cellulose (CAS No. 9004-32-4), with a viscosity, for example, from 1500 to 3000 mPa·s (in the form of a 1% solution).

[0171] A viscosity agent (the term may refer to a specific viscosity agent or a mixture of such agents) is present in a total amount sufficient to provide the desired viscosity (i.e., viscosity within the range mentioned above) in the formulation. As will be apparent to those skilled in the art, the precise amount will vary depending on the one or more specific viscosity agents selected, and will further depend on other components in the formulation and the concentrations of those other components. Based on this specification and the illustrative examples provided herein, those skilled in the art will be able to determine the required amount of viscosity agent.

[0172] In some embodiments, the gel formulations provided herein contain a viscosity agent, such as high-viscosity carboxymethyl cellulose, in an amount ranging from 0.5% w / w to 5% w / w (based on the total weight of the formulation), for example 1 to 5% w / w, or 1 to 4% w / w, or 1 to 3% w / w, or 1 to 2% w / w, or 1 to 1.5% w / w.

[0173] Buffered gel formulations typically contain at least one pH buffer to maintain the pH of the formulation within the range shown herein.

[0174] For example, phosphate buffer solutions of different pH values ​​are commercially available, such as in tablet form, which can be used to prepare phosphate buffered isotonic saline (PBS) of different concentrations. For example, a 1X PBS solution containing 137 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4 and 1.8 mM KH2PO4 can be diluted 1:2 to prepare 0.5X PBS.

[0175] Furthermore, those skilled in the art will fully understand that a phosphate buffer solution having a pH within the desired range can be prepared by mixing a suitable salt component with deionized water and optionally adjusting the pH with a strong acid (such as HCl) or a strong base (such as NaOH).

[0176] In some implementations, the buffer is a phosphate buffer, such as those mentioned herein.

[0177] The gel formulation may optionally contain one or more additional active ingredients other than the compound of formula (I) or its salts and / or one or more additional excipients other than those mentioned above, such as antioxidants, such as EDTA or similar agents, preservatives, such as benzalkonium chloride or similar agents, humectants, such as glycerin or similar agents, tension modifiers, such as mannitol or similar agents, additional pH modifiers, such as strong acids (such as HCl) or strong bases (such as NaOH), etc.

[0178] In some embodiments, the gel formulations provided herein comprise an API as defined herein, in the form of a suspension in the liquid phase of a gel carrier. In such embodiments, an advantageous feature of the gel formulations of the present invention is the homogeneity and high anti-sedimentation stability of the resulting suspension.

[0179] Another advantage of the gel formulations provided in this article is their typically very high stability against chemical degradation of the APIs in the formulation.

[0180] In some embodiments, the gel formulations provided herein contain a compound of formula (I) or a pharmaceutically acceptable salt thereof in a gel medium, said gel medium comprising a solubilizer (such as DMSO and Tween). ® (80 or a combination of similar nonionic surfactants), high-viscosity carboxymethyl cellulose and phosphate buffered brine.

[0181] In some embodiments, the gel formulations provided herein contain about 1 to 5% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and about 5 to 10% by weight of a solubilizer (such as DMSO and Tween). ® 80 or a combination of similar nonionic surfactants), about 1 to 5% by weight of high-viscosity carboxymethyl cellulose, and phosphate-buffered brine optionally as the only additional component (i.e., constituting about 80 to 93% by weight).

[0182] Another aspect of an eye condition or disease involves a gel formulation comprising a compound of formula (I) as defined herein, which is used to treat an eye condition or disease, i.e., a condition affecting the subject's eye, by applying the gel topically to the eye of a subject.

[0183] In some embodiments, the ocular condition or disease is related to intraocular oxidative stress, for example, driven or exacerbated by intraocular oxidative stress. In some embodiments, the condition is caused or driven by elevated intraocular NOX4 and / or NOX2 activity. In some embodiments, the condition is caused or driven by elevated intraocular NOX4 activity. In some embodiments, the condition is caused or driven by elevated intraocular NOX2 activity.

[0184] Eye conditions (or symptoms or diseases) can be selected from, for example, AMD, glaucoma, retinopathy, retinal ischemia-reperfusion injury, cataracts, corneal diseases and conditions, bullous keratopathy, corneal abrasion, herpetic ophthalmopathy, iridocorneal endothelial syndrome, keratoconjunctivitis and pterygium.

[0185] In some implementations, an eye condition is the result of eye injury or trauma such as alkali or acid burns or any other form of injury (cuts or other force-induced damage).

[0186] In some implementations, the ocular condition is ocular neovascularization, such as corneal or retinal neovascularization.

[0187] In some implementations, the ocular condition is corneal neovascularization, such as due to, for example, contact lens wear, ocular surface disease, previous ocular surgery, ocular trauma, ocular acid burns, ocular alkali burns, or herpes infection.

[0188] In some implementations, the ocular condition is scarring, for example, due to injury or trauma to the eye, such as burns from alkali or acid or any other form of injury (cuts or other force-induced damage).

[0189] Therefore, in some implementations, treatment is a preventative measure taken after, for example, alkali burns or other injuries to the eye, to avoid or reduce intraocular neovascularization and / or scarring.

[0190] In some implementations, ocular conditions are selected from AMD, glaucoma, retinopathy, retinal ischemia-reperfusion injury, cataracts (including postoperative capsular opacity), and corneal diseases and conditions.

[0191] In some embodiments, the ocular condition is AMD. In some embodiments, the ocular condition is glaucoma. In some embodiments, the ocular condition is retinopathy. In some embodiments, the ocular condition is retinal ischemia-reperfusion injury. In some embodiments, the ocular condition is cataract (including postoperative capsular opacity). In some embodiments, the ocular condition is corneal disease or condition. In some embodiments, the condition is an inflammatory ocular disease, such as chronic inflammation of the eye. In some embodiments, the condition is a hypertensive ophthalmopathy, such as hypertensive retinopathy.

[0192] AMD can be dry AMD or wet AMD. In some implementations, AMD is dry AMD. In some implementations, AMD is wet AMD.

[0193] Glaucoma can be either open-angle glaucoma or angle-closure glaucoma. In some implementations, the glaucoma is open-angle glaucoma.

[0194] Retinopathy can be, for example, retinopathy of prematurity, hypertensive retinopathy, central serous retinopathy, or diabetic retinopathy. In some embodiments, the retinopathy is hypertensive retinopathy or diabetic retinopathy. In some embodiments, the retinopathy is hypertensive retinopathy. In some embodiments, the retinopathy is diabetic retinopathy.

[0195] Cataracts can be, for example, nuclear cataracts, cortical cataracts, posterior subcapsular cataracts, or congenital cataracts. In some embodiments, the cataract is a nuclear cataract, cortical cataract, or posterior subcapsular cataract. In some embodiments, the cataract is a nuclear cataract or a cortical cataract. In some embodiments, the cataract is a nuclear cataract. In some embodiments, the cataract is a cortical cataract.

[0196] Cataracts can also develop as a secondary condition in patients with glaucoma or diabetes, and in some implementations, the patients being treated are those with glaucoma and / or diabetes. In some other implementations, cataracts are restocytosis of the lens after cataract surgery.

[0197] Corneal diseases or conditions can be, for example, keratitis (infectious or non-infectious), corneal ectasia such as keratoconus, and corneal dystrophy such as Fuchs' dystrophy, epithelial basement membrane dystrophy, lattice keratoconus, and granular keratoconus. In some embodiments, the corneal disease or condition is selected from keratitis and corneal dystrophy. In some embodiments, the corneal disease is keratitis. In some embodiments, the keratitis is non-infectious. In some embodiments, the corneal disease is corneal dystrophy. In some embodiments, the corneal dystrophy is Fuchs' dystrophy. In some embodiments, the corneal disease is corneal ectasia. In some embodiments, the corneal ectasia is keratoconus.

[0198] The use of the gel formulation herein involves the topical application of the gel formulation provided herein to the eye of a subject, for example, from a dosing container that allows small volumes of the formulation to be applied to the eye, to allow, for example, 1-10 drops (or droplets) (having droplet / droplet volumes of 10-100 μl, or 10-50 μl, or 10-40 μl, such as 20-40 μl) to be applied to the eye. In some embodiments, the formulation is administered from a single-dose container or a single-use container. In some embodiments, the formulation is administered from a multi-dose container.

[0199] The therapeutically effective dose of an API can be in the range of 0.05-4.0 mg per administration (or a pharmaceutically acceptable salt equivalent to the API). In some embodiments, the therapeutically effective dose of an API is 0.05-2.0 mg per administration. In some embodiments, the therapeutically effective dose of an API is about 0.05 mg per administration. In some embodiments, the therapeutically effective dose of an API is about 0.1 mg per administration. In some embodiments, the therapeutically effective dose is about 0.5 mg per administration. In some embodiments, the therapeutically effective dose of an API is at least 0.05 mg / day.

[0200] Preferably, the formulation provided herein is applied periodically 1-6 times daily, for example, 1-5 times daily, 1-3 times daily, or 1-2 times daily. In some embodiments, the periodic application is once daily. In some embodiments, the periodic application is twice daily. In some embodiments, the periodic application is three times daily. In some embodiments, the periodic application is once every two days. In some embodiments, the formulation is applied once weekly.

[0201] In some embodiments, the formulation is administered once daily for a period of 2 to 14 days, or for a longer period, such as 1 to 6 months, 2 to 6 months, or 3 to 6 months, for example, up to 12 months, up to 2 years, up to 5 years, or even up to 10 years or longer. In some embodiments, the formulation is administered once daily for a period of 3 days. In some embodiments, the formulation is administered once daily for a period of 5 to 14 days. In some embodiments, the formulation is administered once daily for a period of 10 to 14 days. In some embodiments, the formulation is administered once daily for approximately 7 days. In some embodiments, the formulation is administered for a period of 1 to 12 months, or 1 to 6 months, or 1 to 3 months, for example, once weekly for a period of 3 to 6 months. However, the precise dosage regimen and length of treatment are usually determined by the treating physician.

[0202] Another aspect is a dosing container that holds a gel formulation as provided herein. The dosing container may include, for example, an integral device to allow the appropriate dose of the formulation to be administered to a patient's eye, or such a device may be provided separately. In some embodiments, the dosing container is a multi-dose container that allows the appropriate dose of the formulation to be administered to a patient's eye. For example, in some embodiments, the dosing container is a bottle of the type sold by Nemera. In some embodiments, the dosing container is Novelia. ® PFMD bottles or similar types of bottles. In some of these embodiments, the formulations provided herein are preservative-free.

[0203] Another aspect is a kit (which may also be referred to as a component kit) that includes a dosage container and instructions for use as disclosed herein. In some embodiments, such a kit may also include one or more additional containers that contain additional instruments or materials for administration in conjunction with the formulation, such as rinsing solutions, wipes, separate dosing devices, etc.

[0204] The ocular formulations disclosed herein may be used to treat ocular diseases as mentioned herein, such as ocular diseases related to NOX4 and / or NOX2 activity. Examples

[0205] The invention is illustrated by the following non-limiting examples. Biological test results are shown in Figures 1-23, with significance as follows: * p < 0.05; ** p < 0.01; *** p < 0.001, compared to control tissues; # p < 0.05; ## p < 0.01; ### p < 0.001, compared to AMPA or untreated diabetic tissues.

[0206] Example 1: A gel formulation (50 g) having the composition shown in Table 2 was prepared.

[0207] Table 2 Add one (1) PBS tablet to 400 ml of distilled water and mix with a stirrer until the tablet is completely dissolved to obtain a 0.5X PBS solution (containing 68.5 mM NaCl, 1.35 mM KCl, 5 mM Na2HPO4 and 0.9 mM KH2PO4).

[0208] Individually, API (4-bromo-2,6-dichloro-N-[2-(2-methylphenyl)ethyl]benzene-1-sulfonamide, compound J) (500 mg) in powder form was mixed with 500 μl DMSO and stirred until a colorless solution was obtained. Tween® 80 (2.5 ml) was added to the solution, and the solution was stirred for an additional 10 minutes. PBS 0.5X (40 ml) was added, and the mixture was stirred until completely homogenized. CMC HV (600 mg) was slowly added to the homogenous suspension (without visible particles), and the mixture was stirred for 10–15 minutes until completely homogenized. Finally, a sufficient volume of PBS 0.5X was added to bring the total weight of the solution to 50 g, and the mixture was stirred at room temperature (RT) for approximately 2.5–3 h until a homogenous white gel was obtained. pH, wt. molality, dynamic viscosity, and amount of API (in % of theoretical values) were determined on the day of gel preparation (day 0) and after 7 and 32 days of storage of the gel formulation, respectively, at 5 ± 3 °C and 20 ± 5 °C (RT). The results are reported in Table 3.

[0209] Table 3 The concentration of API was determined by reversed-phase LC-UV using an Agilent Eclipse 3.5 µm × 2.1 × 50 mm column under the following conditions: flow rate: 0.9 ml / min, column temperature: 25 °C, stop time: 4 min, mean pressure: 1.2 × 10⁻⁶. 4 kPa (minimum 0 kPa, maximum 4 × 10) 4The test conditions were: kPa, rack temperature: 20°C, injection volume: 10 μl, and mobile phase: A. 0.05% trifluoroacetic acid (aqueous solution), B. acetonitrile / trifluoroacetic acid (99.95 / 0.05), (A:B 50:50). For injection, 1 g of the gel formulation was diluted in 20 ml of a 50:50 mixture of A and B and mixed for 45 minutes, then 1 ml of the mixture was further diluted in 10 ml of a 50:50 mixture of A and B. UV detection was performed at 254 nm. Analytical results showed that the gel formulation was stable for at least 32 days at both 5 ± 3°C and room temperature, and the measurements of the parameters wt. molality and dynamic viscosity remained acceptable throughout the test period. No API precipitation was observed throughout the test period.

[0210] In some embodiments, the gel formulations provided herein contain a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the form of a suspension in a gel carrier. In such embodiments, an advantageous feature of the gel formulations of the present invention is the homogeneity and high anti-sedimentation stability of the resulting suspension.

[0211] Example 2 uses the ingredients listed in Table 4 to prepare a gel formulation (50 g).

[0212] Table 4. Component Amounts: Compound J (Active Pharmaceutical Ingredient, API) 1 g, Dimethyl Sulfoxide (DMSO) 0.5 ml, Tween ® 802.5 ml of high-viscosity carboxymethyl cellulose (CMC HV) 0.5 g of phosphate-buffered saline 0.5X solution (PBS 0.5X), pH 7.4, to a final volume of 50 g. The API and DMSO were mixed and magnetically stirred for 15 minutes to obtain a colorless solution. The Tween... ® 80 mg of PBS solution was added to the solution, followed by magnetic stirring for 10 minutes to obtain an oily, pale yellow solution. PBS solution (approximately 80% of the final volume) was added, and the mixture was further magnetically stirred for 10 minutes to obtain a white, oily suspension with no visible particles. CMC HV was mixed with the solution under magnetic stirring for 15 minutes to obtain a white, oily gel. The remaining PBS solution was added to the gel, and the mixture was magnetically stirred for 1 hour. A white, oily gel with no visible particles was obtained, with a pH of 7.09, a weight molality of 348 mOsm / kg H₂O, and a dynamic viscosity of 588.8 mPa·s (at 25°C and 100 rpm).

[0213] Example 3 uses the ingredients listed in Table 5 to prepare a gel formulation (50 g).

[0214] Table 5. Component Amounts: Compound J (Active Pharmaceutical Ingredient, API) 0.5 g, Dimethyl Sulfoxide (DMSO) 0.6 ml, Tween ® 802.5 ml of high-viscosity carboxymethyl cellulose (CMC HV) 0.5 g of phosphate-buffered saline 0.5X solution (PBS 0.5X), pH 7.4, to a final volume of 50 g. The procedure was the same as in Example 2, except that the final stirring step was performed for 3 hours. A white, oily gel with no visible particles was obtained, with a pH of 7.07, a weight molality of 355 mOsm / kg H2O, and a dynamic viscosity of 998.4 mPa·s (at 25°C and 100 rpm).

[0215] Example 4: New Zealand White (albino) rabbits (approximately 2-3 months old, weighing 2.0-2.5 kg (18 males)) were obtained from "Charles River," Granja San Bernardo SL, Spain. All animals were ear-tagged upon arrival and the identification number was also marked in the ear with indelible ink after inclusion examination. Animals were observed for 7 days after arrival, with daily observation for signs of disease, paying particular attention to their eyes. Animals were housed individually or in pairs in standard cages. All animals were housed under identical environmental conditions at 18 ± 3°C, 45-80% relative humidity, and continuous ventilation. Animals were continuously exposed (in cages) to 10-200 lx of light during a 12-hour light cycle (7:00 AM to 7:00 PM) and a dark control cycle. Throughout the study, animals had free access to food (approximately 90 g / day) and water.

[0216] On the day of the experiment, 15 animals were selected based on good health and uniform weight (mean weight ± 20%) and the absence of visible ocular defects. Animals were randomly assigned to the study group based on weight. At time point t = 0 h, a single drop (50 μl) of the gel formulation of Example 1 was instilled into each eye of the animal, and at the time points shown in Table 6, the animals were euthanized by intravenous injection of an overdose of pentobarbital after sedation.

[0217] Table 6. Animal identification time points: 1, 2, 30.5 h ± 3 min; 4, 5, 61 h ± 6 min; 7, 8, 92 h ± 12 min; 10, 11, 124 h ± 24 min; 13, 14, 158 h ± 48 min. Immediately after euthanasia, aqueous humor and retina were collected from both eyes, weighed, and an internal standard (4-bromo-2,6-dichloro-N-[2-(2-hydroxyphenyl)ethyl]benzenesulfonamide, compound Z) was added to the sample. The sample was vortexed for 10 seconds, frozen, and stored at -80℃±15℃ until measurement.

[0218] HALO was used to perform rapid separation liquid chromatography / tandem mass spectrometry (RRLC-MS / MS). ® A 2.7 µm C8 column (2.1 mm inner diameter, 100 mm length) was used to determine the API content in aqueous humor and retinal samples under the following conditions: flow rate: 0.2 ml / min, column temperature: 20 °C, stop time: 9 min, mean pressure: 1.28 × 10⁻⁶. 4 kPa (minimum 10) 3 kPa, maximum value 4×10 4 The system was set at kPa, with a rack temperature of 20°C and an injection volume of 10 µl, and gradient elution was performed (mobile phase: A. formic acid 0.1 (aqueous solution), B. acetonitrile, A:B 10:90 to 50:50). Detection was performed using an Agilent G6410B Triple Quadrupole system, with parameters shown in Table 7.

[0219] Table 7 Ionization Mode ESI Positive ΔEMV0 Dry Gas Temperature (°C) 300 Dry Gas Flow Rate (L / min) 11 Sprayer Pressure (kPa) 172 Capillary Voltage (V) 4000 The table uses the average data for each treatment group for C. max (The highest average value measured (ng / g retina or ng / g aqueous humor) and T) max The calculation of the time point of the highest average value is shown in Table 8.

[0220] Table 8. API (ng / g) in Aqueous Humidity and API (ng / g) in Retina at Time Points: 0.5 h ± 3 min 236 156 11 h ± 6 min 946 79 2 h ± 12 min 703 88 4 h ± 24 min 451 85 8 h ± 48 min 131 14 The table quantifies the API levels in aqueous humor up to 8 hours after administration. At this time point, 3 out of 6 values ​​remained above the lower limit of quantification (LLOQ), 5 ng / g aqueous humor. The observed T... max The corresponding C is 0.50 h. maxThe value was 236 ng / g aqueous humor. In one (1) of the 30 eyes, the measured value was above the upper limit of quantification (ULOQ), 523 ng / g aqueous humor, i.e., 4315 ng / g at time point 0.5 h. This value was considered atypical and was not included in the calculation.

[0221] In the retina, API levels remained higher than LLOQ (17 ng / g retina) in all samples 8 h post-dose. T was observed at 0.50 h. max The corresponding C max The measured value was 1561 ng / g retina. For 3 out of 30 eyes, the measured value was higher than ULOQ (1709 ng / g retina), but relatively close to the ULOQ value, therefore extrapolation was performed. The observed T... max The corresponding C is 0.50 h. max The concentration was 915 ng / g of aqueous humor.

[0222] Example 5 followed essentially the experimental protocol described in Dionsopoulou, 2023. Briefly, diabetes-induced retinal changes in rats were obtained by administration of streptozotocin (STZ). Starting 48 hours after STZ administration, the gel formulation of Example 1 was topically applied (20 μl) to rats once daily for 14 days. Control animals and untreated diabetic animals received 20 μl of a similar gel formulation (except that it did not contain API). The results of Example 5 were compared with those of a similar test performed using DMSO as a medium for API (10 mg / ml).

[0223] In both series of tests, tissues were collected 24 hours after the last day of treatment and further processed for immunohistochemical studies or ELISA analysis. Immunohistochemical studies involved the use of antibodies against brain nitric oxide synthase (bNOS), neurofilaments (NFL), cleaving caspase-3, glial fibrillary acidic protein (GFAP), and ionized calcium-binding adaptor molecule 1 (Iba-1). Additionally, ELISA analysis was performed to determine the protein levels of TNF-α and VEGF in the rat retina. The results obtained in Example 5 and the corresponding tests using DMSO mediators are shown in Figures 1-14.

[0224] The results showed that when the API was applied topically to the eyes of rats via the gel according to the invention or as a solution in DMSO, it was able to limit diabetes-induced oxidative damage, apoptosis, loss of retinal ganglion cell axons, activation of macroglia / microglia, and expression of the pro-inflammatory cytokine TNF-α (Figures 1-12). The API also reduced the loss of amacrine cells, which was surprising, as previously published studies have shown that NOX4 inhibition has no effect on amacrine cells in the retina (Dionsopoulou, 2020). The protective effect on amacrine cells was improved when the API was applied as a gel formulation (Figure 1) compared to application as a DMSO solution (Figure 2). Furthermore, the results showed that the API had a substantial effect on reducing VEGF expression when applied using the gel formulation of the invention (Figure 13), while the effect of the DMSO formulation was negligible (Figure 14). This difference is surprising and significant, especially since VEGF has recently been identified as a major initiator of proliferative diabetic retinopathy and a potential mediator of non-proliferative retinopathy (Aiello, 2000).

[0225] Example 6: A gel formulation (50 g) having the composition shown in Table 9 was prepared.

[0226] Table 9. Component Amounts: Compound AF (Active Pharmaceutical Ingredient, API) 0.5 g, Dimethyl Sulfoxide (DMSO) 0.5 ml, Tween ® Add 802.5 ml of high-viscosity carboxymethyl cellulose (CMC HV) 0.6 g of phosphate-buffered saline 0.5X solution (PBS 0.5X) to a final volume of 50 g. The gel formulation was prepared essentially as described in Example 1, but compound J was replaced with 4-hydroxy-N-[2-(2-hydroxyphenyl)ethyl]-2,6-dimethylbenzenesulfonamide (compound AF).

[0227] Example 7 used an in vivo model of diabetic retinopathy as described by Dionysopoulou (2020) by intravitreal injection of (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate hydrobromide (AMPA), with or without 4-hydroxy-N-[2-(2-hydroxyphenyl)ethyl]-2,6-dimethylbenzenesulfonamide (compound AF). At the end of the 24-hour test period, the animals were euthanized, and retinal tissue was collected for immunohistochemical studies (brain nitric oxide synthase (bNOS), glial fibrillary acidic protein (GFAP), and ionized calcium-binding linker molecule-1 (Iba-1)). Quantification was performed using a two-tailed unpaired t-test or one-way ANOVA followed by a Newman-Keuls post-hoc test. The results showed that compound AF protected bNOS-positive adenoid cells from AMPA-induced excitotoxicity (Fig. 15) and reversed AMPA-induced overactivation of both macroglia (Fig. 16) and microglia (Fig. 17).

[0228] Example 8 used an in vivo model of diabetic retinopathy as described by Dionysopoulou (2020) in adult Sprague-Dawley rats, administered streptozotocin intravitreally, followed by topical ocular administration (as eye drops) of a DMSO solution of compound AF (10 mg / ml, 20 μL / eye) for 14 days. At the end of the 14-day test period, the animals were euthanized, and retinal tissue was collected for immunohistochemical studies (bNOS, GFAP, Iba-1) and Western blot analysis. Quantification was performed using a two-tailed unpaired t-test or one-way ANOVA, followed by a Newman-Keuls post-hoc test.

[0229] The results showed that compound AF did not provide protection against diabetic damage to ganglion axons (Fig. 18), but limited the loss of diabetic-induced bNOS-positive amygdalae (Fig. 19), caused upregulation of Bcl-2 protein in the retina during diabetic treatment (Fig. 20), and reduced diabetic-induced macroglia activation (Fig. 21) and microglia activation (Fig. 22), respectively.

[0230] Example 9 repeats the procedure described in Example 8, but instead of DMSO solution, uses the formulation of Example 6 for daily topical ocular application (as 20 μl eye drops).

[0231] Example 10 uses the gel formulation of Example 1 in a rabbit model of blood-retinal barrier disruption caused by VEGF-induced vascular leakage. The gel formulation is applied topically (instilled) into the rabbit eye, and, for comparative purposes, the glucocorticoid Kenacort is administered via intravitreal injection. ® Retard or the fusion protein aflibercept (Eylea) ® Kenacort ® Retard is a general anti-inflammatory agent that combines the functions of several drugs that reduce inflammatory responses, while Eylea ® Binds to circulating VEGF like a VEGF scavenger. Kenacort ® Retard and Eylea ® Clinically, they are used to treat diabetic retinopathy.

[0232] Throughout the procedure, prior to intravitreal administration, induction, fluorescence spectrophotometry, or euthanasia, Rompun is administered via intramuscular injection. ® (xylazine) and Imalgene ® Anesthesia was administered to the animals using a mixture of ketamine. Local anesthesia was achieved by instilling a single drop of 0.4% oxybuprocaine solution onto the cornea prior to intravitreal administration, induction, or fluorescein measurement. The pupil was dilated by instilling a single drop of 0.5% tropicamide and 10% phenylephrine prior to intravitreal administration, induction, or fluorescein measurement.

[0233] Animals accepted the gel formulations of the present invention as outlined in Table 10 (specifically, Example 1, the corresponding API-free gel formulation, Kenacort). ® Retard and Eylea ® Treatment performed.

[0234] Table 10 On day 0, 500 ng rhVEGF165, along with the carrier protein (diluted in PBS), was injected intravitreally into the right eye in a single 50 μl injection to induce increased retinal vascular permeability in all groups. Injections were performed on anesthetized animals using a microscope.

[0235] On day 2, sodium fluorescein (10%, 50 mg / kg in 0.9% saline solution) was injected into the test animals via the marginal ear vein. Following the injection of fluorescein, the animals were anesthetized and their pupils dilated. FM-2 Fluorotron was used. TMThe Master ocular fluorescein spectrophotometer was used to measure ocular fluorescence in both eyes. A series of 148 scans with a step size of 0.25 mm were recorded along the optical axis from the cornea to the retina. The results are shown in Figure 23.

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Claims

1. A gel formulation for topical use in the eye, said gel formulation comprising a compound of formula (I). Or a pharmaceutically acceptable salt thereof, wherein R1 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, hydroxyl and halogen; each R 1a R1 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, hydroxyl and halogen; R2 is selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl and hydroxy-C1-C3 alkyl; R3, R4, R5 and R6 are independently selected from H and F; and any alkyl group is optionally substituted with one or more halogens.

2. The gel formulation according to claim 1, wherein R1 is selected from C1-C3 alkyl, C1-C3 alkoxy, hydroxyl, and halogen; each R 1a R1 is independently selected from C1-C3 alkyl and halogen; R2 is selected from C1-C3 alkyl, halogen and hydroxyl; R3, R4, R5 and R6 are independently selected from H and F; and any alkyl group is optionally substituted with one or more fluorine molecules.

3. The gel formulation according to claim 1, wherein the compound of formula (I) is selected from: N-[2-(2-methoxyphenyl)ethyl]-2,4,6-trimethylbenzene-1-sulfonamide; N-[2-(2-fluorophenyl)ethyl]-2,4,6-trimethylbenzene-1-sulfonamide; 4-bromo-2,6-dichloro-N-[2-(2-methoxyphenyl)ethyl]benzene-1-sulfonamide; 4-bromo-2,6-dichloro-N-[2-(2-fluorophenyl)ethyl]benzene-1-sulfonamide; N-[2-(2-chlorophenyl)ethyl]-2,4,6-trimethylbenzene-1-sulfonamide; N-[2-(2-bromophenyl)ethyl]-2,4,6-trimethylbenzene-1-sulfonamide; 2,4,6- Trimethyl-N-{2-[2-(trifluoromethyl)phenyl]ethyl}benzene-1-sulfonamide; 2,4,6-trimethyl-N-[2-(2-methylphenyl)ethyl]benzene-1-sulfonamide; 2,4,6-trimethyl-N-{2-[2-(trifluoromethoxy)phenyl]ethyl}benzene-1-sulfonamide; 4-bromo-2,6-dichloro-N-[2-(2-methylphenyl)ethyl]benzene-1-sulfonamide; 4-bromo-2,6-dichloro-N-{2-[2-(trifluoromethyl)phenyl]ethyl}benzene-1-sulfonamide; 4-bromo-2,6-dichloro-N-[2-(2-chlorophenyl)ethyl]benzene-1-sulfonamide; 2,6-dichloro-4-cyclopropyl-N-[2-(2-fluorophenyl)ethyl]benzene- 1-Sulfanamide; 2,6-Dichloro-N-[2-(2-chlorophenyl)ethyl]-4-cyclopropylbenzene-1-sulfonamide; 2,6-Dichloro-N-[2-(2-chlorophenyl)ethyl]-4-(trifluoromethyl)benzene-1-sulfonamide; N-[2,2-difluoro-2-(2-methylphenyl)ethyl]-2,4,6-trimethylbenzene-1-sulfonamide; 4-Bromo-2,6-dichloro-N-[2,2-difluoro-2-(2-methylphenyl)ethyl]benzene-1-sulfonamide; N-[2-(2-chlorophenyl)-2,2-difluoroethyl]-2,4,6-trimethylbenzene-1-sulfonamide; 4-Bromo-2,6-dichloro-N-[2-(2-chlorophenyl)-2,2-difluoroethyl]benzene-1-sulfonamide Amides; N-[2-(2-chlorophenyl)ethyl]-2,6-dimethyl-4-(prop-2-yl)benzene-1-sulfonamide; 2,6-dimethyl-N-[2-(2-methylphenyl)ethyl]-4-(prop-2-yl)benzene-1-sulfonamide; N-[2-fluoro-2-(2-methylphenyl)ethyl]-2,4,6-trimethylbenzene-1-sulfonamide; 4-bromo-2,6-dichloro-N-[2-fluoro-2-(2-methylphenyl)ethyl]benzene-1-sulfonamide; N-[2-fluoro-2-(2-methylphenyl)ethyl]-2,6-dimethyl-4-(prop-2-yl)benzene-1-sulfonamide; N-[2-(2-hydroxyphenyl)ethyl]-2,4,6-trimethylbenzene-1-sulfonamide;4-Bromo-2,6-dichloro-N-[2-(2-hydroxyphenyl)ethyl]benzenesulfonamide; 2,6-dichloro-N-[2-(2-hydroxyphenyl)ethyl]-4-(trifluoromethyl)benzenesulfonamide; 2,4-dichloro-6-hydroxy-N-[2-(2-hydroxyphenyl)ethyl]benzenesulfonamide; 2,4-dichloro-6-hydroxy-N-[2-(o-tolyl)ethyl]benzenesulfonamide; N-[2-(2-chlorophenyl)ethyl]-4-methoxy-2,6-dimethylbenzenesulfonamide; N-[2-(2-hydroxyphenyl)ethyl]-4-methoxy-2,6-dimethylbenzenesulfonamide; and 4-hydroxy-N-[2-(2-hydroxyphenyl)ethyl]-2,6-dimethylbenzenesulfonamide.

4. The gel formulation according to claim 3, wherein the compound of formula (I) is 4-bromo-2,6-dichloro-N-[2-(2-methylphenyl)ethyl]benzene-1-sulfonamide.

5. The gel formulation according to any one of claims 1 to 4, wherein the gel formulation has a pH in the range of 6.8 to 8.0, a weight molar osmotic pressure concentration in the range of 200 to 600 mOsm / kg H2O, and a dynamic viscosity in the range of 500 to 2000 mPa·s measured at 100 rpm and 25°C.

6. The gel formulation according to claim 5, wherein the pH is in the range of 6.8 to 7.5, the weight molar osmotic pressure concentration is in the range of 250 to 400 mOsm / kg H2O, and / or the dynamic viscosity is in the range of 700 to 1700 mPa·s.

7. The gel formulation according to any one of claims 1 to 6, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present at a concentration of 0.1 to 5% by weight of the formulation.

8. The gel formulation according to any one of claims 1 to 7, wherein the gel formulation comprises a solubilizer, a buffer, and a viscosity agent.

9. The gel formulation of claim 8, wherein the solubilizer comprises dimethyl sulfoxide and a nonionic surfactant, the buffer is a phosphate-buffered saline solution, and / or the viscosity agent is a cellulose derivative.

10. The gel formulation according to claim 9, wherein the nonionic surfactant is polyoxyethylene sorbitan monooleate.

11. The gel formulation according to any one of claims 8 to 10, wherein the viscosity agent is carboxymethyl cellulose.

12. The gel formulation according to any one of claims 1 to 11, for the prevention or treatment of ocular diseases in mammalian patients.

13. The gel formulation for the stated purpose according to claim 12, wherein the ocular condition is selected from age-related macular degeneration, glaucoma, retinopathy, retinal ischemia-reperfusion injury, cataract, corneal disease, bullous keratopathy, corneal abrasion, corneal alkali or acid burns, corneal neovascularization, herpetic ophthalmopathy, iridocorneal endothelial syndrome, keratoconjunctivitis, pterygium, and ophthalmitis.

14. The gel formulation for the said use according to claim 12 or 13, wherein the treatment comprises periodically applying the gel dropwise into the eye of the mammalian patient.

15. A dosing container for topical ocular application, the dosing container containing a gel formulation according to any one of claims 1 to 14.

16. Use of the gel formulation according to any one of claims 1 to 14 for the manufacture of a medicament for the prevention or treatment of ocular diseases in mammalian patients.

17. The use according to claim 16, wherein the ocular condition is selected from age-related macular degeneration, glaucoma, retinopathy, retinal ischemia-reperfusion injury, cataract, corneal disease, bullous keratopathy, corneal abrasion, corneal alkali or acid burns, corneal neovascularization, herpetic ophthalmopathy, iridocorneal endothelial syndrome, keratoconjunctivitis, pterygium, and ophthalmitis.

18. A method for preventing or treating an eye condition, the method being carried out by administering a therapeutically effective amount of the gel formulation according to any one of claims 1 to 14 to a mammal in need of such prevention or treatment.

19. The method of claim 18, wherein the ocular condition is selected from age-related macular degeneration, glaucoma, retinopathy, retinal ischemia-reperfusion injury, cataract, corneal disease, bullous keratopathy, corneal abrasion, corneal alkali or acid burns, corneal neovascularization, herpetic ophthalmopathy, iridocorneal endothelial syndrome, keratoconjunctivitis, pterygium, and ophthalmitis.

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