Use of caspase inhibitor

Abstract

One aspect of the present invention relates to a pharmaceutical composition for preventing or treating angiogenesis-related ocular diseases, comprising a caspase inhibitor or pharmaceutically acceptable salts thereof. The pharmaceutical composition has an excellent effect of inhibiting apoptosis and inflammatory activity, and exhibits an angiogenesis-inhibitory effect, and thus can be used for the prevention or treatment of angiogenesis-related ocular diseases.

Description

Uses of caspase inhibitors The present invention relates to a method for preventing or treating angiogenesis-related ocular disease using a caspase inhibitor or a pharmaceutically acceptable salt thereof, a pharmaceutical composition for preventing or treating angiogenesis-related ocular disease comprising the caspase inhibitor or a pharmaceutically acceptable salt thereof, a kit comprising the caspase inhibitor or a pharmaceutically acceptable salt thereof or the pharmaceutical composition, and a use of the caspase inhibitor or a pharmaceutically acceptable salt thereof for manufacturing a medicament for preventing or treating angiogenesis-related ocular disease. The caspase inhibitor may be a pan-caspase inhibitor or a caspase-1 inhibitor. Angiogenesis is a condition in which new blood vessels are abnormally created, and angiogenesis, especially in the macula area of the eye, can cause a disease called macular degeneration, which can lead to vision loss. Macular degeneration (AMD) is a chronic eye disease that causes degeneration of the macula. It is the leading cause of blindness in people over 60, and its prevalence is increasing significantly. Meanwhile, macular degeneration is classified into dry macular degeneration and wet macular degeneration, and generally starts from dry (non-exudative) macular degeneration and progresses to wet (exudative) macular degeneration. Dry macular degeneration is a condition in which waste products called drusen accumulate in the retina, causing it to atrophy. Initially, vision loss is not significant, but over time, macular function declines and central vision decreases. Wet macular degeneration is a condition in which choroidal neovascularization occurs beneath the retina. This neovascularization carries a high risk of severe vision loss due to bleeding and exudation, and it is a serious disease that can lead to blindness within several months to years, so active treatment is necessary. It is known that vascular endothelial growth factor (VEGF) plays a major role in choroidal neovascularization in wet AMD. Anti-VEGF agents are currently being developed and used as treatments for wet AMD. However, these agents require intravitreal injection, a complex administration method, and require repeated administration every one to five months, which places a significant financial burden on patients. Furthermore, anti-VEGF agents are known to have insufficient therapeutic effects or relapse in 20-40% of patients, highlighting the need for the development of new treatment methods for AMD patients. Meanwhile, it has been reported that inhibiting IL (interleukin)-1β, one of the inflammatory cytokines, has the effect of reducing wet macular degeneration lesions in an animal model. It is known that prointerleukin-1β, the inactive form of IL-1β, acts as a mediator that induces inflammation by being activated by caspase-1 (or ICE, interleukin-1 converting enzyme). Caspase is a cysteine protease that exists in the form of an α2β2 tetramer, and caspase-1 to caspase-18 are known, which are involved in inflammation and apoptosis. In addition, Emricasan is known as a pan-caspase inhibitor that can inhibit various types of caspases. Emricasan is a drug that suppresses inflammation and apoptosis, and inhibits caspase-1, which plays a key role in IL-1β activation, thereby suppressing major inflammatory responses. Emricasan is being developed and studied as a treatment for nonalcoholic steatohepatitis and cirrhosis, but its effects in treating or preventing angiogenesis are completely unknown. There is a need to develop a treatment method with a new mechanism of action that can be considered as a treatment for patients with macular degeneration who do not respond to existing macular degeneration treatments or whose macular degeneration relapses despite repeated treatments. The inventor of the present invention, as a result of efforts to develop a treatment for macular degeneration, discovered that a caspase inhibitor (e.g., emricasan) can suppress inflammatory responses while inhibiting the occurrence of neovascularization, a major cause of blindness in wet macular degeneration, thereby completing the present invention. [1] In one aspect of the present invention, the present invention relates to a pharmaceutical composition for preventing or treating angiogenesis-related ocular disease, comprising a caspase inhibitor or a pharmaceutically acceptable salt thereof. [2] In the above [1], the caspase inhibitor may be a pan-caspase inhibitor or a caspase-1 inhibitor. [3] In the above [1] or [2], the caspase inhibitor may be Emricasan represented by the chemical formula I ((S)-3-((S)-2-(2-(2-tert-butylphenylamino)-2-oxoacetamido)propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid): [Chemical Formula I] [4] In any one of the above [1] to [3], the neovascularization-related eye disease may be at least one selected from the group consisting of dry macular degeneration, wet macular degeneration, late age-related macular degeneration (late AMD), neovascular age-related macular degeneration (Neovascular AMD), diabetic retinopathy, retinal edema, diabetic macular edema, central retinal vein occlusion, branch retinal vein occlusion, corneal neovascularization, and choroidal neovascularization. [5] In any one of the above [1] to [4], the pharmaceutical composition may be administered orally or parenterally. [6] In the above [5], the pharmaceutical composition may be administered orally. [7] In the above [5], the parenteral administration may be ocular local administration. [8] In the above [7], the ocular local administration may be administered intraocularly, periocularly, retroocularly, subretinally, centrally, outside the fovea, subconjunctivally, intravitreously, intracamerally, or suprachoroidally. [9] In one aspect of the present invention, the present invention relates to a method for preventing or treating angiogenesis-related eye disease, comprising a step of administering to a subject a therapeutically effective amount of a caspase inhibitor or a pharmaceutically acceptable salt thereof.

[0010] In the above [9], the caspase inhibitor may be a pro-caspase inhibitor or a caspase-1 inhibitor.

[0011] In the above [9] or

[0010] , the caspase inhibitor may be Emricasan represented by the chemical formula I ((S)-3-((S)-2-(2-(2-tert-butylphenylamino)-2-oxoacetamido)propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid).

[0012] In any one of the above [9] to

[0011] , the angiogenesis-related eye disease may be at least one selected from the group consisting of dry macular degeneration, wet macular degeneration, late age-related macular degeneration, neovascular age-related macular degeneration, diabetic retinopathy, retinal edema, diabetic macular edema, central retinal vein occlusion, branch retinal vein occlusion, corneal neovascularization, and choroidal neovascularization.

[0013] In any one of the above [9] to

[0012] , the administration may be oral or parenteral administration.

[0014] In the above

[0013] , the administration may be oral administration.

[0015] In the above

[0013] , the parenteral administration may be ocular local administration.

[0016] In the above

[0015] , the ocular local administration may be administered intraocularly, periocularly, retroocularly, subretinally, centrally, extrafoveally, subconjunctivally, intravitreously, intraanteriorly, or suprachoroidally.

[0017] In one aspect of the present invention, the present invention relates to the use of a therapeutically effective amount of a caspase inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any of the above [1] to [8] for the manufacture of a medicament for preventing or treating angiogenesis-related ocular disease.

[0018] In one aspect of the present invention, the present invention relates to a kit for preventing or treating angiogenesis-related ocular disease, comprising a caspase inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any of the above [1] to [8]. The caspase inhibitor and pharmaceutically acceptable salt thereof according to the present invention have excellent effects in inhibiting apoptosis and / or inflammatory activity, and exhibit effects in preventing or treating ocular diseases related to angiogenesis. In addition, the caspase inhibitor of the present invention and its pharmaceutically acceptable salt can be administered orally, and thus is more convenient for patients than existing therapeutic agents that must be administered into the vitreous cavity. Figure 1 is a drawing showing the results of comparing the area of choroidal neovascularization in the control group (7-day oral administration of vehicle BID) and the emricasan administration group (7-day oral administration of emricasan 20 mpk BID, 7-day oral administration of emricasan 40 mpk BID) in a macular degeneration mouse model, measured by staining using the IB4 immunohistochemistry (IHC) method. Figure 2 is a drawing showing the results of comparing the area of choroidal neovascularization in the control group (vehicle) and the emrica acid administration group (emrica acid 37.5 μg) in a macular degeneration mouse model, measured using fluorescein angiography. Hereinafter, the present invention will be described in more detail. Meanwhile, each description and embodiment disclosed in the present invention can also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention should not be considered limited by the specific descriptions described below. Furthermore, those skilled in the art will recognize or be able to ascertain, through routine experimentation, numerous equivalents to the specific embodiments of the invention described herein. Furthermore, such equivalents are intended to be encompassed by the present invention. definition As used herein, the term "consisting of" means that the proportion of a particular component(s) totals 100%. The components or features following the term "consisting of" may be essential or mandatory. As used herein, the term "comprising" means the presence of a feature, step, or component described below, and does not exclude the presence or addition of one or more features, steps, or components. The components or features described below "comprising" in this specification may be essential or mandatory, but some embodiments may further include other optional or non-essential components or features. In this specification, the term "comprising" may, in some implementations, be modified to refer to "consisting essentially of" or "consisting of." In this specification, the term "caspase" refers to a cysteine protease that exists in the form of a tetramer of the α2β2 type, and is involved in inflammation and apoptosis. Meanwhile, various types of caspases are known, from caspase-1 to caspase-18, and initiator caspases and effector caspases exist as caspases involved in apoptosis. Caspase-1, caspase-4, caspase-5, and caspase-11 are known to be involved in inflammation, and caspase-2, caspase-8, caspase-9, and caspase-10 are known as initiator caspases, and caspase-3, caspase-6, and caspase-7 are known as effector caspases. As used herein, the term "caspase inhibitor" refers to a compound that can control inflammation or apoptosis caused by the action of caspases by inhibiting their activity. Among caspase inhibitors, irreversible inhibitors are known to exhibit more effective inhibitory effects because they have a mechanism of inhibiting apoptosis by irreversibly inactivating the enzyme. As used herein, the term "salt" refers to a salt that retains the biological effects and properties of the parent compound and is not biologically harmful at the administered dose, and includes "pharmaceutically acceptable salts." As used herein, the term "pharmaceutically acceptable salt" means a salt which, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, or similar problems, and which has a reasonable benefit / risk ratio, and may refer to a non-toxic acid addition salt derived from inorganic and organic acids. For example, pharmaceutically acceptable salts are described in detail in SMBerge et al. J. Pharmaceutical Sciences, 1977, 66:1 et seq. In this specification, the term "prevention" means any action that inhibits the onset of clinical symptoms of angiogenesis-related ocular disease or inhibits choroidal neovascularization by administering a pharmaceutical composition according to the present invention. As used herein, the term “treatment” means any action by which the clinical symptoms of an angiogenesis-related ocular disease are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention. As used herein, the term "improvement" refers to an observable beneficial effect of a treatment. A beneficial effect may be evidenced by a delayed onset of clinical symptoms of a disease in a subject, a reduction in the severity of some or all clinical symptoms of the disease, a slower progression of the disease, an improvement in the subject's overall health or well-being, or other variables well known in the art to be specific to a particular disease. For example, treatment of an angiogenic eye disease may be evidenced by other variables well known in the art to be specific to angiogenic eye disease, such as improved visual acuity, a reduction in clinical symptoms due to angiogenic eye disease, a reduction in dry eye, or a reduction in the size of choroidal neovascular lesions. As used herein, the term "compound" is intended to include pharmaceutically acceptable salts of the compounds of the present invention, even if no pharmaceutically acceptable salt thereof is mentioned. The compounds and salts may form solvates or exist in substantially uncomplexed forms, for example, in anhydrous form. The solvate refers to a molecular complex in which solvent molecules, for example, a crystallization solvent, are incorporated into the crystal lattice. When the solvent incorporated into the solvate is water, the molecular complex is referred to as a hydrate. Pharmaceutically acceptable solvates include hydrates, methanolates and ethanolates, acetonitrileates, and the like. These compounds may also exist in polymorphic forms. In this specification, the term "advanced age-related macular degeneration" refers to a disease in which degeneration occurs in the macula, the central part of the eye, with age, resulting in decreased vision. As used herein, the term “neovascular age-related macular degeneration” refers to a pathological neovascular disease occurring in the eye, in which new blood vessels grow abnormally and cause damage to the macula. As used herein, the term "diabetic retinopathy" refers to complications of the retina caused by peripheral circulatory disorders due to diabetes. As diabetic retinopathy progresses, weakened blood vessels can cause bleeding, microaneurysms, and other causes, causing blood components to leak out of the blood vessels and accumulate in the retina, resulting in diabetic macular edema, which can lead to vision loss. Furthermore, as diabetic retinopathy worsens, neovascularization can occur. As used herein, the term "retinal edema" refers to swelling of the retina. Retinal edema can occur due to various causes, such as degeneration or abnormalities in the tiny blood vessels, such as capillaries, within the retina or macula, which can lead to hemorrhage. Retinal edema is particularly common in wet macular degeneration. In this specification, the term "diabetic macular edema" refers to a diabetic complication in which blood vessels in the eye become blocked and blood and plasma components leak out and accumulate in the macula at the center of the retina, causing the retina to swell and thicken and damage the optic nerve, resulting in decreased vision. In this specification, the term "retinal vein occlusion" refers to a disease in which vision is rapidly reduced due to blockage or rupture of a retinal vein, bleeding, and damage to the retina caused by impaired blood circulation, and is classified as "central retinal vein occlusion" or "branch retinal vein occlusion" depending on the location of the blocked retinal vein. In this specification, the term "corneal neovascularization" refers to a disease that occurs when new blood vessels around the cornea penetrate into the corneal tissue, resulting in insufficient oxygen supply. As used herein, the term "choroidal neovascularization" refers to a disease in which the choroid is damaged by the formation of abnormal blood vessels, resulting in visual impairment. As used herein, the term "therapeutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level can be determined based on factors including the subject's body weight, sex, age, health status, severity, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. As used herein, the term "kit" refers to a packaged product comprising components for administering the caspase inhibitor of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the treatment of angiogenesis-related ocular diseases. The kit preferably includes a container or box for holding the components of the kit. The box or container may be accompanied by a protocol or label approved by a pharmaceutical regulatory authority. The components of the present invention are contained within a box or container made of plastic, polyethylene, polypropylene, ethylene, or propylene. The container may be a tube or bottle with a cap. The kit may also include instructions for administering the caspase inhibitor of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Pharmaceutical composition for preventing or treating angiogenesis-related eye diseases The present invention provides a pharmaceutical composition for preventing or treating angiogenesis-related ocular disease, comprising a caspase inhibitor or a pharmaceutically acceptable salt thereof. The above caspase inhibitor refers to a substance (e.g., a compound, an antibody, etc.) that can control inflammation or apoptosis caused by the action of caspase by inhibiting the activity of caspase. In one embodiment of the present invention, the caspase inhibitor may be a pro-caspase inhibitor or an inhibitor that can selectively inhibit the activity of caspase-1. The pro-caspase inhibitor is a substance that can inhibit the activity of two or more caspases, and may be at least one selected from the group consisting of GS-9540 (nivocasan), Q-VD-OPh (Quinoline-Val-Asp-OPh) / Q-VD (OMe)-OPh, VX-166, and emricasan, but is not limited thereto. The emricasan may be referred to as IDN-6556, CS-1040, or PF-03491390. In addition, the pro-caspase inhibitor may be a substance that inhibits caspase-1. 본 발명의 일 구현예에서, 상기 선택적 캐스파제-1 저해제는 VE-16084((3R)-5-(2,6-dichlorobenzoyl)oxy-3-[[(2S)-2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]propanoyl]amino]-4-oxopentanoic acid), SDZ-224-015([(3S)-3-[[(2S)-2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]propanoyl]amino]-2-oxo-3-(2-oxoethoxy)propyl] 2,6-dichlorobenzoate), AS101([(5Z)-5-(2,6-dioxo-1,3-dipropylpurin-8-ylidene)-1-methyl-2H-pyrazol-3-yl] 2-[(3,4-dimethoxyphenyl)amino]acetate), M826(3-[2-[5-Tert-butyl-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methylamino]-2-oxopyrazin-1-yl]butanoylamino]-5-(hexyl-methylamino)-4-oxopentanoic acid), Ac-YVAD-CHO(Acetyl-Tyr-Val-Ala-Asp-Aldehyde), Ac-YVAD-CMK(Acetyl-Tyr-Val-Ala-Asp-Chloromethyl ketone), CIB-1476, Minocycline, NSC697923, Pralnacasan, Uracil 20, VRT-043198 (the active metabolite of VX-765), VX-740 (pralnacasan), VX-765 (belnacasan), YVAD(Tyr-Val-Ala-Asp), Z-VAD-CHO(Benzyloxycarbonyl-Val-Ala-Asp-Aldehyde), Z-VAD-FMK(Benzyloxycarbonyl-Val-Ala-Asp-Fluoromethyl Ketone),It may be at least one selected from the group consisting of Z-WEHD-FMK (Benzyloxycarbonyl-Trp-Glu-His-Asp-Fluoromethyl Ketone), Z-YVAD-CHO (Benzyloxycarbonyl-Tyr-Val-Ala-Asp-Aldehyde), Z-YVAD-FMK (Benzyloxycarbonyl-Tyr-Val-Ala-Asp-Fluoromethyl Ketone) and Ac-DEVD-CHO (Acetyl-Asp-Glu-Val-Asp-Aldehyde), but is not limited thereto. The caspase-1 inhibitor may include a substance capable of inhibiting caspase-1 among the above-mentioned pro-caspase inhibitors (for example, emricasan (CS-1040, IDN-6556, PF-03491390)). In another embodiment of the present invention, the pro-caspase inhibitor may be a substance capable of inhibiting a caspase effector. In addition, the pro-caspase inhibitor may be a substance capable of inhibiting at least one of caspase-1, caspase-3, and caspase-8, or the pro-caspase inhibitor may be a substance capable of inhibiting caspase-1. Preferably, the pro-caspase inhibitor is a substance that essentially inhibits the activity of caspase-1, including, but not limited to, emricasan. In one embodiment of the present invention, the caspase inhibitor may be Emricasan represented by the chemical formula I ((S)-3-((S)-2-(2-(2-tert-butylphenylamino)-2-oxoacetamido)propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid). [Chemical Formula I] In one embodiment of the present invention, a pharmaceutically acceptable salt of the caspase inhibitor may be prepared from an inorganic acid, an organic acid, or a base. The compound of the present invention may be used in the form of a pharmaceutically acceptable salt derived from an inorganic acid, an organic acid, or a base. In another embodiment of the present invention, the pharmaceutically acceptable salt of the caspase inhibitor is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid (tosylate salt), 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, alkali cations (e.g., Li + , Na + or K + ), alkaline earth cations (e.g., Mg 2+ , Ca 2+ or Ba 2+ ), an ammonium cation, an organic base containing an aliphatic and aromatic substituted ammonium, triethylamine, N,N-diethylamine, N,N-dicyclohexylamine, lysine, pyridine, N,N-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2,2,2]octane (DABCO), 1,5-diazabicyclo[4,3,0]-non-5-ene (DBN) and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU). The pharmaceutical composition of the present invention can be formulated and used in the form of tablets, pills, powders, granules, capsules, suspensions, liquids, emulsions, syrups, aerosols, or injection solutions, etc., according to conventional methods. In addition, the pharmaceutical composition of the present invention may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, etc. as a carrier, excipient, or diluent. In addition, when formulating the pharmaceutical composition of the present invention, it may include a diluent or excipient such as a filler, a bulking agent, a binder, a wetting agent, a disintegrating agent, or a surfactant. In one embodiment of the present invention, the angiogenesis-related eye disease may be at least one selected from the group consisting of dry macular degeneration, wet macular degeneration, late age-related macular degeneration, neovascular age-related macular degeneration, diabetic retinopathy, retinal edema, diabetic macular edema, central retinal vein occlusion, branch retinal vein occlusion, corneal neovascularization, and choroidal neovascularization. In one embodiment of the present invention, the pharmaceutical composition may be administered orally or parenterally. Parenteral administration may be administered by topical ocular administration, topical skin application, intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. In one embodiment of the present invention, the pharmaceutical composition can be administered orally. In one embodiment of the invention, the parenteral administration may be topical ocular administration. Furthermore, the topical ocular administration may be intraocular, periocular, retroocular, subretinal, central retinal, extrafoveal, subconjunctival, intravitreous, intracameral, or suprachoroidal. Solid preparations for oral administration may include tablets, pills, powders, granules, or capsules, and these solid preparations may include at least one excipient, such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to the excipients, they may also include lubricants such as magnesium stearate or talc. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, or syrups, and may include various excipients, such as wetting agents, sweeteners, flavoring agents, or preservatives, in addition to water or liquid paraffin. Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, or suppositories. Non-aqueous solutions and suspensions may include, for example, vegetable oils such as propylene glycol, polyethylene glycol, or olive oil, and injectable esters such as ethyl oleate. In one embodiment of the present invention, the pharmaceutical composition may be administered in a pharmaceutically effective amount. Furthermore, the pharmaceutical composition of the present invention can be administered as a sole therapeutic agent or in combination with other therapeutic agents, sequentially or simultaneously with conventional therapeutic agents, or in single or multiple doses. Taking all of the above factors into account, it is important to administer an amount that achieves maximum effect with the minimum amount possible without causing side effects, a determination readily made by those skilled in the art. In one embodiment of the present invention, the pharmaceutical composition may be an ophthalmic composition for topical administration to the eye. The ophthalmic composition for topical administration to the eye according to the present invention may further comprise a surfactant. Surfactants include, but are not limited to, lipids such as phospholipids, phosphatidylcholine, lecithin, cardiolipin, fatty acids, phosphatidylethanolamine, phosphatides, tyloxapol, polyethylene glycol, PEG 400, PEG 1500, PEG 2000, poloxamer 407, poloxamer 188, polysorbate 80, polysorbate 20, sorbitan lithium, sorbitan stearate, sorbitan palmitate, or mixtures thereof. The pharmaceutical composition of the present invention may further comprise a stabilizer or gelling agent. Such stabilizers or gelling agents include, but are not limited to, propylene glycol monopalmitostearate, glyceryl monostearate, glyceryl dibehenate, glyceryl distearate, hydrogenated fats, polyvinylpyrrolidone, polyethylene, glycerol, polyoxyethylene stearate, sorbitan fatty acid esters, cholesterol, macrogol-20-glycerol monostearate, poloxamer 124, isopropyl myristate, isopropyl palmitate, colloidal silica, hydrophobic colloidal silica, magnesium stearate, zinc stearate, aluminum stearate, lanolin alcohol, organoclay, petrolatum, or polyoxyl 6 stearate. The ophthalmic composition for topical administration to the eye according to the present invention may further comprise a polymer-based carrier. The polymer-based carrier includes, but is not limited to, for example, cellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), carboxymethyl cellulose (CMC), methylcellulose (MC), hydroxyethylcellulose (HEC), amylase, amylopectin, dextran, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyacrylics such as HEMA, acrylic polymers such as polymethacrylic acid derivatives, carbopol, derivatives thereof, or mixtures thereof. The pharmaceutical composition according to the present invention may further comprise an organic cosolvent. Organic cosolvents include, but are not limited to, ethylene glycol, propylene glycol, N-methyl pyrrolidone, 2-pyrrolidone, 3-pyrrolidinol, 1,4-butanediol, dimethylglycol monomethyl ether, diethylene glycol monomethyl ether, solketal, glycerol, polyethylene glycol, or polypropylene glycol. The pharmaceutical composition according to the present invention may additionally comprise a pH-active ingredient. Suitable pH-active ingredients, such as buffers or pH-adjusting agents, include, but are not limited to, disodium phosphate, monosodium phosphate, boric acid, sodium borate, sodium citrate, hydrochloric acid, or sodium hydroxide. The pharmaceutical composition according to the present invention may additionally comprise an osmotically active ingredient. The osmotically active ingredient includes, but is not limited to, sodium chloride, mannitol, or glycerol. The pharmaceutical composition according to the present invention may further comprise a preservative. Preservatives include, but are not limited to, benzalkonium chloride, alkyldimethylbenzylammonium chloride, cetrimide, cetylpyridinium chloride, benzododecinium bromide, benzethonium chloride, thiomersal, chlorobutanol, benzyl alcohol, phenoxethanol, phenylethyl alcohol, sorbic acid, methyl, propyl paraben, chlorhexidine digluconate, EDTA, or mixtures thereof. The pharmaceutical composition of the present invention can be formulated as an ophthalmic composition. The formulation can include any ophthalmic formulation used in ophthalmology for topical administration to the eye. For example, eye drops are prepared by dissolving the active ingredient in a sterile aqueous solution, such as saline or a buffer. The eye drops can be provided as a powder composition for dissolution prior to use, or can be provided by blending with another powder composition for dissolution prior to use. The eye drops can also be formulated as a sterile unit-dose preparation (daily or single-unit dosage form) that does not contain a preservative, such as benzalkonium chloride. As used herein, the term "unit dosage form" refers to physically discrete units of a therapeutic agent. As another example, ophthalmic ointments are prepared by mixing the active ingredient in an ointment base. All formulations can be prepared according to conventional methods. Additionally, the ophthalmic composition of the present invention may include a sustained-release form, such as, but not limited to, a gel formulation, a liposome formulation, a lipid microemulsion formulation, a microsphere formulation, a nanosphere formulation, or an implant formulation, to provide the active compound continuously to the back of the eye. The concentration and frequency of administration of the active ingredient of the eye drops used in the present invention may vary depending on, for example, the compound used, the type of subject (e.g., animal or human), age, body weight, symptoms, desired therapeutic effect, administration method, dosage, or treatment period. Accordingly, an appropriate concentration and frequency of administration may be selected as needed. The pharmaceutical composition of the present invention may comprise a single active ingredient or a combination of two or more active ingredients. In combinations of multiple active ingredients, the respective contents may be appropriately increased or decreased, taking into account their therapeutic efficacy and safety. The pharmaceutical composition for preventing or treating angiogenesis-related ocular disease of the present invention exhibits an excellent effect of preventing or treating angiogenesis-related ocular disease by inhibiting or destroying the formation or proliferation of new blood vessels in angiogenesis-related ocular disease. Methods for preventing or treating angiogenesis-related eye diseases The present invention provides a method for preventing or treating angiogenesis-related ocular disease, comprising administering to a subject a therapeutically effective amount of a caspase inhibitor or a pharmaceutically acceptable salt thereof. The above caspase inhibitor refers to a substance (e.g., a compound, an antibody, etc.) that can control inflammation or apoptosis caused by the action of caspase by inhibiting the activity of caspase. In one embodiment of the present invention, the caspase inhibitor may be a pro-caspase inhibitor or an inhibitor that can selectively inhibit the activity of caspase-1. The pro-caspase inhibitor is a substance that can inhibit the activity of two or more caspases, and may be at least one selected from the group consisting of GS-9540 (nivocasan), Q-VD-OPh (Quinoline-Val-Asp-OPh) / Q-VD (OMe)-OPh, VX-166, and emricasan, but is not limited thereto. The emricasan may be referred to as IDN-6556, CS-1040, or PF-03491390. In addition, the pro-caspase inhibitor may be a substance that inhibits caspase-1. 본 발명의 일 구현예에서, 상기 선택적 캐스파제-1 저해제는 VE-16084((3R)-5-(2,6-dichlorobenzoyl)oxy-3-[[(2S)-2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]propanoyl]amino]-4-oxopentanoic acid), SDZ-224-015([(3S)-3-[[(2S)-2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]propanoyl]amino]-2-oxo-3-(2-oxoethoxy)propyl] 2,6-dichlorobenzoate), AS101([(5Z)-5-(2,6-dioxo-1,3-dipropylpurin-8-ylidene)-1-methyl-2H-pyrazol-3-yl] 2-[(3,4-dimethoxyphenyl)amino]acetate), M826(3-[2-[5-Tert-butyl-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methylamino]-2-oxopyrazin-1-yl]butanoylamino]-5-(hexyl-methylamino)-4-oxopentanoic acid), Ac-YVAD-CHO(Acetyl-Tyr-Val-Ala-Asp-Aldehyde), Ac-YVAD-CMK(Acetyl-Tyr-Val-Ala-Asp-Chloromethyl ketone), CIB-1476, Minocycline, NSC697923, Pralnacasan, Uracil 20, VRT-043198 (the active metabolite of VX-765), VX-740 (pralnacasan), VX-765 (belnacasan), YVAD(Tyr-Val-Ala-Asp), Z-VAD-CHO(Benzyloxycarbonyl-Val-Ala-Asp-Aldehyde), Z-VAD-FMK(Benzyloxycarbonyl-Val-Ala-Asp-Fluoromethyl Ketone),It may be at least one selected from the group consisting of Z-WEHD-FMK (Benzyloxycarbonyl-Trp-Glu-His-Asp-Fluoromethyl Ketone), Z-YVAD-CHO (Benzyloxycarbonyl-Tyr-Val-Ala-Asp-Aldehyde), Z-YVAD-FMK (Benzyloxycarbonyl-Tyr-Val-Ala-Asp-Fluoromethyl Ketone) and Ac-DEVD-CHO (Acetyl-Asp-Glu-Val-Asp-Aldehyde), but is not limited thereto. The caspase-1 inhibitor may include a substance capable of inhibiting caspase-1 among the above-mentioned procaspase inhibitors (for example, emricasan (CS-1040, IDN-6556, PF-03491390)). In another embodiment of the present invention, the pro-caspase inhibitor may be a substance capable of inhibiting a caspase effector. In addition, the pro-caspase inhibitor may be a substance capable of inhibiting at least one of caspase-1, caspase-3, and caspase-8, or the pro-caspase inhibitor may be a substance capable of inhibiting caspase-1. Preferably, the pro-caspase inhibitor is a substance that essentially inhibits the activity of caspase-1, including, but not limited to, emricasan. In one embodiment of the present invention, the caspase inhibitor may be Emricasan represented by the chemical formula I ((S)-3-((S)-2-(2-(2-tert-butylphenylamino)-2-oxoacetamido)propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid). [Chemical Formula I] In one embodiment of the present invention, the angiogenesis-related eye disease may be at least one selected from the group consisting of dry macular degeneration, wet macular degeneration, late age-related macular degeneration, neovascular age-related macular degeneration, diabetic retinopathy, retinal edema, diabetic macular edema, central retinal vein occlusion, branch retinal vein occlusion, corneal neovascularization, and choroidal neovascularization. In one embodiment of the present invention, the administration may be oral or parenteral. Parenteral administration may be administered by topical ocular administration, external application to the skin, intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. In one embodiment of the present invention, the administration may be oral administration. In one embodiment of the present invention, the parenteral administration may be topical ocular administration. Furthermore, the topical ocular administration may be administered intraocularly, periocularly, retroocularly, subretinally, centrally, extrafoveally, subconjunctivally, intravitreously, intraanteriorly, or suprachoroidally. In one embodiment of the present invention, the dosage of a caspase inhibitor (e.g., Emricasan) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, administered to a mammal, particularly a human, according to the present invention should be sufficient to produce the desired response. Such response includes prevention or reversal of adverse effects of a disease for which treatment is desired or for which a desired benefit is obtained. Those skilled in the art will recognize that the dosage will depend on various factors, such as the age, condition, weight of the subject, the specific type or extent of the disease. The size of the dosage may be determined by the route, timing, and frequency of administration, the combination of specific compounds administered, and the presence, nature, or extent of any adverse effects that may accompany the desired physiological effect. Those skilled in the art will also recognize that various conditions or disease states may require prolonged treatment, including multiple administrations. The appropriate dosage and administration method of the present invention can be determined using conventional techniques known to those skilled in the art. Generally, treatment may be initiated at a dose lower than the optimal dose of the compound. The dosage may then be increased in small increments until the optimal effect is achieved under the appropriate circumstances. In one embodiment of the present invention, the preventive or therapeutic method may typically comprise administering from about 0.1 to about 300 mg of one or more of the compounds per kilogram of body weight of the animal or mammalian subject. The therapeutically effective amount of the administered compound may vary depending on the desired effect and the factors set forth above. The dosage of the present invention can be calculated based on body surface area. Therapeutically effective dosages can be administered over an extended period of time or as multiple daily doses. Accordingly, the dosage can be calculated using the subject's body surface area, based on the appropriate range and preferred dosing schedule cited above. The term "subject" as used herein may be a mammal. Mammals according to the present invention include, but are not limited to, humans, canines, felines, bovines, caprines, equines, ovines, porcines, rodents, lagomorphs, primates, or in utero mammals. The subject may be of either sex and at any stage of development. The subject may alternatively be referred to as a "subject." In one embodiment of the present invention, the subject may be a human. It may also be a human suspected of having an angiogenesis-related eye disease. For the prevention or treatment of angiogenesis-related eye diseases In one aspect of the present invention, the present invention provides a use of a therapeutically effective amount of a caspase inhibitor or a pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof for preventing or treating angiogenesis-related ocular disease. In another aspect of the present invention, the present invention provides a use of a therapeutically effective amount of a caspase inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the manufacture of a medicament for preventing or treating angiogenesis-related ocular disease. Among the terms or elements mentioned in the above use, the composition of the pharmaceutical composition and the preventive or therapeutic method are understood to be the same as those mentioned in the description of the pharmaceutical composition and the preventive or therapeutic method above. Kit The present invention provides a kit for preventing or treating angiogenesis-related ocular disease, comprising a caspase inhibitor or a pharmaceutically acceptable salt thereof or the pharmaceutical composition. Among the terms or elements mentioned in the above kit, the composition of the caspase inhibitor or a pharmaceutically acceptable salt thereof or pharmaceutical composition is understood to be the same as mentioned in the description of the above pharmaceutical composition. In one embodiment of the present invention, the kit may further include a user manual describing optimal reaction conditions. The manual may include a pamphlet, leaflet-style guidebook, a label attached to the kit, or a description on the surface of the package containing the kit. Furthermore, the manual may include information disclosed or provided through electronic media, such as the Internet. The present invention is described in more detail by the following examples. The following examples are merely illustrative of the present invention and are not intended to limit the scope of the present invention. Example 1. Oral administration effect of emricasan (in vivo) Example 1-1. Mouse model of laser-induced choroidal neovascularization When Bruch's membrane is damaged by irradiating the retina of a mouse with a laser of a certain intensity, choroidal neovascularization occurs, which can simulate wet macular degeneration, and is widely used in research on the disease (Lambert, V. et al. (2013). Laser-induced choroidal neovascularization model to study age-related macular degeneration in mice. Nature Protocols, 8(11), 2197-2211. https: / doi.org / 10.1038 / nprot.2013.135). Therefore, in order to confirm the angiogenesis therapeutic effect of the caspase inhibitor of the present invention, a mouse model in which neovascularization was formed in the choroid by irradiating the mouse eye with a laser was established. Specifically, 9-week-old male C57BL / 6J mice were purchased from JABIO Co., Ltd. and stabilized at 25°C, 50% humidity, and lighting (12 / 12 hours). Stabilized mice were divided into control group (n=10 mice), emricasan 20 mg / kg group (n=10 mice), and emricasan 40 mg / kg group (n=10 mice). A laser-induced choroidal neovascularization mouse model was established by irradiating the left eye of each mouse four times with a slit lamp laser (MICRON IV Image Guided Laser system) at a wavelength of 532 nm, intensity of 240 mW, and duration of 100 ms, thereby creating four 50 μm diameter laser spots. Example 1-2. Oral administration experiment of emricasan In the mouse model constructed in Example 1-1, DMSO was administered orally as a vehicle twice a day for 7 days (i.e., control group). In addition, 20 mg / kg of emricasan and 40 mg / kg of emricasan were administered orally twice a day for 7 days. Seven days after the last administration, the eyes were enucleated and fixed in 500 μl of 4% paraformaldehyde at room temperature for 40 minutes. The fixed eyes were washed three times with PBS and then stored in the refrigerator. The fixed eye samples were then processed by the flat mount method to obtain retinal tissues. An isolectin antibody (Isolectin IB4-Alexa Fluor 488, Invitrogen), a vascular marker, was diluted in blocking buffer and added to the retinal tissues to react. The tissues were then stained by immunohistochemistry (IHC), and the stained tissues were observed under a fluorescence microscope to measure the area of neovascularization. The area of neovascular lesions was measured using ImageJ software, and lesions that were not circular in shape or had an area greater than the mean plus one standard deviation were excluded, and then statistical analysis was performed. Outliers with a z-score greater than 1 within a group were excluded from the results (i.e., data that were more than one standard deviation away from the mean were excluded). [Table 1] As a result, as can be confirmed in Figure 1 and Table 1, the group administered 20 mg / kg of emricasan showed a decrease in the area of neovascularization by approximately 20% compared to the vehicle group (p=0.02). Additionally, the group administered 40 mg / kg of emricasan showed a decrease in neovascularization area by approximately 18% compared to the vehicle group (p≤0.01). Therefore, emricasan, a caspase inhibitor, is expected to be effective as a preventive or therapeutic agent for angiogenesis-related eye diseases because it has a superior effect in suppressing neovascularization compared to the vehicle. Example 2: Effect of intravitreal administration of emricasan (in vivo) Twelve-week-old male C57BL / 6N mice were purchased from Koatech and stabilized under conditions of 25°C, 50% humidity, and 12 / 12 h of illumination. The stabilized mice were divided into a control group (n=6) and an emricasan 37.5 μg group (n=6). A slit lamp laser (Iridex Oculight Tx) was used to irradiate the left eye of each mouse three times with a wavelength of 532 nm, intensity of 200 mW, and duration of 100 ms, thereby creating three 50 μm diameter laser spots, thereby establishing a mouse model of laser-induced choroidal neovascularization. Immediately after laser irradiation, the control group received a single intravitreal injection of 1.5 μl DMSO as a vehicle, and the emricasan-treated group received a single intravitreal injection of 37.5 μg / 1.5 μl DMSO. Ten days after intravitreal injection, the eyes of the living mice were subjected to fluorescein angiography (FA) to obtain retinal images and measure the area of neovascularization. The area of neovascularization lesions was measured using ImageJ software, and lesions that were not circular in shape or had an area greater than the mean plus one standard deviation were excluded for statistical analysis. Outliers with a z-score of 1 or more within a group were excluded from the results (i.e., data more than one standard deviation away from the mean were excluded). [Table 2] As a result, as can be confirmed in Fig. 2 and Table 2, the group administered 37.5 μg of emricasan at a dose of 1.5 μl showed a decrease in the area of neovascularization by approximately 60% compared to the vehicle group (p=0.01). Emricasan, a caspase inhibitor, is expected to be effective as a preventive or therapeutic agent for angiogenesis-related eye diseases because it has a superior effect in suppressing neovascularization compared to vehicle even with a single administration.

Claims

1. A pharmaceutical composition for preventing or treating angiogenesis-related ocular disease, comprising a caspase inhibitor or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition for preventing or treating angiogenesis-related eye disease, wherein the caspase inhibitor in paragraph 1 is a pan-caspase inhibitor or a caspase-1 inhibitor.

3. In the first or second paragraph, the caspase inhibitor is Emricasan represented by the chemical formula I ((S)-3-((S)-2-(2-(2-tert-butylphenylamino)-2-oxoacetamido)propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid), a pharmaceutical composition for preventing or treating angiogenesis-related eye disease: [Chemical Formula I] 4. A pharmaceutical composition for preventing or treating angiogenic eye disease according to any one of claims 1 to 3, wherein the neovascular eye disease is at least one selected from the group consisting of dry macular degeneration, wet macular degeneration, late age-related macular degeneration (late AMD), neovascular age-related macular degeneration (Neovascular AMD), diabetic retinopathy, retinal edema, diabetic macular edema, central retinal vein occlusion, branch retinal vein occlusion, corneal neovascularization, and choroidal neovascularization.

5. A pharmaceutical composition for preventing or treating angiogenesis-related eye disease, wherein the pharmaceutical composition is administered orally or parenterally according to any one of claims 1 to 4.

6. A pharmaceutical composition for preventing or treating angiogenesis-related eye disease, wherein the pharmaceutical composition is administered orally in the fifth paragraph.

7. A pharmaceutical composition for preventing or treating angiogenesis-related eye disease, wherein the parenteral administration in paragraph 5 is local administration to the eye.

8. A pharmaceutical composition for preventing or treating angiogenesis-related eye disease, wherein the ocular local administration in paragraph 7 is administered intraocularly, periocularly, retroocularly, subretinally, centrally, outside the fovea, subconjunctivally, intravitreously, intracamerally, or suprachoroidally.

9. A method for preventing or treating angiogenesis-related ocular disease, comprising administering to a subject a therapeutically effective amount of a caspase inhibitor or a pharmaceutically acceptable salt thereof.

10. A method for preventing or treating angiogenesis-related eye disease, wherein the caspase inhibitor in paragraph 9 is a pro-caspase inhibitor or a caspase-1 inhibitor.

11. A method for preventing or treating angiogenesis-related eye disease according to claim 9 or 10, wherein the caspase inhibitor is Emricasan represented by the chemical formula I ((S)-3-((S)-2-(2-(2-tert-butylphenylamino)-2-oxoacetamido)propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid): [Chemical Formula I] 12. A method for preventing or treating an angiogenesis-related eye disease according to any one of claims 9 to 11, wherein the angiogenesis-related eye disease is at least one selected from the group consisting of dry macular degeneration, wet macular degeneration, late age-related macular degeneration, neovascular age-related macular degeneration, diabetic retinopathy, retinal edema, diabetic macular edema, central retinal vein occlusion, branch retinal vein occlusion, corneal neovascularization, and choroidal neovascularization.

13. A method for preventing or treating an angiogenesis-related eye disease according to any one of claims 9 to 12, wherein the administration is oral or parenteral.

14. A method for preventing or treating angiogenesis-related eye disease, wherein the administration is oral administration in the 13th paragraph.

15. A method for preventing or treating an eye disease related to angiogenesis, wherein the parenteral administration is local administration to the eye in the 13th paragraph.

16. A method for preventing or treating angiogenesis-related eye disease in claim 15, wherein the ocular local administration is administered intraocularly, periocularly, retroocularly, subretinally, centrally, extrafoveally, subconjunctivally, intravitreously, intraanteriorly, or suprachoroidally.

17. Use of a therapeutically effective amount of a caspase inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claims 1 to 8 for the manufacture of a medicament for preventing or treating angiogenesis-related ocular diseases.

18. A kit for preventing or treating angiogenesis-related ocular disease, comprising a caspase inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claims 1 to 8.

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